Marc Lipsitch

All Publications

• Defining and Estimating Outcomes Directly Averted by a Vaccination Program when Rollout Occurs Over Time. Epidemiology (Cambridge, Mass.) Jia, K. M., Boyer, C. B., Bilinski, A., Lipsitch, M. 2026

  Abstract

  During the COVID-19 pandemic, estimating the total deaths averted by vaccination was of great public health interest. Instead of estimating total deaths averted by vaccination among both vaccinated and unvaccinated individuals, some studies empirically estimated only "directly averted" deaths among vaccinated individuals, typically suggesting that vaccines prevented more deaths among unvaccinated and vaccinated individuals than directly among vaccinated individuals only, due to the indirect effect. Here, we define the causal estimand to quantify outcomes "directly averted" by vaccination-i.e., the impact of vaccination for vaccinated individuals, holding vaccination coverage fixed-for vaccination at multiple time points, which is a lower bound on the total outcomes averted when the indirect effect is non-negative. We develop an unbiased estimator for the causal estimand in a one-stage randomized controlled trial (RCT) and explore the bias of a popular "hazard difference" estimator frequently used in empirical studies. We show that even in an RCT, the hazard difference estimator is biased if vaccination has a non-null effect, as it fails to incorporate the greater depletion of susceptibles among the unvaccinated individuals. In simulations, the overestimation is small for averted deaths when infection-fatality rate is low, as for many important pathogens. However, the overestimation can be large for averted infections given a high basic reproduction number and a high vaccine efficacy against infection. Additionally, we define and compare estimand and estimators for avertible outcomes (i.e., outcomes that could have been averted by vaccination, but were not due to failure to vaccinate). Future studies can explore the identifiability of the causal estimand in observational settings.

  View details for DOI 10.1097/EDE.0000000000001953

  View details for PubMedID 41570185

• Predicting optimal impact interventions in the post-HPV vaccination world. International journal of cancer Lehtinen, M., Lipsitch, M., Pimenoff, V. N., Sundström, K., Berkhof, J., Baussano, I., Vänskä, S., Dillner, J. 2026

  Abstract

  Prophylactic vaccination is a powerful tool that changes exposure to infections and associated morbidity of preventable diseases. We discuss the impact of pneumococci and human papillomavirus (HPV) vaccination on the population biology of the two micro-organisms and related public health effects. Data on HPV type-replacement in communities where vaccine-covered HPVs are almost eliminated, and interactions of the remaining HPV types on the risk of cervical cancer are reviewed. Results of comprehensive models for European country-specific conduction of cervical screening among HPV-vaccinated and unvaccinated women, assuming different HPV-vaccination coverage and strategies, are discussed in our policy-oriented review. An acceptable balance of benefits and harms of cervical cancer screening in HPV vaccinated populations requires an understanding of cancer risks in differently vaccinated birth cohorts. Finally, the challenges are complex but can be met if strategies are applied that (i) as fast as possible achieve herd effect and (ii) use a risk-based design of HPV screening.

  View details for DOI 10.1002/ijc.70297

  View details for PubMedID 41552838

• How Should We Study the Indirect Effects of Antimicrobial Treatment Strategies?: A Causal Perspective. Epidemiology (Cambridge, Mass.) Gago, J., Boyer, C., Lipsitch, M. 2026; 37 (1): 88-97

  Abstract

  Effective antimicrobial stewardship requires unbiased assessment of the benefits and harms of different treatment strategies, considering both immediate patient outcomes and patterns of antimicrobial resistance. In principle, these benefits and harms can be expressed as causal contrasts between treatment strategies and, therefore, should be ideally suited for study under the potential outcomes framework. However, causal inference in this setting is complicated by interference between individuals (or units) due to the indirect effects of antibiotic treatment, including the spread of resistant bacteria to others. These indirect effects complicate the assessment of trade-offs as benefits are mostly due to the direct effects among those treated, while harms are more diffuse and, therefore, harder to measure. While causal frameworks and study designs that accommodate interference have previously been proposed, they have been applied predominantly to the study of vaccines, which differ from antimicrobial interventions in fundamental ways. In this article, we review these existing approaches and propose alternative adaptations tailored to the study of antimicrobial treatment strategies.

  View details for DOI 10.1097/EDE.0000000000001921

  View details for PubMedID 41176807

• A binary prototype for time-series surveillance and intervention EPIDEMICS Olejarz, J., Hoffmann, T., Zapf, A., Mugahid, D., Molinaro, R., Brown, C., Boltyenkov, A., Dudykevych, T., Gupta, A., Lipsitch, M., Atun, R., Onnela, J., Fortune, S., Sampath, R., Grad, Y. H. 2025; 53: 100866

  Abstract

  Despite much research on early detection of anomalies from surveillance data, a systematic framework for appropriately acting on these signals is lacking. We addressed this gap by formulating a hidden Markov-style model for time-series surveillance, where the system state, the observed data, and the decision rule are all binary. We incur a delayed cost, c, whenever the system is abnormal and no action is taken, or an immediate cost, k, with action, where k

  View details for DOI 10.1016/j.epidem.2025.100866

  View details for Web of Science ID 001622330800001

  View details for PubMedID 41242306

• Defining and Estimating Outcomes Directly Averted by a Vaccination Program when Rollout Occurs Over Time. ArXiv Jia, K. M., Boyer, C. B., Bilinski, A., Lipsitch, M. 2025

  Abstract

  During the COVID-19 pandemic, estimating the total deaths averted by vaccination has been of great public health interest. Instead of estimating total deaths averted by vaccination among both vaccinated and unvaccinated individuals, some studies empirically estimated only "directly averted" deaths among vaccinated individuals, typically suggesting that vaccines prevented more deaths overall than directly due to the indirect effect. Here, we define the causal estimand to quantify outcomes "directly averted" by vaccination-i.e., the impact of vaccination for vaccinated individuals, holding vaccination coverage fixed-for vaccination at multiple time points, and show that this estimand is a lower bound on the total outcomes averted when the indirect effect is non-negative. We develop an unbiased estimator for the causal estimand in a one-stage randomized controlled trial (RCT) and explore the bias of a popular "hazard difference" estimator frequently used in empirical studies. We show that even in an RCT, the hazard difference estimator is biased if vaccination has a non-null effect, as it fails to incorporate the greater depletion of susceptibles among the unvaccinated individuals. In simulations, the overestimation is small for averted deaths when infection-fatality rate is low, as for many important pathogens. However, the overestimation can be large for averted infections given a high basic reproduction number. Additionally, we define and compare estimand and estimators for avertible outcomes (i.e., outcomes that could have been averted by vaccination, but were not due to failure to vaccinate). Future studies can explore the identifiability of the causal estimand in observational settings.

  View details for DOI 10.1001/jamanetworkopen.2021.42725

  View details for PubMedID 41281223

  View details for PubMedCentralID PMC12632696

• What is the relationship between viral prospecting in animals and medical countermeasure development? mBio Aatresh, A. V., Lipsitch, M. 2025; 16 (10): e0203325

  Abstract

  In recent decades, surveillance in non-human animals has aimed to detect novel viruses before they "spill over" to humans. However, the extent to which these viral prospecting efforts have enhanced outbreak preparedness remains poorly characterized, especially in terms of whether they are necessary, sufficient, or feasible to spur vaccine development. We find that several viruses which pose known threats to people lack approved vaccines, and known viruses discovered in human patients before 2000 have caused most major 21st-century outbreaks. With Filoviridae as a case study, we show there is little evidence that viral prospecting has accelerated vaccine or drug development or that systematically discovering novel zoonotic viruses in animal hosts before they cause human outbreaks has been feasible. These results suggest that surveillance for novel viral zoonoses does not accelerate vaccine development and underscore questions about its importance for outbreak preparedness. We consider limitations to these conclusions and alternative approaches to preparedness and response.IMPORTANCESampling in animal populations to detect novel viruses before they infect humans has been a major activity justified by several considerations, notably by the idea that finding such viruses will stimulate the development of medical countermeasures such as vaccines. This article examines the evidence that such research leads to earlier vaccine development and finds the evidence lacking. This is important because, in an era of scarce resources and biosafety considerations for researchers, efforts should be directed to those activities most likely to yield the desired outcomes.

  View details for DOI 10.1128/mbio.02033-25

  View details for PubMedID 40852983

  View details for PubMedCentralID PMC12506108

• Equity considerations in COVID-19 vaccine allocation modelling: a methodological study INTERFACE FOCUS Rumpler, E., Lipsitch, M. 2025; 15 (4): 20240037

  Abstract

  We conducted a methodological study of COVID-19 vaccine allocation modelling papers, specifically looking for publications that considered equity. We found that most models did not take equity into account, with the vast majority of publications presenting aggregated results and no results by any subgroup (e.g. age, race, geography, etc.). We then provide examples of how modelling can be useful to answer equity questions, and highlight some of the findings from the publications that did. Finally, we describe eight considerations that seem important to consider when including equity in future vaccine allocation models.

  View details for DOI 10.1098/rsfs.2024.0037

  View details for Web of Science ID 001581178800005

  View details for PubMedID 41017906

  View details for PubMedCentralID PMC12464572

• Clade I mpox vaccination: strategies for deployment and evaluation. EBioMedicine Pley, C., Panovska-Griffiths, J., Hinch, R., Wymant, C., Abeler-Dörner, L., Ssemwanga, D., Galiwango, R. M., Grabowski, M. K., Di Lauro, F., Ferretti, L., Hay, J., Lipsitch, M., Dunning, J., Kagaayi, J., Kaleebu, P., Fraser, C. 2025; 119: 105890

  View details for DOI 10.1016/j.ebiom.2025.105890

  View details for PubMedID 40840168

  View details for PubMedCentralID PMC12396246

• The Social Disvalue Misconception in Clinical Research. The American journal of bioethics : AJOB Eyal, N., Lipsitch, M., Smith, P. G. 2025; 25 (8): 88-89

  View details for DOI 10.1080/15265161.2025.2526758

  View details for PubMedID 40736979

• Geographic spillover of antimicrobial resistance from mass distribution of azithromycin. medRxiv : the preprint server for health sciences Srivathsan, A., Arzika, A. M., Maliki, R., Abdou, A., Lipsitch, M., Blumberg, S., O'Brien, K. S., Porco, T. C., Hinterwirth, A., Doan, T., Keenan, J. D., Lietman, T. M., Arnold, B. F. 2025

  Abstract

  Large-scale, placebo-controlled, cluster-randomized trials in high-mortality settings in several African countries demonstrated a 14-18% reduction in childhood mortality following twice-annual mass drug administration (MDA) of azithromycin among children aged 1-59 months [1-3]. Azithromycin MDA also selects for antimicrobial resistance (AMR), particularly macrolide resistance in treated populations [4-6]. It is unknown whether the genetic selection of AMR from azithromycin MDA could spill over to neighboring untreated populations. If present, such geographic spillover effects could lead the trials to underestimate the risks of AMR selection from azithromycin MDA. Here, we assessed between-village geographic spillover effects of genotypic resistance to macrolides and other antibiotic classes in rectal swabs collected from 1200 children in 30 monitoring villages in Niger after two years of MDA in 594 surrounding villages. We found no evidence of geographic spillover of macrolide resistance in untreated villages, as the genetic load of AMR remained at baseline levels in placebo-treated villages regardless of surrounding azithromycin treatment intensity. Sensitivity analyses confirmed the robustness of findings to the metric used to quantify the effect of proximal azithromycin MDAs on macrolide AMR, and no geographic spillover effects were detected for AMR to other antibiotic classes. Our results suggest that azithromycin MDA-induced selection of macrolide AMR is localized to treated villages without extending to children in neighboring, untreated villages, mitigating some concerns about geographic spillover of AMR to untreated populations. This analysis illustrates the value of randomized trial designs in assessing indirect effects of large-scale public health interventions.

  View details for DOI 10.1101/2025.07.22.25331994

  View details for PubMedID 40778162

  View details for PubMedCentralID PMC12330416

• Kinetics of SARS-CoV-2 Shedding in Nursing Home Residents and Staff. Journal of the American Geriatrics Society Katz, M. J., Reeves, M., Harris, T. G., Duque, J., Fridkin, S. K., Rebolledo, P. A., Furuno, J. P., Short, E. K., Canaday, D. H., Abul, Y., Gravenstein, S., Cosgrove, S. E., Mody, L., Meddings, J., Nace, D. A., Handler, S., Crnich, C. J., Meece, J., Webby, R. J., Fabrizio, T. P., Harcourt, J. L., Healy, J. M., Lipsitch, M., Lutgring, J. D., Paul, P., Zipfel, C. M., Hernandez-Romieu, A. C., Reddy, S. C., Slayton, R. B. 2025; 73 (7): 2127-2136

  Abstract

  Nursing homes (NHs) were disproportionately affected by the COVID-19 pandemic. However, little is known regarding the kinetics of SARS-CoV-2 shedding in NH residents and staff, which could inform treatment and infection prevention.We enrolled NH residents and staff in eight US states from April to November 2023 and analyzed the kinetics of SARS-CoV-2 using serial antigen and molecular (RT-PCR) tests, whole genome sequencing, and viral culture (VC). Symptoms, vaccination, and treatment were collected via interviews and chart review. Viral load trajectories were modeled with gamma distribution functional forms. Antigen and VC test positivity over time were assessed using a Chi-squared test.Of the 587 enrolled participants, 86 tested positive and 73 underwent testing for ≥ 10 days; most residents (78%) and staff (87%) had ≥ 3 COVID-19 vaccine doses. The modeled SARS-CoV-2 proliferation period (period prior to reaching peak viral load) had ended for 48% (14/29) of residents and 56% (9/16) of staff when they took the initial RT-PCR test. Both antigen and VC showed higher positivity rates early in the course of disease (Days 0-5 vs. Days ≥ 6) (antigen: p < 0·001, VC: p < 0·001). VC positivity was 15% after Day 5 (14/96); two participants were VC positive after Day 10.Peak viral load occurs early in the disease, suggesting asymptomatic and presymptomatic transmission may be a significant driver of transmission. Only two participants had a positive VC after Day 10, supporting current isolation and return to work recommendations.

  View details for DOI 10.1111/jgs.19499

  View details for PubMedID 40317518

  View details for PubMedCentralID PMC12303745

• Seasonal forcing and waning immunity drive the sub-annual periodicity of the COVID-19 epidemic. medRxiv : the preprint server for health sciences Rubin, I. N., Bushman, M., Lipsitch, M., Hanage, W. P. 2025

  Abstract

  Seasonal trends in infectious diseases are shaped by climatic and social factors, with many respiratory viruses peaking in winter. However, the seasonality of COVID-19 remains in dispute, with significant waves of cases across the United States occurring in both winter and summer. Using wavelet analysis of COVID-19 cases, we find that the periodicity of epidemic COVID-19 varies markedly across the U.S. and correlates with winter temperatures, indicating seasonal forcing. However, seasonal forcing alone cannot explain the pattern of multiple waves per year that has been so disruptive and unique to COVID-19. Using a modified SIRS model that allows specification of the tempo of waning immunity, we show that specific forms of non-durable immunity can sufficiently explain the sub-annual waves characteristic of the COVID-19 epidemic.

  View details for DOI 10.1101/2025.03.05.25323464

  View details for PubMedID 40093215

  View details for PubMedCentralID PMC11908326

• Linkage-based ortholog refinement in bacterial pangenomes with CLARC. Nucleic acids research González Ojeda, I., Palace, S. G., Martinez, P. P., Azarian, T., Grant, L. R., Hammitt, L. L., Hanage, W. P., Lipsitch, M. 2025; 53 (12)

  Abstract

  Bacterial genomes exhibit significant variation in gene content and sequence identity. Pangenome analyses explore this diversity by classifying genes into core and accessory clusters of orthologous groups (COGs). However, strict sequence identity cutoffs can misclassify divergent alleles as different genes, inflating accessory gene counts. CLARC (Connected Linkage and Alignment Redefinition of COGs) (https://github.com/IndraGonz/CLARC) improves pangenome analyses by condensing accessory COGs using functional annotation and linkage information. Through this approach, orthologous groups are consolidated into more practical units of selection. Analyzing 8000+ Streptococcus pneumoniae genomes, CLARC reduced accessory gene estimates by >30% and improved evolutionary predictions based on accessory gene frequencies. CLARC is effective across different bacterial species, making it a broadly applicable tool for comparative genomics. By refining COG definitions, CLARC offers critical insights into bacterial evolution, aiding genetic studies across diverse populations.

  View details for DOI 10.1093/nar/gkaf488

  View details for PubMedID 40539515

  View details for PubMedCentralID PMC12204703

• Principal Investigator Responsibility for Flagging Research with Dual-Use or Pandemic Risk. Applied biosafety : journal of the American Biological Safety Association Lipsitch, M. 2025; 30 (2): 139-142

  Abstract

  The new United States Government Policy for Oversight of Dual-Use Research of Concern and Pathogens with Enhanced Pandemic Potential places primary responsibility on the proposing principal investigator to flag potential need for special review. This approach may carry significant risks, given that investigators have incentives to downplay the types of risks the policy aims to address, compounded by substantial opposition to the policy from many virologists. However, this commentary argues that such an approach is much more consistent with proven models of research oversight for protecting human subjects and animals and may be essential in the long run. It identifies the need for several independent but potentially mutually reinforcing preconditions for success-which will require creativity and investment not fully specified in the regulations: researcher training on dual-use and population-level biosafety risks, effective institutional-level support for and scrutiny of investigator evaluation, cultural change, checks and balances, and speedy evaluation of low-risk research.

  View details for DOI 10.1089/apb.2024.0059

  View details for PubMedID 40548084

  View details for PubMedCentralID PMC12179358

• Predicting antibody kinetics and duration of protection against SARS-CoV-2 following vaccination from sparse serological data. PLoS computational biology Deichmann, J., Barda, N., Canetti, M., Peretz, Y., Weiss-Ottolenghi, Y., Lustig, Y., Regev-Yochay, G., Lipsitch, M. 2025; 21 (6): e1013192

  Abstract

  Vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generates an antibody response that shows large inter-individual variability. This variability complicates the use of antibody levels as a correlate of protection and the evaluation of population- and individual-level infection risk without access to broad serological testing. Here, we applied a mathematical model of antibody kinetics to capture individual anti-SARS-CoV-2 IgG antibody trajectories and to identify factors driving the humoral immune response. Subsequently, we evaluated model predictions and inferred the corresponding duration of protection for new individuals based on a single antibody measurement, assuming sparse access to serological testing. We observe a reduced antibody response in older and in male individuals, and in individuals with autoimmune diseases, diabetes and immunosuppression, using data from a longitudinal cohort study conducted in healthcare workers at Sheba Medical Center, Israel, following primary vaccination with the BNT162b2 COVID-19 vaccine. Our results further suggest that model predictions of an individual's antibody response to vaccination can be used to predict the duration of protection when serological data is limited, highlighting the potential of our approach to estimate infection risk over time on both the population and individual level to support public health decision-making in future pandemics.

  View details for DOI 10.1371/journal.pcbi.1013192

  View details for PubMedID 40531962

  View details for PubMedCentralID PMC12193770

• Causal Estimands for Analyses of Averted and Avertible Outcomes due to Infectious Disease Interventions. Epidemiology (Cambridge, Mass.) Jia, K. M., Boyer, C. B., Wallinga, J., Lipsitch, M. 2025; 36 (3): 363-373

  Abstract

  During the coronavirus disease (COVID-19) pandemic, researchers attempted to estimate the number of averted and avertible outcomes due to vaccination campaigns to quantify public health impact. However, the estimands used in these analyses have not been previously formalized. It is also unclear how these analyses relate to the broader framework of direct, indirect, total, and overall causal effects under interference. Here, using potential outcome notation, we adjust the direct and overall effects to accommodate analyses of averted and avertible outcomes. We use this framework to interrogate the commonly held assumption that vaccine-averted outcomes via direct impact among vaccinated individuals (or vaccine-avertible outcomes via direct impact among unvaccinated individuals) is a lower bound on vaccine-averted (or -avertible) outcomes overall. To do so, we describe a susceptible-infected-recovered-death model stratified by vaccination status. When vaccine efficacies wane, the lower bound fails for vaccine-avertible outcomes. When transmission or fatality parameters increase over time, the lower bound fails for both vaccine-averted and -avertible outcomes. Only in the simplest scenario where vaccine efficacies, transmission, and fatality parameters are constant over time, outcomes averted via direct impact among vaccinated individuals (or outcomes avertible via direct impact among unvaccinated individuals) is a lower bound on overall impact. In conclusion, the lower bound can fail under common violations to assumptions on time-invariant vaccine efficacy, pathogen properties, or behavioral parameters. In real data analyses, estimating what seems like a lower bound on overall impact through estimating direct impact may be inadvisable without examining the directions of indirect effects.

  View details for DOI 10.1097/EDE.0000000000001839

  View details for PubMedID 39855261

  View details for PubMedCentralID PMC11957442

• Focusing a viral risk ranking tool on prediction PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Budeski, K., Lipsitch, M. 2025; 122 (16): e2419337122

  Abstract

  Preparing to rapidly respond to emerging infectious diseases is critical. SpillOver: Viral Risk Ranking is an open-source tool developed to assess the risk of novel wildlife-origin viruses spilling over from animals to humans and spreading in human populations. Several risk factors used by the tool depend on evidence of previous zoonotic spillover itself or sustained transmission in humans. Therefore, we reanalyzed the Ranking Comparison after removing eight of the 31 risk factors that require postspillover knowledge and compared the adjusted risk rankings to the originals. The area under the receiver operating characteristic curve deteriorated from 0.94 for the original risk scores to 0.73 for the adjusted ones for predicting the classification as a human virus. We also compared the mean and SD of the risk scores for the human and non-human viruses at the risk factor level. Most excluded spillover-dependent risk factors had dissimilar means between the human and non-human virus classifications, but nonspillover-dependent risk factors frequently showed similar means between the two classifications. The original formulation of the tool depended on the inclusion of spillover-dependent risk factors to quantitatively assess the risk of zoonotic spillover for a novel virus. Future iterations of the tool should omit such risk factors and consider other nonspillover-dependent risk factors to ensure that the tool is fit for risk prediction of novel viruses.

  View details for DOI 10.1073/pnas.2419337122

  View details for Web of Science ID 001477151300001

  View details for PubMedID 40244666

  View details for PubMedCentralID PMC12036980

• The importance of playing the long game when it comes to pandemic surveillance. Proceedings of the National Academy of Sciences of the United States of America Shearer, F. M., Lipsitch, M. 2025; 122 (15): e2500328122

  View details for DOI 10.1073/pnas.2500328122

  View details for PubMedID 40203044

  View details for PubMedCentralID PMC12012523

• Observational research in epidemic settings: a roadmap to reform. BMJ global health Ricotta, E. E., Bustos Carrillo, F. A., Angelli-Nichols, S., Barugahare, J., Benton, A., Carlson, C. J., Chang-Rabley, E., Dean, N. E., Duda, S. N., Federer, L., Fill, M. A., LeRoy, E. C., Linton, N. M., Lipsitch, M., Mathur, M. B., Phelan, A. L., Rid, A., Rosen, J. B., Sauer, L., Sullivan, S. G., Zendt, M., Evans, N. 2025; 10 (2)

  Abstract

  Observational studies are critical tools in clinical research and public health response, but challenges arise in ensuring the data produced by these studies are scientifically robust and socially valuable. Resolving these challenges requires careful attention to prioritising the most valuable research questions, ensuring robust study design, strong data management practices, expansive community engagement, and access and benefit sharing of results and research materials. This paper opens with a discussion of how well-designed observational studies contribute to biomedical evidence and provides examples from across the clinical literature of how these methods generate hypotheses for future research and uncover otherwise unattainable insights by providing examples from across the clinical literature. Then, we present obstacles that remain in ensuring observational studies are optimally designed, conducted and communicated.

  View details for DOI 10.1136/bmjgh-2024-017981

  View details for PubMedID 39929534

  View details for PubMedCentralID PMC11815396

• A Binary Prototype for Time-Series Surveillance and Intervention. medRxiv : the preprint server for health sciences Olejarz, J., Hoffmann, T., Zapf, A., Mugahid, D., Molinaro, R., Brown, C., Boltyenkov, A., Dudykevych, T., Gupta, A., Lipsitch, M., Atun, R., Onnela, J. P., Fortune, S., Sampath, R., Grad, Y. H. 2025

  Abstract

  Despite much research on early detection of anomalies from surveillance data, a systematic framework for appropriately acting on these signals is lacking. We addressed this gap by formulating a hidden Markov-style model for time-series surveillance, where the system state, the observed data, and the decision rule are all binary. We incur a delayed cost, c , whenever the system is abnormal and no action is taken, or an immediate cost, k , with action, where k < c . If action costs are too high, then surveillance is detrimental, and intervention should never occur. If action costs are sufficiently low, then surveillance is detrimental, and intervention should always occur. Only when action costs are intermediate and surveillance costs are sufficiently low is surveillance beneficial. Our equations provide a framework for assessing which approach may apply under a range of scenarios and, if surveillance is warranted, facilitate methodical classification of intervention strategies. Our model thus offers a conceptual basis for designing real-world public health surveillance systems.

  View details for DOI 10.1101/2025.02.03.25321613

  View details for PubMedID 39974019

  View details for PubMedCentralID PMC11838624

• Reduced Effectiveness of Repeat Influenza Vaccination: Distinguishing Among Within-Season Waning, Recent Clinical Infection, and Subclinical Infection. The Journal of infectious diseases Bi, Q., Dickerman, B. A., Nguyen, H. Q., Martin, E. T., Gaglani, M., Wernli, K. J., Balasubramani, G. K., Flannery, B., Lipsitch, M., Cobey, S. 2024; 230 (6): 1309-1318

  Abstract

  Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees. This effect might arise from incomplete consideration of within-season waning and recent infection. Using data from the US Flu Vaccine Effectiveness Network (2011-2012 to 2018-2019 seasons), we found that repeat vaccinees were vaccinated earlier in a season by 1 week. After accounting for waning VE, we determined that repeat vaccinees were still more likely to test positive for A(H3N2) (odds ratio, 1.11; 95% CI, 1.02-1.21) but not influenza B or A(H1N1). We documented clinical infection influenced individuals' decision to vaccinate in the following season while protecting against clinical infection of the same type/subtype. However, adjusting for recent documented clinical infections did not strongly influence the estimated effect of prior-season vaccination. In contrast, we found that adjusting for subclinical or undocumented infection could theoretically attenuate this effect. Additional investigation is needed to determine the impact of subclinical infections on vaccine effectiveness.

  View details for DOI 10.1093/infdis/jiae220

  View details for PubMedID 38687898

  View details for PubMedCentralID PMC11646584

• Trends in infection incidence and antimicrobial resistance in the US Veterans Affairs Healthcare System: a nationwide retrospective cohort study (2007-22). The Lancet. Infectious diseases Pham, T. M., Zhang, Y., Nevers, M., Li, H., Khader, K., Grad, Y. H., Lipsitch, M., Samore, M. 2024; 24 (12): 1333-1346

  Abstract

  Antimicrobial resistance poses a major threat to public health. There are few comprehensive nationwide studies that quantify long-term trends in infection incidence and antimicrobial resistance for multiple pathogens. We aimed to analyse trends in inpatient infection incidence and antimicrobial resistance for nine pathogens over the past 15 years across the USA.In this US nationwide retrospective cohort study, we analysed clinical microbiology data from electronic health records from all patients admitted to all 138 Veterans Affairs (VA) Medical Centers with acute care wards across the USA from Feb 1, 2007, to March 31, 2022. We quantified inpatient antibiotic use as days of therapy (DOT) per 1000 patient-days and antimicrobial resistance by resistance proportion (proportion of incident isolates identified as resistant) and phenotypic incidence (incidence of infections per 1000 admissions classified as resistant, susceptible, or missing). To analyse trends before the COVID-19 pandemic and during the COVID-19 pandemic, we used generalised estimating equation models and reported average annual percentage changes (AAPC).We collected 991 527 30-day incident isolates from 507 760 patients in 138 VA Medical Centers and 50 states in the USA. Between Feb 1, 2007, and Dec 31, 2019, infection incidence and antimicrobial resistance declined for many pathogens and pathogen-drug combinations. The proportion of methicillin resistance in Staphylococcus aureus decreased from 57·7% (11 876 of 20 584 incident isolates) to 44·6% (5916 of 13 257) over these 13 years (AAPC -1·8%; 95% CI -2·4 to -1·2; p<0·0001), and vancomycin-resistant Enterococcus faecium infections decreased from 77·8% (2555 of 3285) to 65·1% (893 of 1371; AAPC -1·2%; 95% CI -2·5 to 0·0; p=0·052). Fluoroquinolone resistance declined in both proportion and incidence for most pathogens. These trends correlated with substantial reductions in fluoroquinolone use, from 125 DOT per 1000 patient-days to 20 DOT per 1000 patient-days. Third generation cephalosporin resistance increased steeply in Escherichia coli infections from 6·7% (942 of 14 042) in 2007 to 15·3% (2153 of 14 053) in 2019 (AAPC 8·5%; 95% CI 6·2 to 10·7; p<0·0001). Carbapenem resistance proportion increased in Enterobacter cloacae infections from 1·1% (30 of 2852) in 2007 to 7·3% (212 of 2919) in 2019 (AAPC 19·8%; 95% CI 13·7 to 26·2; p<0·0001), but remained low for Klebsiella pneumoniae and E coli. During the COVID-19 pandemic between Jan 1, 2020, and March 31, 2022, several pathogen-drug combinations increased in both incidence and resistance for hospital-associated infections. For some pathogen-drug combinations, trends in incidence of resistant and susceptible infections were divergent, whereas for other combinations, these trends were in the same direction.Significant reductions in methicillin resistance in S aureus, vancomycin-resistant E faecium, and fluoroquinolone resistance across multiple pathogens suggest that control efforts have had an effect on resistance. The rise in extended-spectrum β-lactamases-producing Enterobacterales and recent surge in hospital-associated infections emphasise the need for ongoing surveillance and interventions. Our study highlights how coupling the analysis of phenotypic incidence with resistance proportion can enhance interpretation of antimicrobial resistance data.US Centers for Disease Control and Prevention.

  View details for DOI 10.1016/S1473-3099(24)00416-X

  View details for PubMedID 39151443

• Prediction of post-PCV13 pneumococcal evolution using invasive disease data enhanced by inverse-invasiveness weighting. mBio Qiu, X., McGee, L., Hammitt, L. L., Grant, L. R., O'Brien, K. L., Hanage, W. P., Lipsitch, M. 2024; 15 (10): e0335523

  Abstract

  After introducing pneumococcal conjugate vaccines (PCVs), serotype replacement occurred in Streptococcus pneumoniae. Predicting which pneumococcal strains will become common in carriage after vaccination can enhance vaccine design, public health interventions, and understanding of pneumococcal evolution. Invasive pneumococcal isolates were collected during 1998-2018 by the Active Bacterial Core surveillance (ABCs). Carriage data from Massachusetts (MA) and Southwest United States were used to calculate weights. Using pre-vaccine data, serotype-specific inverse-invasiveness weights were defined as the ratio of the proportion of the serotype in carriage to the proportion in invasive data. Genomic data were processed under bioinformatic pipelines to define genetically similar sequence clusters (i.e., strains), and accessory genes (COGs) present in 5-95% of isolates. Weights were applied to adjust observed strain proportions and COG frequencies. The negative frequency-dependent selection (NFDS) model predicted strain proportions by calculating the post-vaccine strain composition in the weighted invasive disease population that would best match pre-vaccine COG frequencies. Inverse-invasiveness weighting increased the correlation of COG frequencies between invasive and carriage data in linear or logit scale for pre-vaccine, post-PCV7, and post-PCV13; and between different epochs in the invasive data. Weighting the invasive data significantly improved the NFDS model's accuracy in predicting strain proportions in the carriage population in the post-PCV13 epoch, with the adjusted R2 increasing from 0.254 before weighting to 0.545 after weighting. The weighting system adjusted invasive disease data to better represent the pneumococcal carriage population, allowing the NFDS mechanism to predict strain proportions in carriage in the post-PCV13 epoch. Our methods enrich the value of genomic sequences from invasive disease surveillance.IMPORTANCEStreptococcus pneumoniae, a common colonizer in the human nasopharynx, can cause invasive diseases including pneumonia, bacteremia, and meningitis mostly in children under 5 years or older adults. The PCV7 was introduced in 2000 in the United States within the pediatric population to prevent disease and reduce deaths, followed by PCV13 in 2010, PCV15 in 2022, and PCV20 in 2023. After the removal of vaccine serotypes, the prevalence of carriage remained stable as the vacated pediatric ecological niche was filled with certain non-vaccine serotypes. Predicting which pneumococcal clones, and which serotypes, will be most successful in colonization after vaccination can enhance vaccine design and public health interventions, while also improving our understanding of pneumococcal evolution. While carriage data, which are collected from the pneumococcal population that is competing to colonize and transmit, are most directly relevant to evolutionary studies, invasive disease data are often more plentiful. Previously, evolutionary models based on negative frequency-dependent selection (NFDS) on the accessory genome were shown to predict which non-vaccine strains and serotypes were most successful in colonization following the introduction of PCV7. Here, we show that an inverse-invasiveness weighting system applied to invasive disease surveillance data allows the NFDS model to predict strain proportions in the projected carriage population in the post-PCV13/pre-PCV15 and pre-PCV20 epoch. The significance of our research lies in using a sample of invasive disease surveillance data to extend the use of NFDS as an evolutionary mechanism to predict post-PCV13 population dynamics. This has shown that we can correct for biased sampling that arises from differences in virulence and can enrich the value of genomic data from disease surveillance and advance our understanding of how NFDS impacts carriage population dynamics after both PCV7 and PCV13 vaccination.

  View details for DOI 10.1128/mbio.03355-23

  View details for PubMedID 39207103

  View details for PubMedCentralID PMC11481909

• Immune escape and attenuated severity associated with the SARS-CoV-2 BA.2.86/JN.1 lineage. Nature communications Lewnard, J. A., Mahale, P., Malden, D., Hong, V., Ackerson, B. K., Lewin, B. J., Link-Gelles, R., Feldstein, L. R., Lipsitch, M., Tartof, S. Y. 2024; 15 (1): 8550

  Abstract

  The SARS-CoV-2 BA.2.86 lineage, and its sublineage JN.1 in particular, achieved widespread transmission in the US during winter 2023-24. However, this surge in infections was not accompanied by COVID-19 hospitalizations and mortality commensurate with prior waves. To understand shifts in COVID-19 epidemiology associated with JN.1 emergence, we compared characteristics and clinical outcomes of time-matched cases infected with BA.2.86 lineages (predominantly representing JN.1) versus co-circulating XBB-derived lineages in December, 2023 and January, 2024. Cases infected with BA.2.86 lineages received greater numbers of COVID-19 vaccine doses, including XBB.1.5-targeted boosters, in comparison to cases infected with XBB-derived lineages. Additionally, cases infected with BA.2.86 lineages experienced greater numbers of documented prior SARS-CoV-2 infections. Cases infected with BA.2.86 lineages also experienced lower risk of progression to severe clinical outcomes requiring emergency department consultations or hospital admission. Sensitivity analyses suggested under-ascertainment of prior infections could not explain this apparent attenuation of severity. Our findings implicate escape from immunity acquired from prior vaccination or infection in the emergence of the JN.1 lineage and suggest infections with this lineage are less likely to experience clinically-severe disease. Monitoring of immune escape and clinical severity in emerging SARS-CoV-2 variants remains a priority to inform responses.

  View details for DOI 10.1038/s41467-024-52668-w

  View details for PubMedID 39362845

  View details for PubMedCentralID PMC11450198

• Emulating target trials of postexposure vaccines using observational data. American journal of epidemiology Boyer, C., Lipsitch, M. 2024

  Abstract

  Postexposure vaccination has the potential to prevent or modify the course of clinical disease among those exposed to a pathogen. However, due to logistical constraints, postexposure vaccine trials have been difficult to implement in practice. In place of trials, investigators have used observational data to estimate the effectiveness or optimal timing window for postexposure vaccines, but the relationship between these analyses and those that would be conducted in a trial is often unclear. Here, we define several possible target trials for postexposure vaccination and show how, under certain conditions, they can be emulated using observational data. We emphasize the importance of the incubation period and the timing of vaccination in trial design and emulation. As an example, we specify a protocol for postexposure vaccination against mpox and provide a step-by-step description of how to emulate it using data from a healthcare database or contact tracing program. We further illustrate some of the benefits of the target trial approach through simulation.

  View details for DOI 10.1093/aje/kwae350

  View details for PubMedID 39270677

• Considerations for viral co-infection studies in human populations. mBio Chin, T., Foxman, E. F., Watkins, T. A., Lipsitch, M. 2024; 15 (7): e0065824

  Abstract

  When respiratory viruses co-circulate in a population, individuals may be infected with multiple pathogens and experience possible virus-virus interactions, where concurrent or recent prior infection with one virus affects the infection process of another virus. While experimental studies have provided convincing evidence for within-host mechanisms of virus-virus interactions, evaluating evidence for viral interference or potentiation using population-level data has proven more difficult. Recent studies have quantified the prevalence of co-detections using populations drawn from clinical settings. Here, we focus on selection bias issues associated with this study design. We provide a quantitative account of the conditions under which selection bias arises in these studies, review previous attempts to address this bias, and propose unbiased study designs with sample size estimates needed to ascertain viral interference. We show that selection bias is expected in cross-sectional co-detection prevalence studies conducted in clinical settings, except under a strict set of assumptions regarding the relative probabilities of being included in a study limited to individuals with clinical disease under different viral states. Population-wide studies that collect samples from participants irrespective of their clinical status would meanwhile require large sample sizes to be sufficiently powered to detect viral interference, suggesting that a study's timing, inclusion criteria, and the expected magnitude of interference are instrumental in determining feasibility.

  View details for DOI 10.1128/mbio.00658-24

  View details for PubMedID 38847531

  View details for PubMedCentralID PMC11253623

• Infectious disease surveillance needs for the United States: lessons from Covid-19. Frontiers in public health Lipsitch, M., Bassett, M. T., Brownstein, J. S., Elliott, P., Eyre, D., Grabowski, M. K., Hay, J. A., Johansson, M. A., Kissler, S. M., Larremore, D. B., Layden, J. E., Lessler, J., Lynfield, R., MacCannell, D., Madoff, L. C., Metcalf, C. J., Meyers, L. A., Ofori, S. K., Quinn, C., Bento, A. I., Reich, N. G., Riley, S., Rosenfeld, R., Samore, M. H., Sampath, R., Slayton, R. B., Swerdlow, D. L., Truelove, S., Varma, J. K., Grad, Y. H. 2024; 12: 1408193

  Abstract

  The COVID-19 pandemic has highlighted the need to upgrade systems for infectious disease surveillance and forecasting and modeling of the spread of infection, both of which inform evidence-based public health guidance and policies. Here, we discuss requirements for an effective surveillance system to support decision making during a pandemic, drawing on the lessons of COVID-19 in the U.S., while looking to jurisdictions in the U.S. and beyond to learn lessons about the value of specific data types. In this report, we define the range of decisions for which surveillance data are required, the data elements needed to inform these decisions and to calibrate inputs and outputs of transmission-dynamic models, and the types of data needed to inform decisions by state, territorial, local, and tribal health authorities. We define actions needed to ensure that such data will be available and consider the contribution of such efforts to improving health equity.

  View details for DOI 10.3389/fpubh.2024.1408193

  View details for PubMedID 39076420

  View details for PubMedCentralID PMC11285106

• Diagnostics for Public Health - Infectious Disease Surveillance and Control. NEJM evidence Lipsitch, M., Grad, Y. 2024; 3 (5): EVIDra2300271

  Abstract

  AbstractAccurate diagnostics are critical in public health to ensure successful disease tracking, prevention, and control. Many of the same characteristics are desirable for diagnostic procedures in both medicine and public health: for example, low cost, high speed, low invasiveness, ease of use and interpretation, day-to-day consistency, and high accuracy. This review lays out five principles that are salient when the goal of diagnosis is to improve the overall health of a population rather than that of a particular patient, and it applies them in two important use cases: pandemic infectious disease and antimicrobial resistance.

  View details for DOI 10.1056/EVIDra2300271

  View details for PubMedID 38815175

• Estimated Excess Deaths Due to COVID-19 Among the Urban Population of Mainland China, December 2022 to January 2023. Epidemiology (Cambridge, Mass.) Raphson, L., Lipsitch, M. 2024; 35 (3): 372-376

  Abstract

  Mainland China experienced a major surge in SARS-CoV-2 infections in December 2022-January 2023, but its impact on mortality was unclear given the underreporting of coronavirus disease 2019 deaths.Using obituary data from the Chinese Academy of Engineering (CAE), we estimated the excess death rate among senior CAE members by taking the difference between the observed rate of all-cause death in December 2022-January 2023 and the expected rate for the same months in 2017-2022, by age groups. We used this to extrapolate an estimate of the number of excess deaths in December 2022-January 2023 among urban dwellers in Mainland China.In December 2022-January 2023, we estimated excess death rates of 0.94 per 100 persons (95% confidence interval [CI] = -0.54, 3.16) in CAE members aged 80-84 years, 3.95 (95% CI = 0.50, 7.84) in 85-89 years, 10.35 (95% CI = 3.59, 17.71) in 90-94 years, and 16.88 (95% CI = 0.00, 34.62) in 95 years and older. Using our baseline assumptions, this extrapolated to 917,000 (95% CI = 425,000, 1.45 million) excess deaths among urban dwellers in Mainland China, much higher than the 81,000 in-hospital deaths officially reported from 9 December 2022 to 30 January 2023.As in many jurisdictions, we estimate that the coronavirus disease 2019 pandemic had a much wider impact on mortality than what was officially documented in Mainland China.

  View details for DOI 10.1097/EDE.0000000000001723

  View details for PubMedID 38300113

  View details for PubMedCentralID PMC11023797

• Public role in research oversight. Journal of virology Lipsitch, M., Inglesby, T. V., Cicero, A., Relman, D. A. 2024: e0006124

  View details for DOI 10.1128/jvi.00061-24

  View details for PubMedID 38477584

• Optimal environmental testing frequency for outbreak surveillance. Epidemics Olejarz, J. W., Roster, K. I., Kissler, S. M., Lipsitch, M., Grad, Y. H. 2024; 46: 100750

  Abstract

  Public health surveillance for pathogens presents an optimization problem: we require enough sampling to identify intervention-triggering shifts in pathogen epidemiology, such as new introductions or sudden increases in prevalence, but not so much that costs due to surveillance itself outweigh those from pathogen-associated illness. To determine this optimal sampling frequency, we developed a general mathematical model for the introduction of a new pathogen that, once introduced, increases in prevalence exponentially. Given the relative cost of infection vs. sampling, we derived equations for the expected combined cost per unit time of disease burden and surveillance for a specified sampling frequency, and thus the sampling frequency for which the expected total cost per unit time is lowest.

  View details for DOI 10.1016/j.epidem.2024.100750

  View details for PubMedID 38394927

  View details for PubMedCentralID PMC10979539

• Comparison of the Test-negative Design and Cohort Design With Explicit Target Trial Emulation for Evaluating COVID-19 Vaccine Effectiveness. Epidemiology (Cambridge, Mass.) Li, G., Gerlovin, H., Figueroa Muñiz, M. J., Wise, J. K., Madenci, A. L., Robins, J. M., Aslan, M., Cho, K., Gaziano, J. M., Lipsitch, M., Casas, J. P., Hernán, M. A., Dickerman, B. A. 2024; 35 (2): 137-149

  Abstract

  Observational studies are used for estimating vaccine effectiveness under real-world conditions. The practical performance of two common approaches-cohort and test-negative designs-need to be compared for COVID-19 vaccines.We compared the cohort and test-negative designs to estimate the effectiveness of the BNT162b2 vaccine against COVID-19 outcomes using nationwide data from the United States Department of Veterans Affairs. Specifically, we (1) explicitly emulated a target trial using follow-up data and evaluated the potential for confounding using negative controls and benchmarking to a randomized trial, (2) performed case-control sampling of the cohort to confirm empirically that the same estimate is obtained, (3) further restricted the sampling to person-days with a test, and (4) implemented additional features of a test-negative design. We also compared their performance in limited datasets.Estimated BNT162b2 vaccine effectiveness was similar under all four designs. Empirical results suggested limited residual confounding by healthcare-seeking behavior. Analyses in limited datasets showed evidence of residual confounding, with estimates biased downward in the cohort design and upward in the test-negative design.Vaccine effectiveness estimates under a cohort design with explicit target trial emulation and a test-negative design were similar when using rich information from the VA healthcare system, but diverged in opposite directions when using a limited dataset. In settings like ours with sufficient information on confounders and other key variables, the cohort design with explicit target trial emulation may be preferable as a principled approach that allows estimation of absolute risks and facilitates interpretation of effect estimates.

  View details for DOI 10.1097/EDE.0000000000001709

  View details for PubMedID 38109485

  View details for PubMedCentralID PMC11022682

• What's next: using infectious disease mathematical modelling to address health disparities. International journal of epidemiology Richard, D. M., Lipsitch, M. 2024; 53 (1)

  View details for DOI 10.1093/ije/dyad180

  View details for PubMedID 38145617

  View details for PubMedCentralID PMC10859128

• JYNNEOS™ effectiveness as post-exposure prophylaxis against mpox: Challenges using real-world outbreak data. Vaccine Rosen, J. B., Arciuolo, R. J., Pathela, P., Boyer, C. B., Baumgartner, J., Latash, J., Malec, L., Lee, E. H., Reddy, V., King, R., Edward Real, J., Lipsitch, M., Zucker, J. R. 2024; 42 (3): 548-555

  Abstract

  JYNNEOSTM vaccine has been used as post-exposure prophylaxis (PEP) during a mpox outbreak in New York City (NYC). Data on effectiveness are limited.Effectiveness of a single dose of JYNNEOSTM vaccine administered subcutaneously ≤ 14 days as PEP for preventing mpox disease was assessed among individuals exposed to case-patients from May 22, 2022-August 24, 2022. Individuals were evaluated for mpox through 21 days post-exposure. An observational study was conducted emulating a sequence of nested "target" randomized trials starting each day after exposure. Results were adjusted for exposure risk and race/ethnicity. Analyses were conducted separately based on last (PEPL) and first (PEPF) exposure date. We evaluated the potential to overestimate PEP effectiveness when using conventional analytic methods due to exposed individuals developing illness before they can obtain PEP (immortal time bias) compared to the target trial.Median time from last exposure to symptom onset (incubation period) among cases that did not receive PEPL was 7 days (range 1-16). Time to PEPL receipt was 7 days (range 0-14). Among 549 individuals, adjusted PEPL and PEPF effectiveness was 19 % (95 % Confidence Interval [CI], -54 % to 57 %) and -7% (95 % CI, -144 % to 53 %) using the target trial emulation, respectively, and 78 % (95 % CI, 50 % to 91 %) and 73 % (95 % CI, 31 % to 91 %) using conventional analysis.Determining PEP effectiveness using real-world data during an outbreak is challenging. Time to PEP in NYC coupled with the observed incubation period resulted in overestimated PEP effectiveness using a conventional method. The target trial emulation, while yielding wide confidence intervals due to small sample size, avoided immortal time bias. While results from these evaluations cannot be used as reliable estimates of PEP effectiveness, we present important methodologic considerations for future evaluations.

  View details for DOI 10.1016/j.vaccine.2023.12.066

  View details for PubMedID 38218669

  View details for PubMedCentralID PMC10960631

• EXAMINING BIAS FROM DIFFERENTIAL DEPLETION OF SUSCEPTIBLES IN VACCINE EFFECTIVENESS ESTIMATES IN SETTINGS OF WANING. American journal of epidemiology Kahn, R., Feikin, D. R., Wiegand, R. E., Lipsitch, M. 2024; 193 (1): 232-234

  View details for DOI 10.1093/aje/kwad191

  View details for PubMedID 37771045

  View details for PubMedCentralID PMC10773472

• Estimated preventable COVID-19-associated deaths due to non-vaccination in the United States. European journal of epidemiology Jia, K. M., Hanage, W. P., Lipsitch, M., Johnson, A. G., Amin, A. B., Ali, A. R., Scobie, H. M., Swerdlow, D. L. 2023; 38 (11): 1125-1128

  Abstract

  While some studies have previously estimated lives saved by COVID-19 vaccination, we estimate how many deaths could have been averted by vaccination in the US but were not because of a failure to vaccinate. We used a simple method based on a nationally representative dataset to estimate the preventable deaths among unvaccinated individuals in the US from May 30, 2021 to September 3, 2022 adjusted for the effects of age and time. We estimated that at least 232,000 deaths could have been prevented among unvaccinated adults during the 15 months had they been vaccinated with at least a primary series. While uncertainties exist regarding the exact number of preventable deaths and more granular data are needed on other factors causing differences in death rates between the vaccinated and unvaccinated groups to inform these estimates, this method is a rapid assessment on vaccine-preventable deaths due to SARS-CoV-2 that has crucial public health implications. The same rapid method can be used for future public health emergencies.

  View details for DOI 10.1007/s10654-023-01006-3

  View details for PubMedID 37093505

  View details for PubMedCentralID PMC10123459

• Some principles for using epidemiologic study results to parameterize transmission models. medRxiv : the preprint server for health sciences Joshi, K., Kahn, R., Boyer, C., Lipsitch, M. 2023

  Abstract

  Infectious disease models, including individual based models (IBMs), can be used to inform public health response. For these models to be effective, accurate estimates of key parameters describing the natural history of infection and disease are needed. However, obtaining these parameter estimates from epidemiological studies is not always straightforward. We aim to 1) outline challenges to parameter estimation that arise due to common biases found in epidemiologic studies and 2) describe the conditions under which careful consideration in the design and analysis of the study could allow us to obtain a causal estimate of the parameter of interest. In this discussion we do not focus on issues of generalizability and transportability.Using examples from the COVID-19 pandemic, we first identify different ways of parameterizing IBMs and describe ideal study designs to estimate these parameters. Given real-world limitations, we describe challenges in parameter estimation due to confounding and conditioning on a post-exposure observation. We then describe ideal study designs that can lead to unbiased parameter estimates. We finally discuss additional challenges in estimating progression probabilities and the consequences of these challenges.Causal estimation can only occur if we are able to accurately measure and control for all confounding variables that create non-causal associations between the exposure and outcome of interest, which is sometimes challenging given the nature of the variables we need to measure. In the absence of perfect control, non-causal parameter estimates should still be used, as sometimes they are the best available information we have.Identifying which estimates from epidemiologic studies correspond to the quantities needed to parameterize disease models, and determining whether these parameters have causal interpretations, can inform future study designs and improve inferences from infectious disease models. Understanding the way in which biases can arise in parameter estimation can inform sensitivity analyses or help with interpretation of results if the magnitude and direction of the bias is understood.

  View details for DOI 10.1101/2023.10.03.23296455

  View details for PubMedID 37873220

  View details for PubMedCentralID PMC10593029

• Geographic Targeting of COVID-19 Testing to Maximize Detection in Los Angeles County. Open forum infectious diseases Jia, K. M., Kahn, R., Fisher, R., Balter, S., Lipsitch, M. 2023; 10 (7): ofad331

  Abstract

  Many severe acute respiratory syndrome coronavirus 2 infections have not been detected, reported, or isolated. For community testing programs to locate the most cases under limited testing resources, we developed and evaluated quantitative approaches for geographic targeting of increased coronavirus disease 2019 testing efforts.For every week from December 5, 2021, to July 23, 2022, testing and vaccination data were obtained in ∼340 cities/communities in Los Angeles County, and models were developed to predict which cities/communities would have the highest test positivity 2 weeks ahead. A series of counterfactual scenarios were constructed to explore the additional number of cases that could be detected under targeted testing.The simplest model based on most recent test positivity performed nearly as well as the best model based on most recent test positivity and weekly tests per 100 persons in identifying communities that would maximize the average yield of cases per test in the following 2 weeks and almost as well as the perfect knowledge of the actual positivity 2 weeks ahead. In the counterfactual scenario, increasing testing by 1% 2 weeks ahead and allocating all tests to communities with the top 10% of predicted positivity would yield a 2% increase in detected cases.Simple models based on current test positivity can predict which communities may have the highest positivity 2 weeks ahead and hence could be allocated with more testing resources.

  View details for DOI 10.1093/ofid/ofad331

  View details for PubMedID 37469616

  View details for PubMedCentralID PMC10352645

• Increased vaccine sensitivity of an emerging SARS-CoV-2 variant. Nature communications Lewnard, J. A., Hong, V., Kim, J. S., Shaw, S. F., Lewin, B., Takhar, H., Lipsitch, M., Tartof, S. Y. 2023; 14 (1): 3854

  Abstract

  Host immune responses are a key source of selective pressure driving pathogen evolution. Emergence of many SARS-CoV-2 lineages has been associated with enhancements in their ability to evade population immunity resulting from both vaccination and infection. Here we show diverging trends of escape from vaccine-derived and infection-derived immunity for the emerging XBB/XBB.1.5 Omicron lineage. Among 31,739 patients tested in ambulatory settings in Southern California from December, 2022 to February, 2023, adjusted odds of prior receipt of 2, 3, 4, and ≥5 COVID-19 vaccine doses were 10% (95% confidence interval: 1-18%), 11% (3-19%), 13% (3-21%), and 25% (15-34%) lower, respectively, among cases infected with XBB/XBB.1.5 than among cases infected with other co-circulating lineages. Similarly, prior vaccination was associated with greater point estimates of protection against progression to hospitalization among cases with XBB/XBB.1.5 than among non-XBB/XBB.1.5 cases (70% [30-87%] and 48% [7-71%], respectively, for recipients of ≥4 doses). In contrast, cases infected with XBB/XBB.1.5 had 17% (11-24%) and 40% (19-65%) higher adjusted odds of having experienced 1 and ≥2 prior documented infections, respectively, including with pre-Omicron variants. As immunity acquired from SARS-CoV-2 infection becomes increasingly widespread, fitness costs associated with enhanced vaccine sensitivity in XBB/XBB.1.5 may be offset by increased ability to evade infection-derived host responses.

  View details for DOI 10.1038/s41467-023-39567-2

  View details for PubMedID 37386005

  View details for PubMedCentralID PMC10310822

• Learning From COVID-19 to Improve Surveillance for Emerging Threats. American journal of public health Jernigan, D. B., George, D., Lipsitch, M. 2023; 113 (5): 520-522

  View details for DOI 10.2105/AJPH.2023.307261

  View details for PubMedID 36926966

  View details for PubMedCentralID PMC10088952

• Comparative performance of between-population vaccine allocation strategies with applications for emerging pandemics. Vaccine Joshi, K., Rumpler, E., Kennedy-Shaffer, L., Bosan, R., Lipsitch, M. 2023; 41 (11): 1864-1874

  Abstract

  Vaccine allocation decisions during emerging pandemics have proven to be challenging due to competing ethical, practical, and political considerations. Complicating decision making, policy makers need to consider vaccine allocation strategies that balance needs both within and between populations. When vaccine stockpiles are limited, doses should be allocated in locations to maximize their impact. Using a susceptible-exposed-infectious-recovered (SEIR) model we examine optimal vaccine allocation decisions across two populations considering the impact of characteristics of the population (e.g., size, underlying immunity, heterogeneous risk structure, interaction), vaccine (e.g., vaccine efficacy), pathogen (e.g., transmissibility), and delivery (e.g., varying speed and timing of rollout). Across a wide range of characteristics considered, we find that vaccine allocation proportional to population size (i.e., pro-rata allocation) performs either better or comparably to nonproportional allocation strategies in minimizing the cumulative number of infections. These results may argue in favor of sharing of vaccines between locations in the context of an epidemic caused by an emerging pathogen, where many epidemiologic characteristics may not be known.

  View details for DOI 10.1016/j.vaccine.2022.12.053

  View details for PubMedID 36697312

  View details for PubMedCentralID PMC10075509

• Mass drug administration of azithromycin: an analysis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases Kahn, R., Eyal, N., Sow, S. O., Lipsitch, M. 2023; 29 (3): 326-331

  Abstract

  WHO recommends mass drug administration (MDA) of the antibiotic azithromycin for children aged 1-11 months in areas with high rates of infant and child mortality. Notwithstanding the substantial potential benefits of lowering childhood mortality, MDA raises understandable concerns about exacerbating antibiotic resistance.In this study, we aimed to evaluate the use of MDA using both quantitative and ethical considerations.We performed a series of literature searches between July 2019 and June 2022.We first compared MDA with other uses of antibiotics using the standard metric of 'number needed to treat', and five additional criteria: (1) other widely accepted uses of anti-infectives (2) absolute use (i.e. total number), of antibiotics, (3) risk-benefit trade-off, (4) availability of short-term alternatives, and (5) the precedent for implementing similar interventions. We found that MDA falls well within a justifiable range when compared with widely accepted uses of antibiotics in terms of the number needed to treat. The other five criteria we considered provided further support for the use of MDA to prevent childhood mortality.Although better data on antibiotic use and resistance are needed, efforts to reduce antibiotic use and resistance should not start with halting MDA of azithromycin in the areas with the highest rates of childhood mortality. Improving data to inform this decision is critical. However, on the basis of the best evidence available, we believe that concerns regarding resistance should not thwart MDA; instead, MDA should be accompanied by robust plans to monitor its efficacy and changes in resistance levels. Similar considerations could be included in a framework for evaluating the benefits of antibiotics against the risk of resistance in other contexts.

  View details for DOI 10.1016/j.cmi.2022.10.022

  View details for PubMedID 36309328

• Leveraging Serosurveillance and Postmortem Surveillance to Quantify the Impact of Coronavirus Disease 2019 in Africa. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Kogan, N. E., Gantt, S., Swerdlow, D., Viboud, C., Semakula, M., Lipsitch, M., Santillana, M. 2023; 76 (3): 424-432

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic has had a devastating impact on global health, the magnitude of which appears to differ intercontinentally: For example, reports suggest that 271 900 per million people have been infected in Europe versus 8800 per million people in Africa. While Africa is the second-largest continent by population, its reported COVID-19 cases comprise <3% of global cases. Although social and environmental explanations have been proposed to clarify this discrepancy, systematic underascertainment of infections may be equally responsible.We sought to quantify magnitudes of underascertainment in COVID-19's cumulative incidence in Africa. Using serosurveillance and postmortem surveillance, we constructed multiplicative factors estimating ratios of true infections to reported cases in Africa since March 2020.Multiplicative factors derived from serology data (subset of 12 nations) suggested a range of COVID-19 reporting rates, from 1 in 2 infections reported in Cape Verde (July 2020) to 1 in 3795 infections reported in Malawi (June 2020). A similar set of multiplicative factors for all nations derived from postmortem data points toward the same conclusion: Reported COVID-19 cases are unrepresentative of true infections, suggesting that a key reason for low case burden in many African nations is significant underdetection and underreporting.While estimating the exact burden of COVID-19 is challenging, the multiplicative factors we present furnish incidence estimates reflecting likely-to-worst-case ranges of infection. Our results stress the need for expansive surveillance to allocate resources in areas experiencing discrepancies between reported cases, projected infections, and deaths.

  View details for DOI 10.1093/cid/ciac797

  View details for PubMedID 36196586

  View details for PubMedCentralID PMC9619616

• Fairness and efficiency considerations in COVID-19 vaccine allocation strategies: A case study comparing front-line workers and 65-74 year olds in the United States. PLOS global public health Rumpler, E., Feldman, J. M., Bassett, M. T., Lipsitch, M. 2023; 3 (2): e0001378

  Abstract

  The COVID-19 epidemic in the United States has been characterized by two stark disparities. COVID-19 burden has been unequally distributed among racial and ethnic groups and at the same time the mortality rates have been sharply higher among older age groups. These disparities have led some to suggest that inequalities could be reduced by vaccinating front-line workers before vaccinating older individuals, as older individuals in the US are disproportionately Non-Hispanic White. We compare the performance of two distribution policies, one allocating vaccines to front-line workers and another to older individuals aged 65-74-year-old. We estimate both the number of lives saved and the number of years of life saved under each of the policies, overall and in every race/ethnicity groups, in the United States and every state. We show that prioritizing COVID-19 vaccines for 65-74-year-olds saves both more lives and more years of life than allocating vaccines front-line workers in each racial/ethnic group, in the United States as a whole and in nearly every state. When evaluating fairness of vaccine allocation policies, the overall benefit to impact of each population subgroup should be considered, not only the proportion of doses that is distributed to each subgroup. Further work can identify prioritization schemes that perform better on multiple equity metrics.

  View details for DOI 10.1371/journal.pgph.0001378

  View details for PubMedID 36962865

  View details for PubMedCentralID PMC10021220

• Strengthen oversight of risky research on pathogens. Science (New York, N.Y.) Pannu, J., Palmer, M. J., Cicero, A., Relman, D. A., Lipsitch, M., Inglesby, T. 2022: eadf6020

  Abstract

  Policy reset and convergence on governance are needed.

  View details for DOI 10.1126/science.adf6020

  View details for PubMedID 36480598

• Prescribing for different antibiotic classes across age groups in the Kaiser Permanente Northern California population in association with influenza incidence, 2010-2018. Epidemiology and infection Goldstein, E., Fireman, B. H., Klein, N. P., Lipsitch, M., Ray, G. T. 2022; 150: e180

  Abstract

  There is limited information on the volume of antibiotic prescribing that is influenza-associated, resulting from influenza infections and their complications (such as streptococcal pharyngitis). We estimated that for the Kaiser Permanente Northern California population during 2010-2018, 3.4% (2.8%-4%) of all macrolide prescriptions (fills), 2.7% (2.3%-3.2%) of all aminopenicillin prescriptions, 3.1% (2.4%-3.9%) of all 3rd generation cephalosporins prescriptions, 2.2% (1.8%-2.6%) of all protected aminopenicillin prescriptions and 1.3% (1%-1.6%) of all quinolone prescriptions were influenza-associated. The corresponding proportions were higher for select age groups, e.g. 4.3% of macrolide prescribing in ages over 50 years, 5.1% (3.3%-6.8%) of aminopenicillin prescribing in ages 5-17 years and 3.3% (1.9%-4.6%) in ages <5 years was influenza-associated. The relative contribution of influenza to antibiotic prescribing for respiratory diagnoses without a bacterial indication in ages over 5 years was higher than the corresponding relative contribution to prescribing for all diagnoses. Our results suggest a modest benefit of increasing influenza vaccination coverage for reducing prescribing for the five studied antibiotic classes, particularly for macrolides in ages over 50 years and aminopenicillins in ages <18 years, and the potential benefit of other measures to reduce unnecessary antibiotic prescribing for respiratory diagnoses with no bacterial indication, both of which may contribute to the mitigation of antimicrobial resistance.

  View details for DOI 10.1017/S0950268822001662

  View details for PubMedID 36285506

  View details for PubMedCentralID PMC9987027

• Infectious disease dynamics and restrictions on social gathering size. Epidemics Boyer, C. B., Rumpler, E., Kissler, S. M., Lipsitch, M. 2022; 40: 100620

  Abstract

  Social gatherings can be an important locus of transmission for many pathogens including SARS-CoV-2. During an outbreak, restricting the size of these gatherings is one of several non-pharmaceutical interventions available to policy-makers to reduce transmission. Often these restrictions take the form of prohibitions on gatherings above a certain size. While it is generally agreed that such restrictions reduce contacts, the specific size threshold separating "allowed" from "prohibited" gatherings often does not have a clear scientific basis, which leads to dramatic differences in guidance across location and time. Building on the observation that gathering size distributions are often heavy-tailed, we develop a theoretical model of transmission during gatherings and their contribution to general disease dynamics. We find that a key, but often overlooked, determinant of the optimal threshold is the distribution of gathering sizes. Using data on pre-pandemic contact patterns from several sources as well as empirical estimates of transmission parameters for SARS-CoV-2, we apply our model to better understand the relationship between restriction threshold and reduction in cases. We find that, under reasonable transmission parameter ranges, restrictions may have to be set quite low to have any demonstrable effect on cases due to relative frequency of smaller gatherings. We compare our conceptual model with observed changes in reported contacts during lockdown in March of 2020.

  View details for DOI 10.1016/j.epidem.2022.100620

  View details for PubMedID 36058184

  View details for PubMedCentralID PMC9384337

• Clinical outcomes associated with SARS-CoV-2 Omicron (B.1.1.529) variant and BA.1/BA.1.1 or BA.2 subvariant infection in Southern California. Nature medicine Lewnard, J. A., Hong, V. X., Patel, M. M., Kahn, R., Lipsitch, M., Tartof, S. Y. 2022; 28 (9): 1933-1943

  Abstract

  Epidemiologic surveillance has revealed decoupling of Coronavirus Disease 2019 (COVID-19) hospitalizations and deaths from case counts after emergence of the Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant globally. However, assessment of the relative severity of Omicron variant infections presents challenges because of differential acquired immune protection against Omicron and prior variants and because longer-term changes have occurred in testing and healthcare practices. Here we show that Omicron variant infections were associated with substantially reduced risk of progression to severe clinical outcomes relative to time-matched Delta (B.1.617.2) variant infections within a large, integrated healthcare system in Southern California. Adjusted hazard ratios (aHRs) for any hospital admission, symptomatic hospital admission, intensive care unit admission, mechanical ventilation and death comparing individuals with Omicron versus Delta variant infection were 0.59 (95% confidence interval: 0.51-0.69), 0.59 (0.51-0.68), 0.50 (0.29-0.87), 0.36 (0.18-0.72) and 0.21 (0.10-0.44), respectively. This reduced severity could not be explained by differential history of prior infection among individuals with Omicron or Delta variant infection and was starkest among individuals not previously vaccinated against COVID-19 (aHR = 0.40 (0.33-0.49) for any hospital admission and 0.14 (0.07-0.28) for death). Infections with the Omicron BA.2 subvariant were not associated with differential risk of severe outcomes in comparison to BA.1/BA.1.1 subvariant infections. Lower risk of severe clinical outcomes among individuals with Omicron variant infection should inform public health response amid establishment of the Omicron variant as the dominant SARS-CoV-2 lineage globally.

  View details for DOI 10.1038/s41591-022-01887-z

  View details for PubMedID 35675841

  View details for PubMedCentralID PMC10208005

• BNT162b2 Vaccine Effectiveness against Omicron in Children 5 to 11 Years of Age. The New England journal of medicine Cohen-Stavi, C. J., Magen, O., Barda, N., Yaron, S., Peretz, A., Netzer, D., Giaquinto, C., Judd, A., Leibovici, L., Hernán, M. A., Lipsitch, M., Reis, B. Y., Balicer, R. D., Dagan, N. 2022; 387 (3): 227-236

  Abstract

  Limited evidence is available on the real-world effectiveness of the BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) and specifically against infection with the omicron variant among children 5 to 11 years of age.Using data from the largest health care organization in Israel, we identified a cohort of children 5 to 11 years of age who were vaccinated on or after November 23, 2021, and matched them with unvaccinated controls to estimate the vaccine effectiveness of BNT162b2 among newly vaccinated children during the omicron wave. Vaccine effectiveness against documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and symptomatic Covid-19 was estimated after the first and second vaccine doses. The cumulative incidence of each outcome in the two study groups through January 7, 2022, was estimated with the use of the Kaplan-Meier estimator, and vaccine effectiveness was calculated as 1 minus the risk ratio. Vaccine effectiveness was also estimated in age subgroups.Among 136,127 eligible children who had been vaccinated during the study period, 94,728 were matched with unvaccinated controls. The estimated vaccine effectiveness against documented infection was 17% (95% confidence interval [CI], 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. The absolute risk difference between the study groups at days 7 to 21 after the second dose was 1905 events per 100,000 persons (95% CI, 1294 to 2440) for documented infection and 599 events per 100,000 persons (95% CI, 296 to 897) for symptomatic Covid-19. The estimated vaccine effectiveness against symptomatic Covid-19 was 18% (95% CI, -2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. We observed a trend toward higher vaccine effectiveness in the youngest age group (5 or 6 years of age) than in the oldest age group (10 or 11 years of age).Our findings suggest that as omicron was becoming the dominant variant, two doses of the BNT162b2 messenger RNA vaccine provided moderate protection against documented SARS-CoV-2 infection and symptomatic Covid-19 in children 5 to 11 years of age. (Funded by the European Union through the VERDI project and others.).

  View details for DOI 10.1056/NEJMoa2205011

  View details for PubMedID 35767475

  View details for PubMedCentralID PMC9258754

• Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies OPEN FORUM INFECTIOUS DISEASES Figueiredo, J. C., Hirsch, F. R., Kushi, L. H., Nembhard, W. N., Crawford, J. M., Mantis, N., Finster, L., Merin, N. M., Merchant, A., Reckamp, K. L., Melmed, G. Y., Braun, J., McGovern, D., Parekh, S., Corley, D. A., Zohoori, N., Amick, B. C., Du, R., Gregersen, P. K., Diamond, B., Taioli, E., Sariol, C., Espino, A., Weiskopf, D., Gifoni, A., Brien, J., Hanege, W., Lipsitch, M., Zidar, D. A., McAlearney, A., Wajnberg, A., LaBaer, J., Lewis, E., Binder, R. A., Moormann, A. M., Forconi, C., Forrester, S., Batista, J., Schieffelin, J., Kim, D., Biancon, G., VanOudenhove, J., Halene, S., Fan, R., Barouch, D. H., Alter, G., Pinninti, S., Boppana, S. B., Pati, S. K., Latting, M., Karaba, A. H., Roback, J., Sekaly, R., Neish, A., Brincks, A. M., Granger, D. A., Karger, A. B., Thyagarajan, B., Thomas, S. N., Klein, S. L., Cox, A. L., Lucas, T., Furr-Holden, D., Key, K., Jones, N., Wrammerr, J., Suthar, M., Wong, S., Bowman, N. M., Simon, V., Richardson, L. D., McBride, R., Krammer, F., Rana, M., Kennedy, J., Boehme, K., Forrest, C., Granger, S. W., Heaney, C. D., Lapinski, M., Wallet, S., Baric, R. S., Schifanella, L., Lopez, M., Fernandez, S., Kenah, E., Panchal, A. R., Britt, W. J., Sanz, I., Dhodapkar, M., Ahmed, R., Bartelt, L. A., Markmann, A. J., Lin, J. T., Hagan, R. S., Wolfgang, M. C., Skarbinski, J. 2022; 9 (6): ofac171

  Abstract

  Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies.In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders).Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes.In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

  View details for DOI 10.1093/ofid/ofac171

  View details for Web of Science ID 000815266400003

  View details for PubMedID 35765315

  View details for PubMedCentralID PMC9129196

• Wrong question and the wrong standard of proof. Journal of medical ethics Lipsitch, M. 2022; 48 (6): 378-379

  View details for DOI 10.1136/medethics-2022-108320

  View details for PubMedID 35444009

• Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. The New England journal of medicine Magen, O., Waxman, J. G., Makov-Assif, M., Vered, R., Dicker, D., Hernán, M. A., Lipsitch, M., Reis, B. Y., Balicer, R. D., Dagan, N. 2022; 386 (17): 1603-1614

  Abstract

  With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose.To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19-related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression.The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction-confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19-related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19-related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19-related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis.A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19-related outcomes among persons who had received a third dose at least 4 months earlier. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

  View details for DOI 10.1056/NEJMoa2201688

  View details for PubMedID 35417631

  View details for PubMedCentralID PMC9020581

• Indirect protection of children from SARS-CoV-2 infection through parental vaccination. Science (New York, N.Y.) Hayek, S., Shaham, G., Ben-Shlomo, Y., Kepten, E., Dagan, N., Nevo, D., Lipsitch, M., Reis, B. Y., Balicer, R. D., Barda, N. 2022; 375 (6585): 1155-1159

  Abstract

  Children not vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may still benefit from vaccines through protection from vaccinated contacts. We estimated the protection provided to children through parental vaccination with the BNT162b2 vaccine. We studied households without prior infection consisting of two parents and unvaccinated children, estimating the effect of parental vaccination on the risk of infection for unvaccinated children. We studied two periods separately-an early period (17 January 2021 to 28 March 2021; Alpha variant, two doses versus no vaccination) and a late period (11 July 2021 to 30 September 2021; Delta variant, booster dose versus two vaccine doses). We found that having a single vaccinated parent was associated with a 26.0 and a 20.8% decreased risk in the early and late periods, respectively, and having two vaccinated parents was associated with a 71.7 and a 58.1% decreased risk, respectively. Thus, parental vaccination confers substantial protection on unvaccinated children in the household.

  View details for DOI 10.1126/science.abm3087

  View details for PubMedID 35084938

  View details for PubMedCentralID PMC9799368

• Near real-time surveillance of the SARS-CoV-2 epidemic with incomplete data. PLoS computational biology De Salazar, P. M., Lu, F., Hay, J. A., Gómez-Barroso, D., Fernández-Navarro, P., Martínez, E. V., Astray-Mochales, J., Amillategui, R., García-Fulgueiras, A., Chirlaque, M. D., Sánchez-Migallón, A., Larrauri, A., Sierra, M. J., Lipsitch, M., Simón, F., Santillana, M., Hernán, M. A. 2022; 18 (3): e1009964

  Abstract

  When responding to infectious disease outbreaks, rapid and accurate estimation of the epidemic trajectory is critical. However, two common data collection problems affect the reliability of the epidemiological data in real time: missing information on the time of first symptoms, and retrospective revision of historical information, including right censoring. Here, we propose an approach to construct epidemic curves in near real time that addresses these two challenges by 1) imputation of dates of symptom onset for reported cases using a dynamically-estimated "backward" reporting delay conditional distribution, and 2) adjustment for right censoring using the NobBS software package to nowcast cases by date of symptom onset. This process allows us to obtain an approximation of the time-varying reproduction number (Rt) in real time. We apply this approach to characterize the early SARS-CoV-2 outbreak in two Spanish regions between March and April 2020. We evaluate how these real-time estimates compare with more complete epidemiological data that became available later. We explore the impact of the different assumptions on the estimates, and compare our estimates with those obtained from commonly used surveillance approaches. Our framework can help improve accuracy, quantify uncertainty, and evaluate frequently unstated assumptions when recovering the epidemic curves from limited data obtained from public health systems in other locations.

  View details for DOI 10.1371/journal.pcbi.1009964

  View details for PubMedID 35358171

  View details for PubMedCentralID PMC9004750

• Infections, hospitalisations, and deaths averted via a nationwide vaccination campaign using the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine in Israel: a retrospective surveillance study. The Lancet. Infectious diseases Haas, E. J., McLaughlin, J. M., Khan, F., Angulo, F. J., Anis, E., Lipsitch, M., Singer, S. R., Mircus, G., Brooks, N., Smaja, M., Pan, K., Southern, J., Swerdlow, D. L., Jodar, L., Levy, Y., Alroy-Preis, S. 2022; 22 (3): 357-366

  Abstract

  On Dec 20, 2020, Israel initiated a nationwide COVID-19 vaccination campaign for people aged 16 years and older and exclusively used the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine (tozinameran). We provide estimates of the number of SARS-CoV-2 infections and COVID-19-related admissions to hospital (ie, hospitalisations) and deaths averted by the nationwide vaccination campaign.In this retrospective surveillance study, we used national surveillance data routinely collected by the Israeli Ministry of Health from the first 112 days (Dec 20, 2020, up to our data cutoff of April 10, 2021) of Israel's vaccination campaign to estimate the averted burden of four outcomes: SARS-CoV-2 infections and COVID-19-related hospitalisations, severe or critical hospitalisations, and deaths. As part of the campaign, all individuals aged 16 years and older were eligible for inoculation with the BNT162b2 vaccine in a two-dose schedule 21 days apart. We estimated the direct effects of the immunisation programme for all susceptible individuals (ie, with no previous evidence of laboratory-confirmed SARS-CoV-2 infection) who were at least partly vaccinated (at least one dose and at least 14 days of follow-up after the first dose). We estimated the number of SARS-CoV-2 infection-related outcomes averted on the basis of cumulative daily, age-specific rate differences, comparing rates among unvaccinated individuals with those of at least partly vaccinated individuals for each of the four outcomes and the (age-specific) size of the susceptible population and proportion that was at least partly vaccinated.We estimated that Israel's vaccination campaign averted 158 665 (95% CI 144 640-172 690) SARS-CoV-2 infections, 24 597 (18 942-30 252) hospitalisations, 17 432 (12 770-22 094) severe or critical hospitalisations, and 5532 (3085-7982) deaths. 16 213 (65·9%) of 24 597 hospitalisations and 5035 (91·0%) of 5532 of deaths averted were estimated to be among those aged 65 years and older. We estimated 116 000 (73·1%) SARS-CoV-2 infections, 19 467 (79·1%) COVID-19-related hospitalisations, and 4351 (79%) deaths averted were accounted for by the fully vaccinated population.Without the national vaccination campaign, Israel probably would have had triple the number of hospitalisations and deaths compared with what actually occurred during its largest wave of the pandemic to date, and the health-care system might have become overwhelmed. Indirect effects and long-term benefits of the programme, which could be substantial, were not included in these estimates and warrant future research.Israel Ministry of Health and Pfizer.

  View details for DOI 10.1016/S1473-3099(21)00566-1

  View details for PubMedID 34562375

  View details for PubMedCentralID PMC8457761

• Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial - BCPP/Ya Tsie trial. eLife Magosi, L. E., Zhang, Y., Golubchik, T., DeGruttola, V., Tchetgen Tchetgen, E., Novitsky, V., Moore, J., Bachanas, P., Segolodi, T., Lebelonyane, R., Pretorius Holme, M., Moyo, S., Makhema, J., Lockman, S., Fraser, C., Essex, M. M., Lipsitch, M. 2022; 11

  Abstract

  Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence.To elucidate patterns of HIV spread in universal test-and-treat trials, we quantified the contribution of geographic-location, gender, age, and randomized-HIV-intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana. We sequenced HIV viral whole genomes from 5114 trial participants among the 30 trial communities.Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 - 56.7] vs. 3% [0.1 - 27.3]) than at baseline (7% [1.5 - 25.3] vs. 5% [0.9 - 22.9]) compatible with a benefit from treatment-as-prevention.Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.This study was supported by the National Institute of General Medical Sciences (U54GM088558), the Fogarty International Center (FIC) of the U.S. National Institutes of Health (D43 TW009610), and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention (CDC) (Cooperative agreements U01 GH000447 and U2G GH001911).

  View details for DOI 10.7554/eLife.72657

  View details for PubMedID 35229714

  View details for PubMedCentralID PMC8912920

• Analysis of multiple bacterial species and antibiotic classes reveals large variation in the association between seasonal antibiotic use and resistance. PLoS biology Sun, D. S., Kissler, S. M., Kanjilal, S., Olesen, S. W., Lipsitch, M., Grad, Y. H. 2022; 20 (3): e3001579

  Abstract

  Understanding how antibiotic use drives resistance is crucial for guiding effective strategies to limit the spread of resistance, but the use-resistance relationship across pathogens and antibiotics remains unclear. We applied sinusoidal models to evaluate the seasonal use-resistance relationship across 3 species (Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae) and 5 antibiotic classes (penicillins, macrolides, quinolones, tetracyclines, and nitrofurans) in Boston, Massachusetts. Outpatient use of all 5 classes and resistance in inpatient and outpatient isolates in 9 of 15 species-antibiotic combinations showed statistically significant amplitudes of seasonality (false discovery rate (FDR) < 0.05). While seasonal peaks in use varied by class, resistance in all 9 species-antibiotic combinations peaked in the winter and spring. The correlations between seasonal use and resistance thus varied widely, with resistance to all antibiotic classes being most positively correlated with use of the winter peaking classes (penicillins and macrolides). These findings challenge the simple model of antibiotic use independently selecting for resistance and suggest that stewardship strategies will not be equally effective across all species and antibiotics. Rather, seasonal selection for resistance across multiple antibiotic classes may be dominated by use of the most highly prescribed antibiotic classes, penicillins and macrolides.

  View details for DOI 10.1371/journal.pbio.3001579

  View details for PubMedID 35263322

  View details for PubMedCentralID PMC8936496

• Antibiotic prescribing across age groups in the Kaiser Permanente Northern California population in association with different diagnoses, and with influenza incidence, 2010-2018. Epidemiology and infection Goldstein, E., Fireman, B. H., Klein, N. P., Lipsitch, M., Ray, G. T. 2022; 150: e85

  Abstract

  There is limited information on the volume of antibiotic prescribing that is influenza-associated, resulting from influenza infections and their complications (such as streptococcal pharyngitis and otitis media). Here, we estimated age/diagnosis-specific proportions of antibiotic prescriptions (fills) for the Kaiser Permanente Northern California population during 2010-2018 that were influenza-associated. The proportion of influenza-associated antibiotic prescribing among all antibiotic prescribing was higher in children aged 5-17 years compared to children aged under 5 years, ranging from 1.4% [95% CI (0.7-2.1)] in aged <1 year to 2.7% (1.9-3.4) in aged 15-17 years. For adults aged over 20 years, the proportion of influenza-associated antibiotic prescribing among all antibiotic prescribing was lower, ranging from 0.7% (0.5-1) for aged 25-29 years to 1.6% (1.2-1.9) for aged 60-64 years. Most of the influenza-associated antibiotic prescribing in children aged under 10 years was for ear infections, while for age groups over 25 years, 45-84% of influenza-associated antibiotic prescribing was for respiratory diagnoses without a bacterial indication. This suggests a modest benefit of increasing influenza vaccination coverage for reducing antibiotic prescribing, as well as the potential benefit of other measures to reduce unnecessary antibiotic prescribing for respiratory diagnoses with no bacterial indication in persons aged over 25 years, both of which may further contribute to the mitigation of antimicrobial resistance.

  View details for DOI 10.1017/S0950268822000371

  View details for PubMedID 35506177

  View details for PubMedCentralID PMC9074113

• Risk of persistent and new clinical sequelae among adults aged 65 years and older during the post-acute phase of SARS-CoV-2 infection: retrospective cohort study. BMJ (Clinical research ed.) Cohen, K., Ren, S., Heath, K., Dasmariñas, M. C., Jubilo, K. G., Guo, Y., Lipsitch, M., Daugherty, S. E. 2022; 376: e068414

  Abstract

  To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection.Retrospective cohort study.UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results.Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490).The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19.Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae.The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.

  View details for DOI 10.1136/bmj-2021-068414

  View details for PubMedID 35140117

  View details for PubMedCentralID PMC8828141

• Antibiotic Use and Presumptive Pathogens in the Veterans Affairs Healthcare System. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Tedijanto, C., Nevers, M., Samore, M. H., Lipsitch, M. 2022; 74 (1): 105-112

  Abstract

  Empirical antibiotic use is common in the hospital. Here, we characterize patterns of antibiotic use, infectious diagnoses, and microbiological laboratory results among hospitalized patients and aim to quantify the proportion of antibiotic use that is potentially attributable to specific bacterial pathogens.We conducted an observational study using electronic health records from acute care facilities in the US Veterans Affairs Healthcare System. From October 2017 to September 2018, 482 381 hospitalizations for 332 657 unique patients that met all criteria were included. At least 1 antibiotic was administered at 202 037 (41.9%) of included hospital stays. We measured frequency of antibiotic use, microbiological specimen collection, and bacterial isolation by diagnosis category and antibiotic group. A tiered system based on specimen collection sites and diagnoses was used to attribute antibiotic use to presumptive causative organisms.Specimens were collected at 130 012 (64.4%) hospitalizations with any antibiotic use, and at least 1 bacterial organism was isolated at 35.1% of these stays. Frequency of bacterial isolation varied widely by diagnosis category and antibiotic group. Under increasingly lenient criteria, 10.2%-31.4% of 974 733 antibiotic days of therapy could be linked to a potential bacterial pathogen.Overall, the vast majority of antibiotic use could be linked to either an infectious diagnosis or microbiological specimen. Nearly one-half of antibiotic use occurred when there was a specimen collected but no bacterial organism identified, underscoring the need for rapid and improved diagnostics to optimize antibiotic use.

  View details for DOI 10.1093/cid/ciab170

  View details for PubMedID 33621326

  View details for PubMedCentralID PMC8752245

• SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact. Nature reviews. Immunology Lipsitch, M., Krammer, F., Regev-Yochay, G., Lustig, Y., Balicer, R. D. 2022; 22 (1): 57-65

  Abstract

  Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in fully vaccinated individuals are receiving intense scrutiny because of their importance in determining how long restrictions to control virus transmission will need to remain in place in highly vaccinated populations as well as in determining the need for additional vaccine doses or changes to the vaccine formulations and/or dosing intervals. Measurement of breakthrough infections is challenging outside of randomized, placebo-controlled, double-blind field trials. However, laboratory and observational studies are necessary to understand the impact of waning immunity, viral variants and other determinants of changing vaccine effectiveness against various levels of coronavirus disease 2019 (COVID-19) severity. Here, we describe the approaches being used to measure vaccine effectiveness and provide a synthesis of the burgeoning literature on the determinants of vaccine effectiveness and breakthrough rates. We argue that, rather than trying to tease apart the contributions of factors such as age, viral variants and time since vaccination, the rates of breakthrough infection are best seen as a consequence of the level of immunity at any moment in an individual, the variant to which that individual is exposed and the severity of disease being considered. We also address key open questions concerning the transition to endemicity, the potential need for altered vaccine formulations to track viral variants, the need to identify immune correlates of protection, and the public health challenges of using various tools to counter breakthrough infections, including boosters in an era of global vaccine shortages.

  View details for DOI 10.1038/s41577-021-00662-4

  View details for PubMedID 34876702

  View details for PubMedCentralID PMC8649989

• Population impact of SARS-CoV-2 variants with enhanced transmissibility and/or partial immune escape. Cell Bushman, M., Kahn, R., Taylor, B. P., Lipsitch, M., Hanage, W. P. 2021; 184 (26): 6229-6242.e18

  Abstract

  SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from acquired immunity. Much effort has been devoted to measuring these phenotypes, but understanding their impact on the course of the pandemic-especially that of immune escape-has remained a challenge. Here, we use a mathematical model to simulate the dynamics of wild-type and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility frequently increase epidemic severity, whereas those with partial immune escape either fail to spread widely or primarily cause reinfections and breakthrough infections. However, when these phenotypes are combined, a variant can continue spreading even as immunity builds up in the population, limiting the impact of vaccination and exacerbating the epidemic. These findings help explain the trajectories of past and present SARS-CoV-2 variants and may inform variant assessment and response in the future.

  View details for DOI 10.1016/j.cell.2021.11.026

  View details for PubMedID 34910927

  View details for PubMedCentralID PMC8603072

• How to Test Severe Acute Respiratory Syndrome Coronavirus 2 Vaccines Ethically Even After One Is Available. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Eyal, N., Lipsitch, M. 2021; 73 (12): 2332-2334

  Abstract

  Although vaccines against severe acute respiratory syndrome coronavirus 2 have now been found safe and efficacious, there remains an urgent global health need to test both these vaccines and additional vaccines against the same virus. Under variable conditions, either standard or unusual designs would for both familiar and often-missed reasons make continued testing possible and ethical.

  View details for DOI 10.1093/cid/ciab182

  View details for PubMedID 33639622

  View details for PubMedCentralID PMC7989578

• Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. Lancet (London, England) Barda, N., Dagan, N., Cohen, C., Hernán, M. A., Lipsitch, M., Kohane, I. S., Reis, B. Y., Balicer, R. D. 2021; 398 (10316): 2093-2100

  Abstract

  Many countries are experiencing a resurgence of COVID-19, driven predominantly by the delta (B.1.617.2) variant of SARS-CoV-2. In response, these countries are considering the administration of a third dose of mRNA COVID-19 vaccine as a booster dose to address potential waning immunity over time and reduced effectiveness against the delta variant. We aimed to use the data repositories of Israel's largest health-care organisation to evaluate the effectiveness of a third dose of the BNT162b2 mRNA vaccine for preventing severe COVID-19 outcomes.Using data from Clalit Health Services, which provides mandatory health-care coverage for over half of the Israeli population, individuals receiving a third vaccine dose between July 30, 2020, and Sept 23, 2021, were matched (1:1) to demographically and clinically similar controls who did not receive a third dose. Eligible participants had received the second vaccine dose at least 5 months before the recruitment date, had no previous documented SARS-CoV-2 infection, and had no contact with the health-care system in the 3 days before recruitment. Individuals who are health-care workers, live in long-term care facilities, or are medically confined to their homes were excluded. Primary outcomes were COVID-19-related admission to hospital, severe disease, and COVID-19-related death. The third dose effectiveness for each outcome was estimated as 1 - risk ratio using the Kaplan-Meier estimator.1 158 269 individuals were eligible to be included in the third dose group. Following matching, the third dose and control groups each included 728 321 individuals. Participants had a median age of 52 years (IQR 37-68) and 51% were female. The median follow-up time was 13 days (IQR 6-21) in both groups. Vaccine effectiveness evaluated at least 7 days after receipt of the third dose, compared with receiving only two doses at least 5 months ago, was estimated to be 93% (231 events for two doses vs 29 events for three doses; 95% CI 88-97) for admission to hospital, 92% (157 vs 17 events; 82-97) for severe disease, and 81% (44 vs seven events; 59-97) for COVID-19-related death.Our findings suggest that a third dose of the BNT162b2 mRNA vaccine is effective in protecting individuals against severe COVID-19-related outcomes, compared with receiving only two doses at least 5 months ago.The Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.

  View details for DOI 10.1016/S0140-6736(21)02249-2

  View details for PubMedID 34756184

  View details for PubMedCentralID PMC8555967

• Effectiveness of BNT162b2 mRNA COVID-19 vaccine against SARS-CoV-2 variant Beta (B.1.351) among persons identified through contact tracing in Israel: A prospective cohort study. EClinicalMedicine Singer, S. R., Angulo, F. J., Swerdlow, D. L., McLaughlin, J. M., Hazan, I., Ginish, N., Anis, E., Mendelson, E., Mor, O., Zuckerman, N. S., Erster, O., Southern, J., Pan, K., Mircus, G., Lipsitch, M., Haas, E. J., Jodar, L., Levy, Y., Alroy-Preis, S. 2021; 42: 101190

  Abstract

  SARS-CoV-2 variant Beta (B.1.351) was designated as a Variant of Concern (VoC) after becoming the dominant strain in South Africa and spreading internationally. BNT162b2 showed lower levels of neutralizing antibodies against Beta than against other strains raising concerns about effectiveness of vaccines against infections caused by Beta. We estimated BNT162b2 vaccine effectiveness (VE) against Beta infections in Israel, a country with high vaccine uptake.The Ministry of Health (MoH) identified Beta cases through mandatory reporting of SARS-CoV-2 cases and whole genome sequencing (WGS) of specimens from vaccination-breakthrough infections, reinfections, arriving international travelers, and a selection of other infected persons. A cohort analysis was conducted of exposure events of contacts of primary Beta cases. WGS was conducted on available PCR-positive specimens collected from contacts. VE estimates with 95% confidence intervals (CIs) against confirmed and probable Beta infections were determined by comparing infection risk between unvaccinated and fully-vaccinated (≥7 days after the second dose) contacts, and between unvaccinated and partially-vaccinated (<7 days after the second dose) contacts.MoH identified 310 Beta cases through Jun 27, 2021. During the study period (Dec 11, 2020 - Mar 25, 2021), 164 non-institutionalized primary Beta cases, with 552 contacts aged ≥16 years, were identified. 343/552 (62%) contacts were interviewed and tested. 71/343 (21%) contacts were PCR-positive. WGS was performed on 7/71 (10%) PCR-positive specimens; all were Beta. Among SARS-CoV-2-infected contacts, 48/71 (68%) were symptomatic, 10/71 (14%) hospitalized, and 2/71 (3%) died. Fully-vaccinated VE against confirmed or probable Beta infections was 72% (95% CI -5 - 97%; p=0·04) and against symptomatic confirmed or probable Beta infections was 100% (95% CI 19 - 100%; p=0·01). There was no evidence of protection in partially-vaccinated contacts.In a prospective observational study, two doses of BNT162b2 were effective against confirmed and probable Beta infections. Through the end of June 2021, introductions of Beta did not interrupt control of the pandemic in Israel.Israel Ministry of Health and Pfizer.

  View details for DOI 10.1016/j.eclinm.2021.101190

  View details for PubMedID 34870134

  View details for PubMedCentralID PMC8628463

• Effectiveness of BNT162b2 Vaccine against Delta Variant in Adolescents. The New England journal of medicine Reis, B. Y., Barda, N., Leshchinsky, M., Kepten, E., Hernán, M. A., Lipsitch, M., Dagan, N., Balicer, R. D. 2021; 385 (22): 2101-2103

  View details for DOI 10.1056/NEJMc2114290

  View details for PubMedID 34670036

  View details for PubMedCentralID PMC8552532

• Estimating Vaccine Efficacy Against Transmission via Effect on Viral Load. Epidemiology (Cambridge, Mass.) Kennedy-Shaffer, L., Kahn, R., Lipsitch, M. 2021; 32 (6): 820-828

  Abstract

  Determining policies to end the SARS-CoV-2 pandemic will require an understanding of the efficacy and effectiveness (hereafter, efficacy) of vaccines. Beyond the efficacy against severe disease and symptomatic and asymptomatic infection, understanding vaccine efficacy against virus transmission, including efficacy against transmission of different viral variants, will help model epidemic trajectory and determine appropriate control measures. Recent studies have proposed using random virologic testing in individual randomized controlled trials to improve estimation of vaccine efficacy against infection. We propose to further use the viral load measures from these tests to estimate efficacy against transmission. This estimation requires a model of the relationship between viral load and transmissibility and assumptions about the vaccine effect on transmission and the progress of the epidemic. We describe these key assumptions, potential violations of them, and solutions that can be implemented to mitigate these violations. Assessing these assumptions and implementing this random sampling, with viral load measures, will enable better estimation of the crucial measure of vaccine efficacy against transmission.

  View details for DOI 10.1097/EDE.0000000000001415

  View details for PubMedID 34469363

  View details for PubMedCentralID PMC8478108

• Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. The New England journal of medicine Bergwerk, M., Gonen, T., Lustig, Y., Amit, S., Lipsitch, M., Cohen, C., Mandelboim, M., Levin, E. G., Rubin, C., Indenbaum, V., Tal, I., Zavitan, M., Zuckerman, N., Bar-Chaim, A., Kreiss, Y., Regev-Yochay, G. 2021; 385 (16): 1474-1484

  Abstract

  Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.

  View details for DOI 10.1056/NEJMoa2109072

  View details for PubMedID 34320281

  View details for PubMedCentralID PMC8362591

• Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in pregnancy. Nature medicine Dagan, N., Barda, N., Biron-Shental, T., Makov-Assif, M., Key, C., Kohane, I. S., Hernán, M. A., Lipsitch, M., Hernandez-Diaz, S., Reis, B. Y., Balicer, R. D. 2021; 27 (10): 1693-1695

  Abstract

  To evaluate the effectiveness of the BNT162b2 messenger RNA vaccine in pregnant women, we conducted an observational cohort study of pregnant women aged 16 years or older, with no history of SARS-CoV-2, who were vaccinated between 20 December 2020 and 3 June 2021. A total of 10,861 vaccinated pregnant women were matched to 10,861 unvaccinated pregnant controls using demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic COVID-19, COVID-19-related hospitalization, severe illness and death. Estimated vaccine effectiveness from 7 through to 56 d after the second dose was 96% (95% confidence interval 89-100%) for any documented infection, 97% (91-100%) for infections with documented symptoms and 89% (43-100%) for COVID-19-related hospitalization. Only one event of severe illness was observed in the unvaccinated group and no deaths were observed in either group. In summary, the BNT162b2 mRNA vaccine was estimated to have high vaccine effectiveness in pregnant women, which is similar to the effectiveness estimated in the general population.

  View details for DOI 10.1038/s41591-021-01490-8

  View details for PubMedID 34493859

• Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. The New England journal of medicine Barda, N., Dagan, N., Ben-Shlomo, Y., Kepten, E., Waxman, J., Ohana, R., Hernán, M. A., Lipsitch, M., Kohane, I., Netzer, D., Reis, B. Y., Balicer, R. D. 2021; 385 (12): 1078-1090

  Abstract

  Preapproval trials showed that messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed.We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan-Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2-infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses.In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia.In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).

  View details for DOI 10.1056/NEJMoa2110475

  View details for PubMedID 34432976

  View details for PubMedCentralID PMC8427535

• Leveraging Pathogen Sequence and Contact Tracing Data to Enhance Vaccine Trials in Emerging Epidemics. Epidemiology (Cambridge, Mass.) Kahn, R., Wang, R., Leavitt, S. V., Hanage, W. P., Lipsitch, M. 2021; 32 (5): 698-704

  Abstract

  Advance planning of vaccine trials conducted during outbreaks increases our ability to rapidly define the efficacy and potential impact of a vaccine. Vaccine efficacy against infectiousness (VEI) is an important measure for understanding a vaccine's full impact, yet it is currently not identifiable in many trial designs because it requires knowledge of infectors' vaccination status. Recent advances in genomics have improved our ability to reconstruct transmission networks. We aim to assess if augmenting trials with pathogen sequence and contact tracing data can permit them to estimate VEI.We develop a transmission model with a vaccine trial in an outbreak setting, incorporate pathogen sequence data and contact tracing data, and assign probabilities to likely infectors. We then propose and evaluate the performance of an estimator of VEI.We find that under perfect knowledge of infector-infectee pairs, we are able to accurately estimate VEI. Use of sequence data results in imperfect reconstruction of transmission networks, biasing estimates of VEI towards the null, with approaches using deep sequence data performing better than approaches using consensus sequence data. Inclusion of contact tracing data reduces the bias.Pathogen genomics enhance identifiability of VEI, but imperfect transmission network reconstruction biases estimate toward the null and limits our ability to detect VEI. Given the consistent direction of the bias, estimates obtained from trials using these methods will provide lower bounds on the true VEI. A combination of sequence and epidemiologic data results in the most accurate estimates, underscoring the importance of contact tracing.

  View details for DOI 10.1097/EDE.0000000000001367

  View details for PubMedID 34039898

  View details for PubMedCentralID PMC8338748

• Assessing the feasibility of Nipah vaccine efficacy trials based on previous outbreaks in Bangladesh. Vaccine Nikolay, B., Ribeiro Dos Santos, G., Lipsitch, M., Rahman, M., Luby, S. P., Salje, H., Gurley, E. S., Cauchemez, S. 2021

  Abstract

  BACKGROUND: Nipah virus (NiV) is an emerging, bat-borne pathogen that can be transmitted from person-to-person. Vaccines are currently being developed for NiV, and studies have been funded to evaluate their safety and immunogenicity. An important unanswered question is whether it will be possible to evaluate the efficacy of vaccine candidates in phase III clinical trials in a context where spillovers from the zoonotic reservoir are infrequent and associated with small outbreaks. The objective of this study was to investigate the feasibility of conducting a phase III vaccine trial in Bangladesh, the only country regularly reporting NiV cases.METHODS: We used simulations based on previously observed NiV cases from Bangladesh, an assumed vaccine efficacy of 90% and other NiV vaccine target characteristics, to compare three vaccination study designs: (i) cluster randomized ring vaccination, (ii) cluster randomized mass vaccination, and (iii) an observational case-control study design.RESULTS: The simulations showed that, assuming a ramp-up period of 10days and a mean hospitalization delay of 4days,a cluster-randomized ring vaccination trial would require 516years and over 163,000 vaccine doses to run a ring vaccination trial under current epidemic conditions. A cluster-randomized mass vaccination trial in the two most affected districts would take 43years and 1.83 million vaccine doses. An observational case-control design in these two districts would require seven years and 2.5 million vaccine doses.DISCUSSION: Without a change in the epidemiology of NiV, ring vaccination or mass vaccination trials are unlikely to be completed within a reasonable time window. In this light, the remaining options are: (i) not conducting a phase III trial until the epidemiology of NiV changes, (ii) identifying alternative ways to licensure such as observational studies or controlled studies in animals such as in the US Food and Drug Administration's (FDA) Animal Rule.

  View details for DOI 10.1016/j.vaccine.2021.08.027

  View details for PubMedID 34426025

• Leveraging Vaccines to Reduce Antibiotic Use and Prevent Antimicrobial Resistance: A World Health Organization Action Framework. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Vekemans, J., Hasso-Agopsowicz, M., Kang, G., Hausdorff, W. P., Fiore, A., Tayler, E., Klemm, E. J., Laxminarayan, R., Srikantiah, P., Friede, M., Lipsitch, M. 2021; 73 (4): e1011-e1017

  Abstract

  This Action Framework identifies priority actions to prevent antimicrobial-resistant (AMR) through expanding the use of licensed vaccines, developing new vaccines that contribute to the prevention and control of AMR, and expanding knowledge about the impact of vaccines on AMR.

  View details for DOI 10.1093/cid/ciab062

  View details for PubMedID 33493317

  View details for PubMedCentralID PMC8366823

• Decreased infectivity following BNT162b2 vaccination: A prospective cohort study in Israel. The Lancet regional health. Europe Regev-Yochay, G., Amit, S., Bergwerk, M., Lipsitch, M., Leshem, E., Kahn, R., Lustig, Y., Cohen, C., Doolman, R., Ziv, A., Novikov, I., Rubin, C., Gimpelevich, I., Huppert, A., Rahav, G., Afek, A., Kreiss, Y. 2021; 7: 100150

  Abstract

  BNT162b2 was shown to be 92% effective in preventing COVID-19. Prioritizing vaccine rollout, and achievement of herd immunity depend on SARS-CoV-2 transmission reduction. The vaccine's effect on infectivity is thus a critical priority.Among all 9650 HCW of a large tertiary medical center in Israel, we calculated the prevalence of positive SARS-CoV-2 qRT-PCR cases with asymptomatic presentation, tested following known or presumed exposure and the infectious subset (N-gene-Ct-value<30) of these. Additionally, infection incidence rates were calculated for symptomatic cases and infectious (Ct<30) cases. Vaccine effectiveness within three months of vaccine rollout was measured as one minus the relative risk or rate ratio, respectively. To further assess infectiousness, we compared the mean Ct-value and the proportion of infections with a positive SARS-CoV-2 antigen test of vaccinated vs. unvaccinated. The correlation between IgG levels within the week before detection and Ct level was assessed.Reduced prevalence among fully vaccinated HCW was observed for (i) infections detected due to exposure, with asymptomatic presentation (VE(i)=65.1%, 95%CI 45-79%), (ii) the presumed infectious (Ct<30) subset of these (VE(ii)=69.6%, 95%CI 43-84%) (iii) never-symptomatic infections (VE(iii)=72.3%, 95%CI 48-86%), and (iv) the presumed infectious (Ct<30) subset (VE(iv)=83.0%, 95%CI 51-94%).Incidence of (v) symptomatic and (vi) symptomatic-infectious cases was significantly lower among fully vaccinated vs. unvaccinated individuals (VE(v)= 89.7%, 95%CI 84-94%, VE(vi)=88.1%, 95%CI 80-95%).The mean Ct-value was significantly higher in vaccinated vs. unvaccinated (27.3±1.2 vs. 22.2±1.0, p<0.001) and the proportion of positive SARS-CoV-2 antigen tests was also significantly lower among vaccinated vs. unvaccinated PCR-positive HCW (80% vs. 31%, p<0.001). Lower infectivity was correlated with higher IgG concentrations (R=0.36, p=0.01).These results suggest that BNT162b2 is moderately to highly effective in reducing infectivity, via preventing infection and through reducing viral shedding.Sheba Medical Center, Israel.

  View details for DOI 10.1016/j.lanepe.2021.100150

  View details for PubMedID 34250518

  View details for PubMedCentralID PMC8261633

• Estimating epidemiologic dynamics from cross-sectional viral load distributions. Science (New York, N.Y.) Hay, J. A., Kennedy-Shaffer, L., Kanjilal, S., Lennon, N. J., Gabriel, S. B., Lipsitch, M., Mina, M. J. 2021; 373 (6552)

  Abstract

  Estimating an epidemic's trajectory is crucial for developing public health responses to infectious diseases, but case data used for such estimation are confounded by variable testing practices. We show that the population distribution of viral loads observed under random or symptom-based surveillance-in the form of cycle threshold (Ct) values obtained from reverse transcription quantitative polymerase chain reaction testing-changes during an epidemic. Thus, Ct values from even limited numbers of random samples can provide improved estimates of an epidemic's trajectory. Combining data from multiple such samples improves the precision and robustness of this estimation. We apply our methods to Ct values from surveillance conducted during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in a variety of settings and offer alternative approaches for real-time estimates of epidemic trajectories for outbreak management and response.

  View details for DOI 10.1126/science.abh0635

  View details for PubMedID 34083451

  View details for PubMedCentralID PMC8527857

• Interpreting vaccine efficacy trial results for infection and transmission. Vaccine Lipsitch, M., Kahn, R. 2021; 39 (30): 4082-4088

  Abstract

  Randomized controlled trials (RCTs) have shown high efficacy of multiple vaccines against SARS-CoV-2 disease (COVID-19), and recent studies have shown the vaccines are also effective against infection. Evidence for the effect of each of these vaccines on ability to transmit the virus is also beginning to emerge. We describe an approach to estimate these vaccines' effects on viral positivity, a prevalence measure which under the reasonable assumption that vaccinated individuals who become infected are no more infectious than unvaccinated individuals forms a lower bound on efficacy against transmission. Specifically, we recommend separate analysis of positive tests triggered by symptoms (usually the primary RCT outcome) and cross-sectional prevalence of positive tests obtained regardless of symptoms. The odds ratio of carriage for vaccine vs. placebo provides an unbiased estimate of vaccine effectiveness against viral positivity, under certain assumptions, and we show through simulations that likely departures from these assumptions will only modestly bias this estimate. Applying this approach to published data from the RCT of the Moderna vaccine, we estimate that one dose of vaccine reduces the potential for transmission by at least 61%, possibly considerably more. We describe how these approaches can be translated into observational studies of vaccine effectiveness.

  View details for DOI 10.1016/j.vaccine.2021.06.011

  View details for PubMedID 34130883

  View details for PubMedCentralID PMC8197448

• Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization. Vaccine Patel, M. K., Bergeri, I., Bresee, J. S., Cowling, B. J., Crowcroft, N. S., Fahmy, K., Hirve, S., Kang, G., Katz, M. A., Lanata, C. F., L'Azou Jackson, M., Joshi, S., Lipsitch, M., Mwenda, J. M., Nogareda, F., Orenstein, W. A., Ortiz, J. R., Pebody, R., Schrag, S. J., Smith, P. G., Srikantiah, P., Subissi, L., Valenciano, M., Vaughn, D. W., Verani, J. R., Wilder-Smith, A., Feikin, D. R. 2021; 39 (30): 4013-4024

  Abstract

  Phase 3 randomized-controlled trials have provided promising results of COVID-19 vaccine efficacy, ranging from 50 to 95% against symptomatic disease as the primary endpoints, resulting in emergency use authorization/listing for several vaccines. However, given the short duration of follow-up during the clinical trials, strict eligibility criteria, emerging variants of concern, and the changing epidemiology of the pandemic, many questions still remain unanswered regarding vaccine performance. Post-introduction vaccine effectiveness evaluations can help us to understand the vaccine's effect on reducing infection and disease when used in real-world conditions. They can also address important questions that were either not studied or were incompletely studied in the trials and that will inform evolving vaccine policy, including assessment of the duration of effectiveness; effectiveness in key subpopulations, such as the very old or immunocompromised; against severe disease and death due to COVID-19; against emerging SARS-CoV-2 variants of concern; and with different vaccination schedules, such as number of doses and varying dosing intervals. WHO convened an expert panel to develop interim best practice guidance for COVID-19 vaccine effectiveness evaluations. We present a summary of the interim guidance, including discussion of different study designs, priority outcomes to evaluate, potential biases, existing surveillance platforms that can be used, and recommendations for reporting results.

  View details for DOI 10.1016/j.vaccine.2021.05.099

  View details for PubMedID 34119350

  View details for PubMedCentralID PMC8166525

• Estimating the cumulative incidence of COVID-19 in the United States using influenza surveillance, virologic testing, and mortality data: Four complementary approaches. PLoS computational biology Lu, F. S., Nguyen, A. T., Link, N. B., Molina, M., Davis, J. T., Chinazzi, M., Xiong, X., Vespignani, A., Lipsitch, M., Santillana, M. 2021; 17 (6): e1008994

  Abstract

  Effectively designing and evaluating public health responses to the ongoing COVID-19 pandemic requires accurate estimation of the prevalence of COVID-19 across the United States (US). Equipment shortages and varying testing capabilities have however hindered the usefulness of the official reported positive COVID-19 case counts. We introduce four complementary approaches to estimate the cumulative incidence of symptomatic COVID-19 in each state in the US as well as Puerto Rico and the District of Columbia, using a combination of excess influenza-like illness reports, COVID-19 test statistics, COVID-19 mortality reports, and a spatially structured epidemic model. Instead of relying on the estimate from a single data source or method that may be biased, we provide multiple estimates, each relying on different assumptions and data sources. Across our four approaches emerges the consistent conclusion that on April 4, 2020, the estimated case count was 5 to 50 times higher than the official positive test counts across the different states. Nationally, our estimates of COVID-19 symptomatic cases as of April 4 have a likely range of 2.3 to 4.8 million, with possibly as many as 7.6 million cases, up to 25 times greater than the cumulative confirmed cases of about 311,000. Extending our methods to May 16, 2020, we estimate that cumulative symptomatic incidence ranges from 4.9 to 10.1 million, as opposed to 1.5 million positive test counts. The proposed combination of approaches may prove useful in assessing the burden of COVID-19 during resurgences in the US and other countries with comparable surveillance systems.

  View details for DOI 10.1371/journal.pcbi.1008994

  View details for PubMedID 34138845

• Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study. BMJ (Clinical research ed.) Daugherty, S. E., Guo, Y., Heath, K., Dasmariñas, M. C., Jubilo, K. G., Samranvedhya, J., Lipsitch, M., Cohen, K. 2021; 373: n1098

  Abstract

  To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65.Retrospective cohort study.Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database.Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness.More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated.14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group.The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

  View details for DOI 10.1136/bmj.n1098

  View details for PubMedID 34011492

  View details for PubMedCentralID PMC8132065

• Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics. eLife Ma, K. C., Menkir, T. F., Kissler, S., Grad, Y. H., Lipsitch, M. 2021; 10

  Abstract

  The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown.Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk change across groups.A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites.Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection.K.C.M. was supported by National Science Foundation GRFP grant DGE1745303. Y.H.G. and M.L. were funded by the Morris-Singer Foundation. M.L. was supported by SeroNet cooperative agreement U01 CA261277.

  View details for DOI 10.7554/eLife.66601

  View details for PubMedID 34003112

  View details for PubMedCentralID PMC8221808

• Investigate the origins of COVID-19. Science (New York, N.Y.) Bloom, J. D., Chan, Y. A., Baric, R. S., Bjorkman, P. J., Cobey, S., Deverman, B. E., Fisman, D. N., Gupta, R., Iwasaki, A., Lipsitch, M., Medzhitov, R., Neher, R. A., Nielsen, R., Patterson, N., Stearns, T., van Nimwegen, E., Worobey, M., Relman, D. A. 2021; 372 (6543): 694

  View details for DOI 10.1126/science.abj0016

  View details for PubMedID 33986172

• Concerns about SARS-CoV-2 evolution should not hold back efforts to expand vaccination. Nature reviews. Immunology Cobey, S., Larremore, D. B., Grad, Y. H., Lipsitch, M. 2021; 21 (5): 330-335

  Abstract

  When vaccines are in limited supply, expanding the number of people who receive some vaccine, such as by halving doses or increasing the interval between doses, can reduce disease and mortality compared with concentrating available vaccine doses in a subset of the population. A corollary of such dose-sparing strategies is that the vaccinated individuals may have less protective immunity. Concerns have been raised that expanding the fraction of the population with partial immunity to SARS-CoV-2 could increase selection for vaccine-escape variants, ultimately undermining vaccine effectiveness. We argue that, although this is possible, preliminary evidence instead suggests such strategies should slow the rate of viral escape from vaccine or naturally induced immunity. As long as vaccination provides some protection against escape variants, the corresponding reduction in prevalence and incidence should reduce the rate at which new variants are generated and the speed of adaptation. Because there is little evidence of efficient immune selection of SARS-CoV-2 during typical infections, these population-level effects are likely to dominate vaccine-induced evolution.

  View details for DOI 10.1038/s41577-021-00544-9

  View details for PubMedID 33795856

  View details for PubMedCentralID PMC8014893

• Negative frequency-dependent selection and asymmetrical transformation stabilise multi-strain bacterial population structures. The ISME journal Harrow, G. L., Lees, J. A., Hanage, W. P., Lipsitch, M., Corander, J., Colijn, C., Croucher, N. J. 2021; 15 (5): 1523-1538

  Abstract

  Streptococcus pneumoniae can be divided into many strains, each a distinct set of isolates sharing similar core and accessory genomes, which co-circulate within the same hosts. Previous analyses suggested the short-term vaccine-associated dynamics of S. pneumoniae strains may be mediated through multi-locus negative frequency-dependent selection (NFDS), which maintains accessory loci at equilibrium frequencies. Long-term simulations demonstrated NFDS stabilised clonally-evolving multi-strain populations through preventing the loss of variation through drift, based on polymorphism frequencies, pairwise genetic distances and phylogenies. However, allowing symmetrical recombination between isolates evolving under multi-locus NFDS generated unstructured populations of diverse genotypes. Replication of the observed data improved when multi-locus NFDS was combined with recombination that was instead asymmetrical, favouring deletion of accessory loci over insertion. This combination separated populations into strains through outbreeding depression, resulting from recombinants with reduced accessory genomes having lower fitness than their parental genotypes. Although simplistic modelling of recombination likely limited these simulations' ability to maintain some properties of genomic data as accurately as those lacking recombination, the combination of asymmetrical recombination and multi-locus NFDS could restore multi-strain population structures from randomised initial populations. As many bacteria inhibit insertions into their chromosomes, this combination may commonly underlie the co-existence of strains within a niche.

  View details for DOI 10.1038/s41396-020-00867-w

  View details for PubMedID 33408365

  View details for PubMedCentralID PMC8115253

• BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. The New England journal of medicine Dagan, N., Barda, N., Kepten, E., Miron, O., Perchik, S., Katz, M. A., Hernán, M. A., Lipsitch, M., Reis, B., Balicer, R. D. 2021; 384 (15): 1412-1423

  Abstract

  As mass vaccination campaigns against coronavirus disease 2019 (Covid-19) commence worldwide, vaccine effectiveness needs to be assessed for a range of outcomes across diverse populations in a noncontrolled setting. In this study, data from Israel's largest health care organization were used to evaluate the effectiveness of the BNT162b2 mRNA vaccine.All persons who were newly vaccinated during the period from December 20, 2020, to February 1, 2021, were matched to unvaccinated controls in a 1:1 ratio according to demographic and clinical characteristics. Study outcomes included documented infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), symptomatic Covid-19, Covid-19-related hospitalization, severe illness, and death. We estimated vaccine effectiveness for each outcome as one minus the risk ratio, using the Kaplan-Meier estimator.Each study group included 596,618 persons. Estimated vaccine effectiveness for the study outcomes at days 14 through 20 after the first dose and at 7 or more days after the second dose was as follows: for documented infection, 46% (95% confidence interval [CI], 40 to 51) and 92% (95% CI, 88 to 95); for symptomatic Covid-19, 57% (95% CI, 50 to 63) and 94% (95% CI, 87 to 98); for hospitalization, 74% (95% CI, 56 to 86) and 87% (95% CI, 55 to 100); and for severe disease, 62% (95% CI, 39 to 80) and 92% (95% CI, 75 to 100), respectively. Estimated effectiveness in preventing death from Covid-19 was 72% (95% CI, 19 to 100) for days 14 through 20 after the first dose. Estimated effectiveness in specific subpopulations assessed for documented infection and symptomatic Covid-19 was consistent across age groups, with potentially slightly lower effectiveness in persons with multiple coexisting conditions.This study in a nationwide mass vaccination setting suggests that the BNT162b2 mRNA vaccine is effective for a wide range of Covid-19-related outcomes, a finding consistent with that of the randomized trial.

  View details for DOI 10.1056/NEJMoa2101765

  View details for PubMedID 33626250

  View details for PubMedCentralID PMC7944975

• Testing SARS-CoV-2 vaccine efficacy through deliberate natural viral exposure. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases Eyal, N., Lipsitch, M. 2021; 27 (3): 372-377

  Abstract

  A vaccine trial with a conventional challenge design can be very fast once it starts, but it requires a long prior process, in part to grow and standardize challenge virus in the laboratory. This detracts somewhat from its overall promise for accelerated efficacy testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidates, and from the ability of developing countries and small companies to conduct it.We set out to identify a challenge design that avoids this part of the long prior process.Literature in trial design (including a proof of concept flu challenge trial by B. Killingley et al.), vaccinology, medical ethics, and various aspects of COVID response.A challenge design with deliberate natural viral exposure avoids the need to grow culture. This new design is described and compared both to a conventional challenge design and to a conventional phase III field trial. In comparison, the proposed design has ethical, scientific, and feasibility strengths.The proposed new design should be considered for future vaccine trials.

  View details for DOI 10.1016/j.cmi.2020.12.032

  View details for PubMedID 33421580

  View details for PubMedCentralID PMC7787506

• Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. Science (New York, N.Y.) Bubar, K. M., Reinholt, K., Kissler, S. M., Lipsitch, M., Cobey, S., Grad, Y. H., Larremore, D. B. 2021; 371 (6532): 916-921

  Abstract

  Limited initial supply of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine raises the question of how to prioritize available doses. We used a mathematical model to compare five age-stratified prioritization strategies. A highly effective transmission-blocking vaccine prioritized to adults ages 20 to 49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults greater than 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact. Although maximum impact prioritization strategies were broadly consistent across countries, transmission rates, vaccination rollout speeds, and estimates of naturally acquired immunity, this framework can be used to compare impacts of prioritization strategies across contexts.

  View details for DOI 10.1126/science.abe6959

  View details for PubMedID 33479118

  View details for PubMedCentralID PMC7963218

• On the Effect of Age on the Transmission of SARS-CoV-2 in Households, Schools, and the Community. The Journal of infectious diseases Goldstein, E., Lipsitch, M., Cevik, M. 2021; 223 (3): 362-369

  Abstract

  There is limited information on the effect of age on the transmission of SARS-CoV-2 infection in different settings.We reviewed published studies/data on detection of SARS-CoV-2 infection in contacts of COVID-19 cases, serological studies, and studies of infections in schools.Compared to younger/middle-aged adults, susceptibility to infection for children younger than 10 years is estimated to be significantly lower, while estimated susceptibility to infection in adults older than 60 years is higher. Serological studies suggest that younger adults (particularly those younger than 35 years) often have high cumulative incidence of SARS-CoV-2 infection in the community. There is some evidence that given limited control measures, SARS-CoV-2 may spread robustly in secondary/high schools, and to a lesser degree in primary schools, with class size possibly affecting that spread. There is also evidence of more limited spread in schools when some mitigation measures are implemented. Several potential biases that may affect these studies are discussed.Mitigation measures should be implemented when opening schools, particularly secondary/high schools. Efforts should be undertaken to diminish mixing in younger adults, particularly individuals aged 18-35 years, to mitigate the spread of the epidemic in the community.

  View details for DOI 10.1093/infdis/jiaa691

  View details for PubMedID 33119738

  View details for PubMedCentralID PMC7665686

• How to detect and reduce potential sources of biases in studies of SARS-CoV-2 and COVID-19. European journal of epidemiology Accorsi, E. K., Qiu, X., Rumpler, E., Kennedy-Shaffer, L., Kahn, R., Joshi, K., Goldstein, E., Stensrud, M. J., Niehus, R., Cevik, M., Lipsitch, M. 2021; 36 (2): 179-196

  Abstract

  In response to the coronavirus disease (COVID-19) pandemic, public health scientists have produced a large and rapidly expanding body of literature that aims to answer critical questions, such as the proportion of the population in a geographic area that has been infected; the transmissibility of the virus and factors associated with high infectiousness or susceptibility to infection; which groups are the most at risk of infection, morbidity and mortality; and the degree to which antibodies confer protection to re-infection. Observational studies are subject to a number of different biases, including confounding, selection bias, and measurement error, that may threaten their validity or influence the interpretation of their results. To assist in the critical evaluation of a vast body of literature and contribute to future study design, we outline and propose solutions to biases that can occur across different categories of observational studies of COVID-19. We consider potential biases that could occur in five categories of studies: (1) cross-sectional seroprevalence, (2) longitudinal seroprotection, (3) risk factor studies to inform interventions, (4) studies to estimate the secondary attack rate, and (5) studies that use secondary attack rates to make inferences about infectiousness and susceptibility.

  View details for DOI 10.1007/s10654-021-00727-7

  View details for PubMedID 33634345

  View details for PubMedCentralID PMC7906244

• The Ethics of Continuing Placebo in SARS-CoV-2 Vaccine Trials. JAMA Rid, A., Lipsitch, M., Miller, F. G. 2021; 325 (3): 219-220

  View details for DOI 10.1001/jama.2020.25053

  View details for PubMedID 33315080

• Nowcasting for Real-Time COVID-19 Tracking in New York City: An Evaluation Using Reportable Disease Data From Early in the Pandemic. JMIR public health and surveillance Greene, S. K., McGough, S. F., Culp, G. M., Graf, L. E., Lipsitch, M., Menzies, N. A., Kahn, R. 2021; 7 (1): e25538

  Abstract

  Nowcasting approaches enhance the utility of reportable disease data for trend monitoring by correcting for delays, but implementation details affect accuracy.To support real-time COVID-19 situational awareness, the New York City Department of Health and Mental Hygiene used nowcasting to account for testing and reporting delays. We conducted an evaluation to determine which implementation details would yield the most accurate estimated case counts.A time-correlated Bayesian approach called Nowcasting by Bayesian Smoothing (NobBS) was applied in real time to line lists of reportable disease surveillance data, accounting for the delay from diagnosis to reporting and the shape of the epidemic curve. We retrospectively evaluated nowcasting performance for confirmed case counts among residents diagnosed during the period from March to May 2020, a period when the median reporting delay was 2 days.Nowcasts with a 2-week moving window and a negative binomial distribution had lower mean absolute error, lower relative root mean square error, and higher 95% prediction interval coverage than nowcasts conducted with a 3-week moving window or with a Poisson distribution. Nowcasts conducted toward the end of the week outperformed nowcasts performed earlier in the week, given fewer patients diagnosed on weekends and lack of day-of-week adjustments. When estimating case counts for weekdays only, metrics were similar across days when the nowcasts were conducted, with Mondays having the lowest mean absolute error of 183 cases in the context of an average daily weekday case count of 2914.Nowcasting using NobBS can effectively support COVID-19 trend monitoring. Accounting for overdispersion, shortening the moving window, and suppressing diagnoses on weekends-when fewer patients submitted specimens for testing-improved the accuracy of estimated case counts. Nowcasting ensured that recent decreases in observed case counts were not overinterpreted as true declines and supported officials in anticipating the magnitude and timing of hospitalizations and deaths and allocating resources geographically.

  View details for DOI 10.2196/25538

  View details for PubMedID 33406053

  View details for PubMedCentralID PMC7812916

• Estimating internationally imported cases during the early COVID-19 pandemic. Nature communications Menkir, T. F., Chin, T., Hay, J. A., Surface, E. D., De Salazar, P. M., Buckee, C. O., Watts, A., Khan, K., Sherbo, R., Yan, A. W., Mina, M. J., Lipsitch, M., Niehus, R. 2021; 12 (1): 311

  Abstract

  Early in the COVID-19 pandemic, predictions of international outbreaks were largely based on imported cases from Wuhan, China, potentially missing imports from other cities. We provide a method, combining daily COVID-19 prevalence and flight passenger volume, to estimate importations from 18 Chinese cities to 43 international destinations, including 26 in Africa. Global case importations from China in early January came primarily from Wuhan, but the inferred source shifted to other cities in mid-February, especially for importations to African destinations. We estimate that 10.4 (6.2 - 27.1) COVID-19 cases were imported to these African destinations, which exhibited marked variation in their magnitude and main sources of importation. We estimate that 90% of imported cases arrived between 17 January and 7 February, prior to the first case detections. Our results highlight the dynamic role of source locations, which can help focus surveillance and response efforts.

  View details for DOI 10.1038/s41467-020-20219-8

  View details for PubMedID 33436574

  View details for PubMedCentralID PMC7804934

• Determinants of Staphylococcus aureus carriage in the developing infant nasal microbiome. Genome biology Accorsi, E. K., Franzosa, E. A., Hsu, T., Joice Cordy, R., Maayan-Metzger, A., Jaber, H., Reiss-Mandel, A., Kline, M., DuLong, C., Lipsitch, M., Regev-Yochay, G., Huttenhower, C. 2020; 21 (1): 301

  Abstract

  Staphylococcus aureus is a leading cause of healthcare- and community-associated infections and can be difficult to treat due to antimicrobial resistance. About 30% of individuals carry S. aureus asymptomatically in their nares, a risk factor for later infection, and interactions with other species in the nasal microbiome likely modulate its carriage. It is thus important to identify ecological or functional genetic elements within the maternal or infant nasal microbiomes that influence S. aureus acquisition and retention in early life.We recruited 36 mother-infant pairs and profiled a subset of monthly longitudinal nasal samples from the first year after birth using shotgun metagenomic sequencing. The infant nasal microbiome is highly variable, particularly within the first 2 months. It is weakly influenced by maternal nasal microbiome composition, but primarily shaped by developmental and external factors, such as daycare. Infants display distinctive patterns of S. aureus carriage, positively associated with Acinetobacter species, Streptococcus parasanguinis, Streptococcus salivarius, and Veillonella species and inversely associated with maternal Dolosigranulum pigrum. Furthermore, we identify a gene family, likely acting as a taxonomic marker for an unclassified species, that is significantly anti-correlated with S. aureus in infants and mothers. In gene content-based strain profiling, infant S. aureus strains are more similar to maternal strains.This improved understanding of S. aureus colonization is an important first step toward the development of novel, ecological therapies for controlling S. aureus carriage.

  View details for DOI 10.1186/s13059-020-02209-7

  View details for PubMedID 33308267

  View details for PubMedCentralID PMC7731505

• Practical considerations for measuring the effective reproductive number, Rt. PLoS computational biology Gostic, K. M., McGough, L., Baskerville, E. B., Abbott, S., Joshi, K., Tedijanto, C., Kahn, R., Niehus, R., Hay, J. A., De Salazar, P. M., Hellewell, J., Meakin, S., Munday, J. D., Bosse, N. I., Sherrat, K., Thompson, R. N., White, L. F., Huisman, J. S., Scire, J., Bonhoeffer, S., Stadler, T., Wallinga, J., Funk, S., Lipsitch, M., Cobey, S. 2020; 16 (12): e1008409

  Abstract

  Estimation of the effective reproductive number Rt is important for detecting changes in disease transmission over time. During the Coronavirus Disease 2019 (COVID-19) pandemic, policy makers and public health officials are using Rt to assess the effectiveness of interventions and to inform policy. However, estimation of Rt from available data presents several challenges, with critical implications for the interpretation of the course of the pandemic. The purpose of this document is to summarize these challenges, illustrate them with examples from synthetic data, and, where possible, make recommendations. For near real-time estimation of Rt, we recommend the approach of Cori and colleagues, which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t, such as Wallinga and Teunis, are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to the spread. We advise caution when using methods derived from the approach of Bettencourt and Ribeiro, as the resulting Rt estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in Rt estimation.

  View details for DOI 10.1371/journal.pcbi.1008409

  View details for PubMedID 33301457

  View details for PubMedCentralID PMC7728287

• Testing COVID-19 therapies to prevent progression of mild disease. The Lancet. Infectious diseases Lipsitch, M., Perlman, S., Waldor, M. K. 2020; 20 (12): 1367

  View details for DOI 10.1016/S1473-3099(20)30372-8

  View details for PubMedID 32618282

  View details for PubMedCentralID PMC7202831

• The role of "spillover" in antibiotic resistance. Proceedings of the National Academy of Sciences of the United States of America Olesen, S. W., Lipsitch, M., Grad, Y. H. 2020; 117 (46): 29063-29068

  Abstract

  Antibiotic use is a key driver of antibiotic resistance. Understanding the quantitative association between antibiotic use and resulting resistance is important for predicting future rates of antibiotic resistance and for designing antibiotic stewardship policy. However, the use-resistance association is complicated by "spillover," in which one population's level of antibiotic use affects another population's level of resistance via the transmission of bacteria between those populations. Spillover is known to have effects at the level of families and hospitals, but it is unclear if spillover is relevant at larger scales. We used mathematical modeling and analysis of observational data to address this question. First, we used dynamical models of antibiotic resistance to predict the effects of spillover. Whereas populations completely isolated from one another do not experience any spillover, we found that if even 1% of interactions are between populations, then spillover may have large consequences: The effect of a change in antibiotic use in one population on antibiotic resistance in that population could be reduced by as much as 50%. Then, we quantified spillover in observational antibiotic use and resistance data from US states and European countries for three pathogen-antibiotic combinations, finding that increased interactions between populations were associated with smaller differences in antibiotic resistance between those populations. Thus, spillover may have an important impact at the level of states and countries, which has ramifications for predicting the future of antibiotic resistance, designing antibiotic resistance stewardship policy, and interpreting stewardship interventions.

  View details for DOI 10.1073/pnas.2013694117

  View details for PubMedID 33139558

  View details for PubMedCentralID PMC7682407

• Understanding COVID-19 vaccine efficacy. Science (New York, N.Y.) Lipsitch, M., Dean, N. E. 2020; 370 (6518): 763-765

  View details for DOI 10.1126/science.abe5938

  View details for PubMedID 33087460

• Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution. The New England journal of medicine Doan, T., Worden, L., Hinterwirth, A., Arzika, A. M., Maliki, R., Abdou, A., Zhong, L., Chen, C., Cook, C., Lebas, E., O'Brien, K. S., Oldenburg, C. E., Chow, E. D., Porco, T. C., Lipsitch, M., Keenan, J. D., Lietman, T. M. 2020; 383 (20): 1941-1950

  Abstract

  Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear.We investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months.Over the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa.Among villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).

  View details for DOI 10.1056/NEJMoa2002606

  View details for PubMedID 33176084

  View details for PubMedCentralID PMC7492079

• Cross-reactive memory T cells and herd immunity to SARS-CoV-2. Nature reviews. Immunology Lipsitch, M., Grad, Y. H., Sette, A., Crotty, S. 2020; 20 (11): 709-713

  Abstract

  Immunity is a multifaceted phenomenon. For T cell-mediated memory responses to SARS-CoV-2, it is relevant to consider their impact both on COVID-19 disease severity and on viral spread in a population. Here, we reflect on the immunological and epidemiological aspects and implications of pre-existing cross-reactive immune memory to SARS-CoV-2, which largely originates from previous exposure to circulating common cold coronaviruses. We propose four immunological scenarios for the impact of cross-reactive CD4+ memory T cells on COVID-19 severity and viral transmission. For each scenario, we discuss its implications for the dynamics of herd immunity and on projections of the global impact of SARS-CoV-2 on the human population, and assess its plausibility. In sum, we argue that key potential impacts of cross-reactive T cell memory are already incorporated into epidemiological models based on data of transmission dynamics, particularly with regard to their implications for herd immunity. The implications of immunological processes on other aspects of SARS-CoV-2 epidemiology are worthy of future study.

  View details for DOI 10.1038/s41577-020-00460-4

  View details for PubMedID 33024281

  View details for PubMedCentralID PMC7537578

• Scientific consensus on the COVID-19 pandemic: we need to act now. Lancet (London, England) Alwan, N. A., Burgess, R. A., Ashworth, S., Beale, R., Bhadelia, N., Bogaert, D., Dowd, J., Eckerle, I., Goldman, L. R., Greenhalgh, T., Gurdasani, D., Hamdy, A., Hanage, W. P., Hodcroft, E. B., Hyde, Z., Kellam, P., Kelly-Irving, M., Krammer, F., Lipsitch, M., McNally, A., McKee, M., Nouri, A., Pimenta, D., Priesemann, V., Rutter, H., Silver, J., Sridhar, D., Swanton, C., Walensky, R. P., Yamey, G., Ziauddeen, H. 2020; 396 (10260): e71-e72

  View details for DOI 10.1016/S0140-6736(20)32153-X

  View details for PubMedID 33069277

  View details for PubMedCentralID PMC7557300

• Evaluation of Nowcasting for Real-Time COVID-19 Tracking - New York City, March-May 2020. medRxiv : the preprint server for health sciences Greene, S. K., McGough, S. F., Culp, G. M., Graf, L. E., Lipsitch, M., Menzies, N. A., Kahn, R. 2020

  Abstract

  To account for delays between specimen collection and report, the New York City Department of Health and Mental Hygiene used a time-correlated Bayesian nowcasting approach to support real-time COVID-19 situational awareness. We retrospectively evaluated nowcasting performance for case counts among residents diagnosed during March-May 2020, a period when the median reporting delay was 2 days. Nowcasts with a 2-week moving window and a negative binomial distribution had lower mean absolute error, lower relative root mean square error, and higher 95% prediction interval coverage than nowcasts conducted with a 3-week moving window or with a Poisson distribution. Nowcasts conducted toward the end of the week outperformed nowcasts performed earlier in the week, given fewer patients diagnosed on weekends and lack of day-of-week adjustments. When estimating case counts for weekdays only, metrics were similar across days the nowcasts were conducted, with Mondays having the lowest mean absolute error, of 183 cases in the context of an average daily weekday case count of 2,914. Nowcasting ensured that recent decreases in observed case counts were not overinterpreted as true declines and supported health department leadership in anticipating the magnitude and timing of hospitalizations and deaths and allocating resources geographically.

  View details for DOI 10.1101/2020.10.18.20209189

  View details for PubMedID 33106814

  View details for PubMedCentralID PMC7587834

• Frequency-dependent selection can forecast evolution in Streptococcus pneumoniae. PLoS biology Azarian, T., Martinez, P. P., Arnold, B. J., Qiu, X., Grant, L. R., Corander, J., Fraser, C., Croucher, N. J., Hammitt, L. L., Reid, R., Santosham, M., Weatherholtz, R. C., Bentley, S. D., O'Brien, K. L., Lipsitch, M., Hanage, W. P. 2020; 18 (10): e3000878

  Abstract

  Predicting how pathogen populations will change over time is challenging. Such has been the case with Streptococcus pneumoniae, an important human pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use the frequencies of accessory genes to predict changes in the pneumococcal population after vaccination, hypothesizing that these frequencies reflect negative frequency-dependent selection (NFDS) on the gene products. We find that the standardized predicted fitness of a strain, estimated by an NFDS-based model at the time the vaccine is introduced, enables us to predict whether the strain increases or decreases in prevalence following vaccination. Further, we are able to forecast the equilibrium post-vaccine population composition and assess the invasion capacity of emerging lineages. Overall, we provide a method for predicting the impact of an intervention on pneumococcal populations with potential application to other bacterial pathogens in which NFDS is a driving force.

  View details for DOI 10.1371/journal.pbio.3000878

  View details for PubMedID 33091022

  View details for PubMedCentralID PMC7580979

• Reply to Hasford and to Spinola et al. The Journal of infectious diseases Eyal, N., Lipsitch, M., Smith, P. G. 2020; 222 (9): 1574-1575

  View details for DOI 10.1093/infdis/jiaa458

  View details for PubMedID 32845306

  View details for PubMedCentralID PMC7529012

• Reopening Primary Schools during the Pandemic. The New England journal of medicine Levinson, M., Cevik, M., Lipsitch, M. 2020; 383 (10): 981-985

  View details for DOI 10.1056/NEJMms2024920

  View details for PubMedID 32726550

• Individual quarantine versus active monitoring of contacts for the mitigation of COVID-19: a modelling study. The Lancet. Infectious diseases Peak, C. M., Kahn, R., Grad, Y. H., Childs, L. M., Li, R., Lipsitch, M., Buckee, C. O. 2020; 20 (9): 1025-1033

  Abstract

  Voluntary individual quarantine and voluntary active monitoring of contacts are core disease control strategies for emerging infectious diseases such as COVID-19. Given the impact of quarantine on resources and individual liberty, it is vital to assess under what conditions individual quarantine can more effectively control COVID-19 than active monitoring. As an epidemic grows, it is also important to consider when these interventions are no longer feasible and broader mitigation measures must be implemented.To estimate the comparative efficacy of individual quarantine and active monitoring of contacts to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we fit a stochastic branching model to reported parameters for the dynamics of the disease. Specifically, we fit a model to the incubation period distribution (mean 5·2 days) and to two estimates of the serial interval distribution: a shorter one with a mean serial interval of 4·8 days and a longer one with a mean of 7·5 days. To assess variable resource settings, we considered two feasibility settings: a high-feasibility setting with 90% of contacts traced, a half-day average delay in tracing and symptom recognition, and 90% effective isolation; and a low-feasibility setting with 50% of contacts traced, a 2-day average delay, and 50% effective isolation.Model fitting by sequential Monte Carlo resulted in a mean time of infectiousness onset before symptom onset of 0·77 days (95% CI -1·98 to 0·29) for the shorter serial interval, and for the longer serial interval it resulted in a mean time of infectiousness onset after symptom onset of 0·51 days (95% CI -0·77 to 1·50). Individual quarantine in high-feasibility settings, where at least 75% of infected contacts are individually quarantined, contains an outbreak of SARS-CoV-2 with a short serial interval (4·8 days) 84% of the time. However, in settings where the outbreak continues to grow (eg, low-feasibility settings), so too will the burden of the number of contacts traced for active monitoring or quarantine, particularly uninfected contacts (who never develop symptoms). When resources are prioritised for scalable interventions such as physical distancing, we show active monitoring or individual quarantine of high-risk contacts can contribute synergistically to mitigation efforts. Even under the shorter serial interval, if physical distancing reduces the reproductive number to 1·25, active monitoring of 50% of contacts can result in overall outbreak control (ie, effective reproductive number <1).Our model highlights the urgent need for more data on the serial interval and the extent of presymptomatic transmission to make data-driven policy decisions regarding the cost-benefit comparisons of individual quarantine versus active monitoring of contacts. To the extent that these interventions can be implemented, they can help mitigate the spread of SARS-CoV-2.National Institute of General Medical Sciences, National Institutes of Health.

  View details for DOI 10.1016/S1473-3099(20)30361-3

  View details for PubMedID 32445710

  View details for PubMedCentralID PMC7239635

• Opinion: It's ethical to test promising coronavirus vaccines against less-promising ones. Proceedings of the National Academy of Sciences of the United States of America Eyal, N., Lipsitch, M. 2020; 117 (32): 18898-18901

  View details for DOI 10.1073/pnas.2014154117

  View details for PubMedID 32699147

  View details for PubMedCentralID PMC7431044

• Estimating internationally imported cases during the early COVID-19 pandemic. medRxiv : the preprint server for health sciences Menkir, T. F., Chin, T., Hay, J., Surface, E. D., De Salazar, P. M., Buckee, C. O., Watts, A., Khan, K., Sherbo, R., Yan, A. W., Mina, M., Lipsitch, M., Niehus, R. 2020

  Abstract

  Early in the COVID-19 pandemic, when cases were predominantly reported in the city of Wuhan, China, local outbreaks in Europe, North America, and Asia were largely predicted from imported cases on flights from Wuhan, potentially missing imports from other key source cities. Here, we account for importations from Wuhan and from other cities in China, combining COVID-19 prevalence estimates in 18 Chinese cities with estimates of flight passenger volume to predict for each day between early December 2019 to late February 2020 the number of cases exported from China. We predict that the main source of global case importation in early January was Wuhan, but due to the Wuhan lockdown and the rapid spread of the virus, the main source of case importation from mid February became Chinese cities outside of Wuhan. For destinations in Africa in particular, non-Wuhan cities were an important source of case imports (1 case from those cities for each case from Wuhan, range of model scenarios: 0.1-9.8). Our model predicts that 18.4 (8.5 - 100) COVID-19 cases were imported to 26 destination countries in Africa, with most of them (90%) predicted to have arrived between 7th January (±10 days) and 5th February (±3 days), and all of them predicted prior to the first case detections. We finally observed marked heterogeneities in expected imported cases across those locations. Our estimates shed light on shifting sources and local risks of case importation which can help focus surveillance efforts and guide public health policy during the final stages of the pandemic. We further provide a time window for the seeding of local epidemics in African locations, a key parameter for estimating expected outbreak size and burden on local health care systems and societies, that has yet to be defined in these locations.

  View details for DOI 10.1101/2020.03.23.20038331

  View details for PubMedID 32511613

  View details for PubMedCentralID PMC7276040

• Response to Dawson et al. The Journal of infectious diseases Eyal, N., Lipsitch, M., Smith, P. G. 2020; 222 (3): 516-517

  View details for DOI 10.1093/infdis/jiaa315

  View details for PubMedID 32495823

  View details for PubMedCentralID PMC8494001

• Addendum: Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nature medicine Wu, J. T., Leung, K., Bushman, M., Kishore, N., Niehus, R., de Salazar, P. M., Cowling, B. J., Lipsitch, M., Leung, G. M. 2020; 26 (7): 1149-1150

  View details for DOI 10.1038/s41591-020-0920-6

  View details for PubMedID 32661399

  View details for PubMedCentralID PMC7608360

• Estimating case fatality rates of COVID-19. The Lancet. Infectious diseases Lipsitch, M. 2020; 20 (7): 775

  View details for DOI 10.1016/S1473-3099(20)30245-0

  View details for PubMedID 32243813

  View details for PubMedCentralID PMC7270796

• Using observational data to quantify bias of traveller-derived COVID-19 prevalence estimates in Wuhan, China. The Lancet. Infectious diseases Niehus, R., De Salazar, P. M., Taylor, A. R., Lipsitch, M. 2020; 20 (7): 803-808

  Abstract

  The incidence of coronavirus disease 2019 (COVID-19) in Wuhan, China, has been estimated using imported case counts of international travellers, generally under the assumptions that all cases of the disease in travellers have been ascertained and that infection prevalence in travellers and residents is the same. However, findings indicate variation among locations in the capacity for detection of imported cases. Singapore has had very strong epidemiological surveillance and contact tracing capacity during previous infectious disease outbreaks and has consistently shown high sensitivity of case-detection during the COVID-19 outbreak.We used a Bayesian modelling approach to estimate the relative capacity for detection of imported cases of COVID-19 for 194 locations (excluding China) compared with that for Singapore. We also built a simple mathematical model of the point prevalence of infection in visitors to an epicentre relative to that in residents.The weighted global ability to detect Wuhan-to-location imported cases of COVID-19 was estimated to be 38% (95% highest posterior density interval [HPDI] 22-64) of Singapore's capacity. This value is equivalent to 2·8 (95% HPDI 1·5-4·4) times the current number of imported and reported cases that could have been detected if all locations had had the same detection capacity as Singapore. Using the second component of the Global Health Security index to stratify likely case-detection capacities, the ability to detect imported cases relative to Singapore was 40% (95% HPDI 22-67) among locations with high surveillance capacity, 37% (18-68) among locations with medium surveillance capacity, and 11% (0-42) among locations with low surveillance capacity. Treating all travellers as if they were residents (rather than accounting for the brief stay of some of these travellers in Wuhan) contributed modestly to underestimation of prevalence.Estimates of case counts in Wuhan based on assumptions of 100% detection in travellers could have been underestimated by several fold. Furthermore, severity estimates will be inflated several fold since they also rely on case count estimates. Finally, our model supports evidence that underdetected cases of COVID-19 have probably spread in most locations around the world, with greatest risk in locations of low detection capacity and high connectivity to the epicentre of the outbreak.US National Institute of General Medical Sciences, and Fellowship Foundation Ramon Areces.

  View details for DOI 10.1016/S1473-3099(20)30229-2

  View details for PubMedID 32246905

  View details for PubMedCentralID PMC7270516

• Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants. eLife Hicks, A. L., Kissler, S. M., Mortimer, T. D., Ma, K. C., Taiaroa, G., Ashcroft, M., Williamson, D. A., Lipsitch, M., Grad, Y. H. 2020; 9

  Abstract

  Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate antibiotic use. However, because such assays infer resistance based on known genetic markers, their utility will wane with the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance to ensure early detection of novel resistance variants, but efficient strategies to do so remain undefined. We evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting antibiotic resistance and diagnostic escape variants in Neisseria gonorrhoeae, a pathogen associated with a high burden of disease and antibiotic resistance and the development of genotype-based diagnostics. We show that patient characteristic-informed sampling is not a reliable strategy for efficient variant detection. In contrast, sampling informed by pathogen characteristics, such as genomic diversity and genomic background, is significantly more efficient than random sampling in identifying genetic variants associated with resistance and diagnostic escape.

  View details for DOI 10.7554/eLife.56367

  View details for PubMedID 32602459

  View details for PubMedCentralID PMC7326491

• Estimating the Early Outbreak Cumulative Incidence of COVID-19 in the United States: Three Complementary Approaches. medRxiv : the preprint server for health sciences Lu, F. S., Nguyen, A. T., Link, N. B., Davis, J. T., Chinazzi, M., Xiong, X., Vespignani, A., Lipsitch, M., Santillana, M. 2020

  Abstract

  Effectively designing and evaluating public health responses to the ongoing COVID-19 pandemic requires accurate estimation of the weekly incidence of COVID-19. Unfortunately, a lack of systematic testing across the United States (US) due to equipment shortages and varying testing strategies has hindered the usefulness of the reported positive COVID-19 case counts. We introduce three complementary approaches to estimate the cumulative incidence of symptomatic COVID-19 during the early outbreak in each state in the US as well as in New York City, using a combination of excess influenza-like illness reports, COVID-19 test statistics, and COVID-19 mortality reports. Instead of relying on an estimate from a single data source or method that may be biased, we provide multiple estimates, each relying on different assumptions and data sources. Across our three approaches, there is a consistent conclusion that estimated state-level COVID-19 symptomatic case counts from March 1 to April 4, 2020 varied from 5 to 50 times greater than the official positive test counts. Nationally, our estimates of COVID-19 symptomatic cases in the US as of April 4 have a likely range of 2.2 to 5.1 million cases, with possibly as high as 8.1 million cases, up to 26 times greater than the cumulative confirmed cases of about 311,000. Extending our method to May 16, 2020, we estimate that cumulative symptomatic incidence ranges from 6.0 to 12.2 million, which compares with 1.5 million positive test counts. Our approaches demonstrate the value of leveraging existing influenza-like-illness surveillance systems during the flu season for measuring the burden of new diseases that share symptoms with influenza-like-illnesses. Our methods may prove useful in assessing the burden of COVID-19 during upcoming flu seasons in the US and other countries with comparable influenza surveillance systems.

  View details for DOI 10.1101/2020.04.18.20070821

  View details for PubMedID 32587997

  View details for PubMedCentralID PMC7310656

• Response to Cioffi. The Journal of infectious diseases Eyal, N., Lipsitch, M., Smith, P. G. 2020; 222 (1): 169-170

  View details for DOI 10.1093/infdis/jiaa217

  View details for PubMedID 32348499

• Estimating the contribution of different age strata to vaccine serotype pneumococcal transmission in the pre vaccine era: a modelling study. BMC medicine Flasche, S., Lipsitch, M., Ojal, J., Pinsent, A. 2020; 18 (1): 129

  Abstract

  Herd protection through interruption of transmission has contributed greatly to the impact of pneumococcal conjugate vaccines (PCVs) and may enable the use of cost-saving reduced dose schedules. To aid PCV age targeting to achieve herd protection, we estimated which population age groups contribute most to vaccine serotype (VT) pneumococcal transmission.We used transmission dynamic models to mirror pre-PCV epidemiology in England and Wales, Finland, Kilifi in Kenya and Nha Trang in Vietnam where data on carriage prevalence in infants, pre-school and school-aged children and adults as well as social contact patterns was available. We used Markov Chain Monte Carlo methods to fit the models and then extracted the per capita and population-based contribution of different age groups to VT transmission.We estimated that in all settings, < 1-year-old infants cause very frequent secondary vaccine type pneumococcal infections per capita. However, 1-5-year-old children have the much higher contribution to the force of infection at 51% (28, 73), 40% (27, 59), 37% (28, 48) and 67% (41, 86) of the total infection pressure in E&W, Finland, Kilifi and Nha Trang, respectively. Unlike the other settings, school-aged children in Kilifi were the dominant source for VT infections with 42% (29, 54) of all infections caused. Similarly, we estimated that the main source of VT infections in infants are pre-school children and that in Kilifi 39% (28, 51) of VT infant infections stem from school-aged children whereas this was below 15% in the other settings.Vaccine protection of pre-school children is key for PCV herd immunity. However, in high transmission settings, school-aged children may substantially contribute to transmission and likely have waned much of their PCV protection under currently recommended schedules.

  View details for DOI 10.1186/s12916-020-01601-1

  View details for PubMedID 32517683

  View details for PubMedCentralID PMC7285529

• Good science is good science: we need specialists, not sects. European journal of epidemiology Lipsitch, M. 2020; 35 (6): 519-522

  View details for DOI 10.1007/s10654-020-00651-2

  View details for PubMedID 32564181

  View details for PubMedCentralID PMC7305476

• Antibody testing will enhance the power and accuracy of COVID-19-prevention trials. Nature medicine Lipsitch, M., Kahn, R., Mina, M. J. 2020; 26 (6): 818-819

  View details for DOI 10.1038/s41591-020-0887-3

  View details for PubMedID 32341581

• Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science (New York, N.Y.) Kissler, S. M., Tedijanto, C., Goldstein, E., Grad, Y. H., Lipsitch, M. 2020; 368 (6493): 860-868

  Abstract

  It is urgent to understand the future of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) transmission. We used estimates of seasonality, immunity, and cross-immunity for human coronavirus OC43 (HCoV-OC43) and HCoV-HKU1 using time-series data from the United States to inform a model of SARS-CoV-2 transmission. We projected that recurrent wintertime outbreaks of SARS-CoV-2 will probably occur after the initial, most severe pandemic wave. Absent other interventions, a key metric for the success of social distancing is whether critical care capacities are exceeded. To avoid this, prolonged or intermittent social distancing may be necessary into 2022. Additional interventions, including expanded critical care capacity and an effective therapeutic, would improve the success of intermittent distancing and hasten the acquisition of herd immunity. Longitudinal serological studies are urgently needed to determine the extent and duration of immunity to SARS-CoV-2. Even in the event of apparent elimination, SARS-CoV-2 surveillance should be maintained because a resurgence in contagion could be possible as late as 2024.

  View details for DOI 10.1126/science.abb5793

  View details for PubMedID 32291278

  View details for PubMedCentralID PMC7164482

• Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure. The Journal of infectious diseases Eyal, N., Lipsitch, M., Smith, P. G. 2020; 221 (11): 1752-1756

  Abstract

  Controlled human challenge trials of SARS-CoV-2 vaccine candidates could accelerate the testing and potential rollout of efficacious vaccines. By replacing conventional phase 3 testing of vaccine candidates, such trials may subtract many months from the licensure process, making efficacious vaccines available more quickly. Obviously, challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity. Volunteers in such studies could autonomously authorize the risks to themselves, and their net risk could be acceptable if participants comprise healthy young adults, who are at relatively low risk of serious disease following natural infection, if they have a high baseline risk of natural infection, and if during the trial they receive frequent monitoring and, following any infection, the best available care.

  View details for DOI 10.1093/infdis/jiaa152

  View details for PubMedID 32232474

  View details for PubMedCentralID PMC7184325

• Epidemiology of Covid-19. Reply. The New England journal of medicine Swerdlow, D. L., Finelli, L., Lipsitch, M. 2020; 382 (19): 1869-1870

  View details for DOI 10.1056/NEJMc2005157

  View details for PubMedID 32220201

• Horizontal gene transfer rate is not the primary determinant of observed antibiotic resistance frequencies in Streptococcus pneumoniae. Science advances Lehtinen, S., Chewapreecha, C., Lees, J., Hanage, W. P., Lipsitch, M., Croucher, N. J., Bentley, S. D., Turner, P., Fraser, C., Mostowy, R. J. 2020; 6 (21): eaaz6137

  Abstract

  The extent to which evolution is constrained by the rate at which horizontal gene transfer (HGT) allows DNA to move between genetic lineages is an open question, which we address in the context of antibiotic resistance in Streptococcus pneumoniae. We analyze microbiological, genomic, and epidemiological data from the largest-to-date sequenced pneumococcal carriage study in 955 infants from a refugee camp on the Thailand-Myanmar border. Using a unified framework, we simultaneously test prior hypotheses on rates of HGT and a key evolutionary covariate (duration of carriage) as determinants of resistance frequencies. We conclude that in this setting, there is little evidence of HGT playing a major role in determining resistance frequencies. Instead, observed resistance frequencies are best explained as the outcome of selection acting on a pool of variants, irrespective of the rate at which resistance determinants move between genetic lineages.

  View details for DOI 10.1126/sciadv.aaz6137

  View details for PubMedID 32671212

  View details for PubMedCentralID PMC7314567

• Estimated Demand for US Hospital Inpatient and Intensive Care Unit Beds for Patients With COVID-19 Based on Comparisons With Wuhan and Guangzhou, China. JAMA network open Li, R., Rivers, C., Tan, Q., Murray, M. B., Toner, E., Lipsitch, M. 2020; 3 (5): e208297

  Abstract

  Sustained spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has happened in major US cities. Capacity needs in cities in China could inform the planning of local health care resources.To describe and compare the intensive care unit (ICU) and inpatient bed needs for patients with coronavirus disease 2019 (COVID-19) in 2 cities in China to estimate the peak ICU bed needs in US cities if an outbreak equivalent to that in Wuhan occurs.This comparative effectiveness study analyzed the confirmed cases of COVID-19 in Wuhan and Guangzhou, China, from January 10 to February 29, 2020.Timing of disease control measures relative to timing of SARS-CoV-2 community spread.Number of critical and severe patient-days and peak number of patients with critical and severe illness during the study period.In Wuhan, strict disease control measures were implemented 6 weeks after sustained local transmission of SARS-CoV-2. Between January 10 and February 29, 2020, patients with COVID-19 accounted for a median (interquartile range) of 429 (25-1143) patients in the ICU and 1521 (111-7202) inpatients with serious illness each day. During the epidemic peak, 19 425 patients (24.5 per 10 000 adults) were hospitalized, 9689 (12.2 per 10 000 adults) were considered in serious condition, and 2087 (2.6 per 10 000 adults) needed critical care per day. In Guangzhou, strict disease control measures were implemented within 1 week of case importation. Between January 24 and February 29, COVID-19 accounted for a median (interquartile range) of 9 (7-12) patients in the ICU and 17 (15-26) inpatients with serious illness each day. During the epidemic peak, 15 patients were in critical condition and 38 were classified as having serious illness. The projected number of prevalent critically ill patients at the peak of a Wuhan-like outbreak in US cities was estimated to range from 2.2 to 4.4 per 10 000 adults, depending on differences in age distribution and comorbidity (ie, hypertension) prevalence.Even after the lockdown of Wuhan on January 23, the number of patients with serious COVID-19 illness continued to rise, exceeding local hospitalization and ICU capacities for at least a month. Plans are urgently needed to mitigate the consequences of COVID-19 outbreaks on the local health care systems in US cities.

  View details for DOI 10.1001/jamanetworkopen.2020.8297

  View details for PubMedID 32374400

  View details for PubMedCentralID PMC7203604

• Using Genetic Distance from Archived Samples for the Prediction of Antibiotic Resistance in Escherichia coli. Antimicrobial agents and chemotherapy MacFadden, D. R., Coburn, B., Břinda, K., Corbeil, A., Daneman, N., Fisman, D., Lee, R. S., Lipsitch, M., McGeer, A., Melano, R. G., Mubareka, S., Hanage, W. P. 2020; 64 (5)

  Abstract

  The rising rates of antibiotic resistance increasingly compromise empirical treatment. Knowing the antibiotic susceptibility of a pathogen's close genetic relative(s) may improve empirical antibiotic selection. Using genomic and phenotypic data for Escherichia coli isolates from three separate clinically derived databases, we evaluated multiple genomic methods and statistical models for predicting antibiotic susceptibility, focusing on potentially rapidly available information, such as lineage or genetic distance from archived isolates. We applied these methods to derive and validate the prediction of antibiotic susceptibility to common antibiotics. We evaluated 968 separate episodes of suspected and confirmed infection with Escherichia coli from three geographically and temporally separated databases in Ontario, Canada, from 2010 to 2018. Across all approaches, model performance (area under the curve [AUC]) ranges for predicting antibiotic susceptibility were the greatest for ciprofloxacin (AUC, 0.76 to 0.97) and the lowest for trimethoprim-sulfamethoxazole (AUC, 0.51 to 0.80). When a model predicted that an isolate was susceptible, the resulting (posttest) probabilities of susceptibility were sufficient to warrant empirical therapy for most antibiotics (mean, 92%). An approach combining multiple models could permit the use of narrower-spectrum oral agents in 2 out of every 3 patients while maintaining high treatment adequacy (∼90%). Methods based on genetic relatedness to archived samples of E. coli could be used to predict antibiotic resistance and improve antibiotic selection.

  View details for DOI 10.1128/AAC.02417-19

  View details for PubMedID 32152083

  View details for PubMedCentralID PMC7179619

• Temporal rise in the proportion of both younger adults and older adolescents among COVID-19 cases in Germany: evidence of lesser adherence to social distancing practices? medRxiv : the preprint server for health sciences Goldstein, E., Lipsitch, M. 2020

  Abstract

  There is uncertainty about the role of different age groups in propagating the SARS-CoV-2 epidemics in different countries, particularly under current social distancing practices.We used the Robert Koch Institute data on weekly COVID-19 cases in different age groups in Germany. To minimize the effect of changes in healthcare seeking behavior (e.g. for older adults) and testing practices, we included the following eight 5-year age groups in the analyses: 10-14y through 45-49y. For each age group g, we considered the proportion PL(g) of individuals in age group g among all detected cases aged 10-49y during weeks 13-14, 2020 (later period), as well as corresponding proportion PE(g) for weeks 10-11, 2020 (early period), and defined the relative risk RR(g) for the age group g to be the ratio RR(g) = PL(g)/PE(g). For each pair of age groups g1, g2, a higher value of RR(g1) compared to RR(g2), or, alternatively, a value above 1 for the odds ratio OR(g1, g2) = RR(g1)/RR(g2) for a COVID-19 case to be in group g1 vs. g2 for the later vs. early periods is interpreted as the relative increase in the population incidence of SARS-Cov-2 in the age group g1 compared to g2 for the later vs. early period.The relative risk RR(g) was highest for individuals aged 20-24y (RR=1.4(95% CI (1.27,1.55))), followed by individuals aged 15-19y (RR=1.14(0.99,1.32)), aged 30-34y (RR=1.07(0.99,1.16)), aged 25-29y (RR= 1.06(0.98,1.15)), aged 35-39y (RR=0.95(0.87,1.03)), aged 40-44y (RR=0.9(0.83,0.98)), aged 45-49y (RR=0.83(0.77,0.89)) and aged 10-14y (RR=0.78(0.64,0.95)). For the age group 20-24y, the odds ratio relative to any other age group for a case to be during the later vs. early period was significantly above 1. For the age group 15-19y, the odds ratio relative to any other age group either above 35y or 10-14y for a case to be during the later vs. early period was significantly above 1.The observed relative increase with time in the prevalence of individuals aged 15-34y (particularly those aged 20-24y) among detected COVID-19 cases in Germany is unlikely to be explained by increases in the likelihood of seeking medical care or the likelihood of being tested for individuals in those age groups compared to individuals aged 35-49y or 10-14y, and should be indicative of the actual increase in the prevalence of individuals aged 15-34y among SARS-CoV-2 infections in the German population. That increase likely reflects elevated mixing among individuals aged 15-34y (particularly those aged 20-24y) compared to other age groups, possibly due to lesser adherence to social distancing practices.

  View details for DOI 10.1101/2020.04.08.20058719

  View details for PubMedID 32511603

  View details for PubMedCentralID PMC7276030

• Aggregated mobility data could help fight COVID-19. Science (New York, N.Y.) Buckee, C. O., Balsari, S., Chan, J., Crosas, M., Dominici, F., Gasser, U., Grad, Y. H., Grenfell, B., Halloran, M. E., Kraemer, M. U., Lipsitch, M., Metcalf, C. J., Meyers, L. A., Perkins, T. A., Santillana, M., Scarpino, S. V., Viboud, C., Wesolowski, A., Schroeder, A. 2020; 368 (6487): 145-146

  View details for DOI 10.1126/science.abb8021

  View details for PubMedID 32205458

• Temporal rise in the proportion of younger adults and older adolescents among coronavirus disease (COVID-19) cases following the introduction of physical distancing measures, Germany, March to April 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin Goldstein, E., Lipsitch, M. 2020; 25 (17)

  Abstract

  Using data on coronavirus disease (COVID-19) cases in Germany from the Robert Koch Institute, we found a relative increase with time in the prevalence in 15-34 year-olds (particularly 20-24-year-olds) compared with 35-49- and 10-14-year-olds (we excluded older and younger ages because of different healthcare seeking behaviour). This suggests an elevated role for that age group in propagating the epidemic following the introduction of physical distancing measures.

  View details for DOI 10.2807/1560-7917.ES.2020.25.17.2000596

  View details for PubMedID 32372753

  View details for PubMedCentralID PMC7201953

• Nowcasting by Bayesian Smoothing: A flexible, generalizable model for real-time epidemic tracking. PLoS computational biology McGough, S. F., Johansson, M. A., Lipsitch, M., Menzies, N. A. 2020; 16 (4): e1007735

  Abstract

  Achieving accurate, real-time estimates of disease activity is challenged by delays in case reporting. "Nowcast" approaches attempt to estimate the complete case counts for a given reporting date, using a time series of case reports that is known to be incomplete due to reporting delays. Modeling the reporting delay distribution is a common feature of nowcast approaches. However, many nowcast approaches ignore a crucial feature of infectious disease transmission-that future cases are intrinsically linked to past reported cases-and are optimized to one or two applications, which may limit generalizability. Here, we present a Bayesian approach, NobBS (Nowcasting by Bayesian Smoothing) capable of producing smooth and accurate nowcasts in multiple disease settings. We test NobBS on dengue in Puerto Rico and influenza-like illness (ILI) in the United States to examine performance and robustness across settings exhibiting a range of common reporting delay characteristics (from stable to time-varying), and compare this approach with a published nowcasting software package while investigating the features of each approach that contribute to good or poor performance. We show that introducing a temporal relationship between cases considerably improves performance when the reporting delay distribution is time-varying, and we identify trade-offs in the role of moving windows to accurately capture changes in the delay. We present software implementing this new approach (R package "NobBS") for widespread application and provide practical guidance on implementation.

  View details for DOI 10.1371/journal.pcbi.1007735

  View details for PubMedID 32251464

  View details for PubMedCentralID PMC7162546

• Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nature medicine Wu, J. T., Leung, K., Bushman, M., Kishore, N., Niehus, R., de Salazar, P. M., Cowling, B. J., Lipsitch, M., Leung, G. M. 2020; 26 (4): 506-510

  Abstract

  As of 29 February 2020 there were 79,394 confirmed cases and 2,838 deaths from COVID-19 in mainland China. Of these, 48,557 cases and 2,169 deaths occurred in the epicenter, Wuhan. A key public health priority during the emergence of a novel pathogen is estimating clinical severity, which requires properly adjusting for the case ascertainment rate and the delay between symptoms onset and death. Using public and published information, we estimate that the overall symptomatic case fatality risk (the probability of dying after developing symptoms) of COVID-19 in Wuhan was 1.4% (0.9-2.1%), which is substantially lower than both the corresponding crude or naïve confirmed case fatality risk (2,169/48,557 = 4.5%) and the approximator1 of deaths/deaths + recoveries (2,169/2,169 + 17,572 = 11%) as of 29 February 2020. Compared to those aged 30-59 years, those aged below 30 and above 59 years were 0.6 (0.3-1.1) and 5.1 (4.2-6.1) times more likely to die after developing symptoms. The risk of symptomatic infection increased with age (for example, at ~4% per year among adults aged 30-60 years).

  View details for DOI 10.1038/s41591-020-0822-7

  View details for PubMedID 32284616

  View details for PubMedCentralID PMC7094929

• Novel methods for the analysis of stepped wedge cluster randomized trials. Statistics in medicine Kennedy-Shaffer, L., de Gruttola, V., Lipsitch, M. 2020; 39 (7): 815-844

  Abstract

  Stepped wedge cluster randomized trials (SW-CRTs) have become increasingly popular and are used for a variety of interventions and outcomes, often chosen for their feasibility advantages. SW-CRTs must account for time trends in the outcome because of the staggered rollout of the intervention. Robust inference procedures and nonparametric analysis methods have recently been proposed to handle such trends without requiring strong parametric modeling assumptions, but these are less powerful than model-based approaches. We propose several novel analysis methods that reduce reliance on modeling assumptions while preserving some of the increased power provided by the use of mixed effects models. In one method, we use the synthetic control approach to find the best matching clusters for a given intervention cluster. Another method makes use of within-cluster crossover information to construct an overall estimator. We also consider methods that combine these approaches to further improve power. We test these methods on simulated SW-CRTs, describing scenarios in which these methods have increased power compared with existing nonparametric methods while preserving nominal validity when mixed effects models are misspecified. We also demonstrate theoretical properties of these estimators with less restrictive assumptions than mixed effects models. Finally, we propose avenues for future research on the use of these methods; motivation for such research arises from their flexibility, which allows the identification of specific causal contrasts of interest, their robustness, and the potential for incorporating covariates to further increase power. Investigators conducting SW-CRTs might well consider such methods when common modeling assumptions may not hold.

  View details for DOI 10.1002/sim.8451

  View details for PubMedID 31876979

  View details for PubMedCentralID PMC7247054

• Defining the Epidemiology of Covid-19 - Studies Needed. The New England journal of medicine Lipsitch, M., Swerdlow, D. L., Finelli, L. 2020; 382 (13): 1194-1196

  View details for DOI 10.1056/NEJMp2002125

  View details for PubMedID 32074416

• Depletion-of-susceptibles Bias in Analyses of Intra-season Waning of Influenza Vaccine Effectiveness. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Ray, G. T., Lewis, N., Klein, N. P., Daley, M. F., Lipsitch, M., Fireman, B. 2020; 70 (7): 1484-1486

  Abstract

  Bias arises in studies of waning vaccine effectiveness when higher-risk individuals are depleted from the at-risk population at different rates between study groups. We examined how this bias arises and how to avoid it. A reanalysis of data from California confirmed a finding of intra-season waning of influenza vaccine effectiveness.

  View details for DOI 10.1093/cid/ciz706

  View details for PubMedID 31351439

  View details for PubMedCentralID PMC7318775

• The relation between prescribing of different antibiotics and rates of mortality with sepsis in US adults. BMC infectious diseases Goldstein, E., Lipsitch, M. 2020; 20 (1): 169

  Abstract

  Antibiotic use contributes to the rates of sepsis and the associated mortality, particularly through lack of clearance of resistant infections following antibiotic treatment. At the same time, there is limited information on the effects of prescribing of some antibiotics vs. others on subsequent sepsis and sepsis-related mortality.We used a multivariable mixed-effects model to relate state-specific rates of outpatient prescribing overall for oral fluoroquinolones, penicillins, macrolides, and cephalosporins between 2014 and 2015 to state-specific rates of mortality with sepsis (ICD-10 codes A40-41 present as either underlying or contributing causes of death on a death certificate) in different age groups of US adults between 2014 and 2015, adjusting for additional covariates and random effects associated with the ten US Health and Human Services (HHS) regions.Increase in the rate of prescribing of oral penicillins by 1 annual dose per 1000 state residents was associated with increases in annual rates of mortality with sepsis of 0.95 (95% CI (0.02,1.88)) per 100,000 persons aged 75-84y, and of 2.97 (0.72,5.22) per 100,000 persons aged 85 + y. Additionally, the percent of individuals aged 50-64y lacking health insurance, as well as the percent of individuals aged 65-84y who are African-American were associated with rates of mortality with sepsis in the corresponding age groups.Our results suggest that prescribing of penicillins is associated with rates of mortality with sepsis in older US adults. Those results, as well as the related epidemiological data suggest that replacement of certain antibiotics, particularly penicillins in the treatment of different syndromes should be considered with the aim of reducing the rates of severe outcomes, including mortality related to bacterial infections.

  View details for DOI 10.1186/s12879-020-4901-7

  View details for PubMedID 32087679

  View details for PubMedCentralID PMC7036250

• Quantifying bias of COVID-19 prevalence and severity estimates in Wuhan, China that depend on reported cases in international travelers. medRxiv : the preprint server for health sciences Niehus, R., De Salazar, P. M., Taylor, A. R., Lipsitch, M. 2020

  Abstract

  Risk of COVID-19 infection in Wuhan has been estimated using imported case counts of international travelers, often under the assumption that all cases in travelers are ascertained. Recent work indicates variation among countries in detection capacity for imported cases. Singapore has historically had very strong epidemiological surveillance and contact-tracing capacity and has shown in the COVID-19 epidemic evidence of a high sensitivity of case detection. We therefore used a Bayesian modeling approach to estimate the relative imported case detection capacity for other countries compared to that of Singapore. We estimate that the global ability to detect imported cases is 38% (95% HPDI 22% - 64%) of Singapore's capacity. Equivalently, an estimate of 2.8 (95% HPDI 1.5 - 4.4) times the current number of imported cases, could have been detected, if all countries had had the same detection capacity as Singapore. Using the second component of the Global Health Security index to stratify likely case-detection capacities, we found that the ability to detect imported cases relative to Singapore among high surveillance locations is 40% (95% HPDI 22% - 67%), among intermediate surveillance locations it is 37% (95% HPDI 18% - 68%), and among low surveillance locations it is 11% (95% HPDI 0% - 42%). Using a simple mathematical model, we further find that treating all travelers as if they were residents (rather than accounting for the brief stay of some of these travelers in Wuhan) can modestly contribute to underestimation of prevalence as well. We conclude that estimates of case counts in Wuhan based on assumptions of perfect detection in travelers may be underestimated by several fold, and severity correspondingly overestimated by several fold. Undetected cases are likely in countries around the world, with greater risk in countries of low detection capacity and high connectivity to the epicenter of the outbreak.

  View details for DOI 10.1101/2020.02.13.20022707

  View details for PubMedID 32511442

  View details for PubMedCentralID PMC7239063

• Potential impact of outpatient stewardship interventions on antibiotic exposures of common bacterial pathogens. eLife Tedijanto, C., Grad, Y. H., Lipsitch, M. 2020; 9

  Abstract

  The relationship between antibiotic stewardship and population levels of antibiotic resistance remains unclear. In order to better understand shifts in selective pressure due to stewardship, we use publicly available data to estimate the effect of changes in prescribing on exposures to frequently used antibiotics experienced by potentially pathogenic bacteria that are asymptomatically colonizing the microbiome. We quantify this impact under four hypothetical stewardship strategies. In one scenario, we estimate that elimination of all unnecessary outpatient antibiotic use could avert 6% to 48% (IQR: 17% to 31%) of exposures across pairwise combinations of sixteen common antibiotics and nine bacterial pathogens. All scenarios demonstrate that stewardship interventions, facilitated by changes in clinician behavior and improved diagnostics, have the opportunity to broadly reduce antibiotic exposures across a range of potential pathogens. Concurrent approaches, such as vaccines aiming to reduce infection incidence, are needed to further decrease exposures occurring in 'necessary' contexts.

  View details for DOI 10.7554/eLife.52307

  View details for PubMedID 32022685

  View details for PubMedCentralID PMC7025820

• Proposed Changes to U.S. Policy on Potential Pandemic Pathogen Oversight and Implementation. mSphere Inglesby, T. V., Lipsitch, M. 2020; 5 (1)

  Abstract

  We propose here changes to the U.S. government policy on potential pandemic pathogen (PPP) oversight and implementation, emphasizing transparency of the review process and the content of the review, publication of the review in advance, responsible publication of enhanced PPP research, high-level signoff on approvals of enhanced PPP experiments, and the need for a significant effort to establish a common international approach to enhanced PPP work. We advocate that the U.S. government recommend, and non-U.S. government funders and journals adopt, a set of best practices that would extend important considerations of biosafety and biosecurity to all work on enhanced potential pandemic pathogens regardless of funding source.

  View details for DOI 10.1128/mSphere.00990-19

  View details for PubMedID 31969482

  View details for PubMedCentralID PMC6977183

• Association Between Congenital Cytomegalovirus and the Prevalence at Birth of Microcephaly in the United States. JAMA pediatrics Messinger, C. J., Lipsitch, M., Bateman, B. T., He, M., Huybrechts, K. F., MacDonald, S., Mogun, H., Mott, K., Hernández-Díaz, S. 2020; 174 (12): 1159-1167

  Abstract

  Congenital cytomegalovirus (cCMV) has received far less clinical and public health attention as a teratogenic infection than the Zika virus epidemic. However, cCMV may be responsible for a large fraction of microcephaly cases in the United States.To evaluate the association between cCMV and the prevalence at birth of microcephaly in the United States.This population-based cohort study included pregnant women and their newborns identified in 2 insurance claims databases from the United States: Medicaid Analytic eXtract (January 1, 2000, to December 31, 2013) and IBM Research MarketScan, a database for employer-sponsored private health insurance (January 1, 2011, to September 30, 2015). All pregnancies that resulted in live births in women with full health benefits were included. Analysis began June 2016 and ended May 2020.Congenital cytomegalovirus infection documented in inpatient or outpatient newborn claims records.The primary outcome was microcephaly at birth documented in inpatient or outpatient newborn and/or maternal claims records. Cases with chromosomal abnormalities or neural tube defects were excluded. The association between cCMV and microcephaly was estimated in the pooled cohort using prevalence ratios (PRs) and 95% CIs.In the pooled cohort of 2 338 580 pregnancies (2 075 410 pregnancies [88.7%] were among women younger than 35 years), 336 infants (0.014%) had a cCMV diagnosis. The prevalence of microcephaly among newborns with and without a cCMV diagnosis was 655 and 2.8 per 10 000 live births, respectively (PR, 232; 95% CI, 154-350). After restricting to CMV-tested newborns (572 [0.024%]) to correct for preferential testing of infants with microcephaly, the PR was 15 (95% CI, 5.2-41). However, this PR is biased if other cCMV-related outcomes (eg, hearing loss) trigger testing because cCMV prevalence in tested infants, with ([46%]) or without microcephaly (22 of 559 [3.9%]), would overestimate that in the source population. Therefore, the prevalence of cCMV in overall infants with microcephaly (22 of 669 [3.2%]) was compared with that from an external unbiased sample of US infants screened at birth (449 of 100 332 [0.45%]) to estimate a PR of 7.4 (95% CI, 4.8-11.5) as a conservative lower bound.Congenital cytomegalovirus infection increases the prevalence of microcephaly at birth by at least 7-fold. Prevention of CMV infection during pregnancy might substantially reduce the number of newborns with microcephaly and other cCMV-related outcomes in the United States.

  View details for DOI 10.1001/jamapediatrics.2020.3009

  View details for PubMedID 32926077

  View details for PubMedCentralID PMC7490747

• The Use of Test-negative Controls to Monitor Vaccine Effectiveness: A Systematic Review of Methodology. Epidemiology (Cambridge, Mass.) Chua, H., Feng, S., Lewnard, J. A., Sullivan, S. G., Blyth, C. C., Lipsitch, M., Cowling, B. J. 2020; 31 (1): 43-64

  Abstract

  The test-negative design is an increasingly popular approach for estimating vaccine effectiveness (VE) due to its efficiency. This review aims to examine published test-negative design studies of VE and to explore similarities and differences in methodological choices for different diseases and vaccines.We conducted a systematic search on PubMed, Web of Science, and Medline, for studies reporting the effectiveness of any vaccines using a test-negative design. We screened titles and abstracts and reviewed full texts to identify relevant articles. We created a standardized form for each included article to extract information on the pathogen of interest, vaccine(s) being evaluated, study setting, clinical case definition, choices of cases and controls, and statistical approaches used to estimate VE.We identified a total of 348 articles, including studies on VE against influenza virus (n = 253), rotavirus (n = 48), pneumococcus (n = 24), and nine other pathogens. Clinical case definitions used to enroll patients were similar by pathogens of interest but the sets of symptoms that defined them varied substantially. Controls could be those testing negative for the pathogen of interest, those testing positive for nonvaccine type of the pathogen of interest, or a subset of those testing positive for alternative pathogens. Most studies controlled for age, calendar time, and comorbidities.Our review highlights similarities and differences in the application of the test-negative design that deserve further examination. If vaccination reduces disease severity in breakthrough infections, particular care must be taken in interpreting vaccine effectiveness estimates from test-negative design studies.

  View details for DOI 10.1097/EDE.0000000000001116

  View details for PubMedID 31609860

  View details for PubMedCentralID PMC6888869

• Case-based surveillance of antimicrobial resistance with full susceptibility profiles. JAC-antimicrobial resistance Ryu, S., Cowling, B. J., Wu, P., Olesen, S., Fraser, C., Sun, D. S., Lipsitch, M., Grad, Y. H. 2019; 1 (3): dlz070

  Abstract

  Surveillance of antimicrobial resistance (AMR) is essential for clinical decision-making and for public health authorities to monitor patterns in resistance and evaluate the effectiveness of interventions and control measures. Existing AMR surveillance is typically based on reports from hospital laboratories and public health laboratories, comprising reports of pathogen frequencies and resistance frequencies among each species detected. Here we propose an improved framework for AMR surveillance, in which the unit of surveillance is patients with specific conditions, rather than biological samples of a particular type. In this 'case-based' surveillance, denominators as well as numerators will be clearly defined with clinical relevance and more comparable at the local, national and international level. In locations with sufficient resources, individual-based data on patient characteristics and full antibiotic susceptibility profiles would provide high-quality evidence for monitoring resistant pathogens of clinical importance, clinical treatment of infections and public health responses to outbreaks of infections with resistant bacteria.

  View details for DOI 10.1093/jacamr/dlz070

  View details for PubMedID 32280945

  View details for PubMedCentralID PMC7134534

• Mathematical modelling for antibiotic resistance control policy: do we know enough? BMC infectious diseases Knight, G. M., Davies, N. G., Colijn, C., Coll, F., Donker, T., Gifford, D. R., Glover, R. E., Jit, M., Klemm, E., Lehtinen, S., Lindsay, J. A., Lipsitch, M., Llewelyn, M. J., Mateus, A. L., Robotham, J. V., Sharland, M., Stekel, D., Yakob, L., Atkins, K. E. 2019; 19 (1): 1011

  Abstract

  Antibiotics remain the cornerstone of modern medicine. Yet there exists an inherent dilemma in their use: we are able to prevent harm by administering antibiotic treatment as necessary to both humans and animals, but we must be mindful of limiting the spread of resistance and safeguarding the efficacy of antibiotics for current and future generations. Policies that strike the right balance must be informed by a transparent rationale that relies on a robust evidence base.One way to generate the evidence base needed to inform policies for managing antibiotic resistance is by using mathematical models. These models can distil the key drivers of the dynamics of resistance transmission from complex infection and evolutionary processes, as well as predict likely responses to policy change in silico. Here, we ask whether we know enough about antibiotic resistance for mathematical modelling to robustly and effectively inform policy. We consider in turn the challenges associated with capturing antibiotic resistance evolution using mathematical models, and with translating mathematical modelling evidence into policy.We suggest that in spite of promising advances, we lack a complete understanding of key principles. From this we advocate for priority areas of future empirical and theoretical research.

  View details for DOI 10.1186/s12879-019-4630-y

  View details for PubMedID 31783803

  View details for PubMedCentralID PMC6884858

• Surveillance to maintain the sensitivity of genotype-based antibiotic resistance diagnostics. PLoS biology Hicks, A. L., Kissler, S. M., Lipsitch, M., Grad, Y. H. 2019; 17 (11): e3000547

  Abstract

  The sensitivity of genotype-based diagnostics that predict antimicrobial susceptibility is limited by the extent to which they detect genes and alleles that lead to resistance. As novel resistance variants are expected to emerge, such sensitivity is expected to decline unless the new variants are detected and incorporated into the diagnostic. Here, we present a mathematical framework to define how many diagnostic failures may be expected under varying surveillance regimes and thus quantify the surveillance needed to maintain the sensitivity of genotype-based diagnostics.

  View details for DOI 10.1371/journal.pbio.3000547

  View details for PubMedID 31714937

  View details for PubMedCentralID PMC6874359

• Comment on: 'Antibiotic footprint' as a communication tool to aid reduction of antibiotic consumption. The Journal of antimicrobial chemotherapy Lipsitch, M., Shaman, J. 2019; 74 (11): 3404-3406

  View details for DOI 10.1093/jac/dkz320

  View details for PubMedID 31314102

• Hospitalizations Associated with Respiratory Syncytial Virus and Influenza in Children, Including Children Diagnosed with Asthma. Epidemiology (Cambridge, Mass.) Goldstein, E., Finelli, L., O'Halloran, A., Liu, P., Karaca, Z., Steiner, C. A., Viboud, C., Lipsitch, M. 2019; 30 (6): 918-926

  Abstract

  There is uncertainty about the burden of hospitalization associated with respiratory syncytial virus (RSV) and influenza in children, including those with underlying medical conditions.We applied previously developed methodology to Health Care Cost and Utilization Project hospitalization data and additional data related to asthma diagnosis/previous history in hospitalized children to estimate RSV and influenza-associated hospitalization rates in different subpopulations of US children between 2003 and 2010.The estimated average annual rates (per 100,000 children) of RSV-associated hospitalization with a respiratory cause (ICD-9 codes 460-519) present anywhere in the discharge diagnosis were 2,381 (95% CI(2252,2515)) in children <1 year of age; 710.6 (609.1, 809.2) (1 y old); 395 (327.7, 462.4) (2 y old); 211.3 (154.6, 266.8) (3 y old); 111.1 (62.4, 160.1) (4 y old); 72.3 (29.3, 116.4) (5-6 y of age); 35.6 (9.9,62.2) (7-11 y of age); and 39 (17.5, 60.6) (12-17 y of age). The corresponding rates of influenza-associated hospitalization were lower, ranging from 181 (142.5, 220.3) in <1 year old to 17.9 (11.7, 24.2) in 12-17 years of age. The relative risks for RSV-related hospitalization associated with a prior diagnosis of asthma in age groups <5 y ranged between 3.1 (2.1, 4.7) (<1 y old) and 6.7 (4.2, 11.8) (2 y old; the corresponding risks for influenza-related hospitalization ranged from 2.8 (2.1, 4) (<1y old) to 4.9 (3.8, 6.4) (3 y old).RSV-associated hospitalization rates in young children are high and decline rapidly with age. There are additional risks for both RSV and influenza hospitalization associated with a prior diagnosis of asthma, with the rates of RSV-related hospitalization in the youngest children diagnosed with asthma being particularly high.

  View details for DOI 10.1097/EDE.0000000000001092

  View details for PubMedID 31469696

  View details for PubMedCentralID PMC6768705

• Regulating impact on bystanders in clinical trials: An unsettled frontier. Clinical trials (London, England) Eyal, N., Kimmelman, J., Holtzman, L. G., Lipsitch, M. 2019; 16 (5): 450-454

  Abstract

  This article informally reviews key research ethics guidelines and regulations, academic scholarship, and research studies and finds wide variety in how they consider risk to bystanders in medical research (namely, non-participants whom studies nevertheless place at risk). Some of these key sources give no or very little consideration to bystanders, while others offer them the utmost protection (greater than they offer study participants). This unsettled frontier would benefit from a deeper investigation of the ethics of protecting research bystanders.

  View details for DOI 10.1177/1740774519862783

  View details for PubMedID 31368813

  View details for PubMedCentralID PMC6742522

• Interaction Patterns of Men Who Have Sex With Men on a Geosocial Networking Mobile App in Seven United States Metropolitan Areas: Observational Study. Journal of medical Internet research Abuelezam, N. N., Reshef, Y. A., Novak, D., Grad, Y. H., Seage Iii, G. R., Mayer, K., Lipsitch, M. 2019; 21 (9): e13766

  Abstract

  The structure of the sexual networks and partnership characteristics of young black men who have sex with men (MSM) may be contributing to their high risk of contracting HIV in the United States. Assortative mixing, which refers to the tendency of individuals to have partners from one's own group, has been proposed as a potential explanation for disparities.The objective of this study was to identify the age- and race-related search patterns of users of a diverse geosocial networking mobile app in seven metropolitan areas in the United States to understand the disparities in sexually transmitted infection and HIV risk in MSM communities.Data were collected on user behavior between November 2015 and May 2016. Data pertaining to behavior on the app were collected for men who had searched for partners with at least one search parameter narrowed from defaults or used the app to send at least one private chat message and used the app at least once during the study period. Newman assortativity coefficient (R) was calculated from the study data to understand assortativity patterns of men by race. Pearson correlation coefficient was used to assess assortativity patterns by age. Heat maps were used to visualize the relationship between searcher's and candidate's characteristics by age band, race, or age band and race.From November 2015 through May 2016, there were 2,989,737 searches in all seven metropolitan areas among 122,417 searchers. Assortativity by age was important for looking at the profiles of candidates with correlation coefficients ranging from 0.284 (Birmingham) to 0.523 (San Francisco). Men tended to look at the profiles of candidates that matched their race in a highly assortative manner with R ranging from 0.310 (Birmingham) to 0.566 (Los Angeles). For the initiation of chats, race appeared to be slightly assortative for some groups with R ranging from 0.023 (Birmingham) to 0.305 (Los Angeles). Asian searchers were most assortative in initiating chats with Asian candidates in Boston, Los Angeles, New York, and San Francisco. In Birmingham and Tampa, searchers from all races tended to initiate chats with black candidates.Our results indicate that the age preferences of MSM are relatively consistent across cities, that is, younger MSM are more likely to be chatted with and have their profiles viewed compared with older MSM, but the patterns of racial mixing are more variable. Although some generalizations can be made regarding Web-based behaviors across all cities, city-specific usage patterns and trends should be analyzed to create targeted and localized interventions that may make the most difference in the lives of MSM in these areas.

  View details for DOI 10.2196/13766

  View details for PubMedID 31516124

  View details for PubMedCentralID PMC6746104

• Influenza A Hemagglutinin Passage Bias Sites and Host Specificity Mutations. Cells Lee, R. T., Chang, H. H., Russell, C. A., Lipsitch, M., Maurer-Stroh, S. 2019; 8 (9)

  Abstract

  Animal studies aimed at understanding influenza virus mutations that change host specificity to adapt to replication in mammalian hosts are necessarily limited in sample numbers due to high cost and safety requirements. As a safe, higher-throughput alternative, we explore the possibility of using readily available passage bias data obtained mostly from seasonal H1 and H3 influenza strains that were differentially grown in mammalian (MDCK) and avian cells (eggs). Using a statistical approach over 80,000 influenza hemagglutinin sequences with passage information, we found that passage bias sites are most commonly found in three regions: (i) the globular head domain around the receptor binding site, (ii) the region that undergoes pH-dependent structural changes and (iii) the unstructured N-terminal region harbouring the signal peptide. Passage bias sites were consistent among different passage cell types as well as between influenza A subtypes. We also find epistatic interactions of site pairs supporting the notion of host-specific dependency of mutations on virus genomic background. The sites identified from our large-scale sequence analysis substantially overlap with known host adaptation sites in the WHO H5N1 genetic changes inventory suggesting information from passage bias can provide candidate sites for host specificity changes to aid in risk assessment for emerging strains.

  View details for DOI 10.3390/cells8090958

  View details for PubMedID 31443542

  View details for PubMedCentralID PMC6770435

• Levels of outpatient prescribing for four major antibiotic classes and rates of septicemia hospitalization in adults in different US states - a statistical analysis. BMC public health Goldstein, E., Olesen, S. W., Karaca, Z., Steiner, C. A., Viboud, C., Lipsitch, M. 2019; 19 (1): 1138

  Abstract

  Rates of sepsis/septicemia hospitalization in the US have risen significantly during recent years. Antibiotic resistance and use may contribute to those rates through various mechanisms, including lack of clearance of resistant infections following antibiotic treatment, with some of those infections subsequently devolving into sepsis. At the same time, there is limited information on the effect of prescribing of certain antibiotics vs. others on the rates of septicemia and sepsis-related hospitalizations and mortality.We used multivariable linear regression to relate state-specific rates of outpatient prescribing overall for oral fluoroquinolones, penicillins, macrolides, and cephalosporins between 2011 and 2012 to state-specific rates of septicemia hospitalization (ICD-9 codes 038.xx present anywhere on a discharge diagnosis) in each of the following age groups of adults: (18-49y, 50-64y, 65-74y, 75-84y, 85 + y) reported to the Healthcare Cost and Utilization Project (HCUP) between 2011 and 2012, adjusting for additional covariates, and random effects associated with the ten US Health and Human Services (HHS) regions.Increase in the rate of prescribing of oral penicillins by 1 annual dose per 1000 state residents was associated with increases in annual septicemia hospitalization rates of 0.19 (95% CI (0.02,0.37)) per 10,000 persons aged 50-64y, of 0.48(0.12,0.84) per 10,000 persons aged 65-74y, and of 0.81(0.17,1.40) per 10,000 persons aged 74-84y. Increase by 1 in the percent of African Americans among state residents in a given age group was associated with increases in annual septicemia hospitalization rates of 2.3(0.32,4.2) per 10,000 persons aged 75-84y, and of 5.3(1.1,9.5) per 10,000 persons aged over 85y. Average minimal daily temperature was positively associated with septicemia hospitalization rates in persons aged 18-49y, 50-64y, 75-84y and over 85y.Our results suggest positive associations between the rates of prescribing for penicillins and the rates of hospitalization with septicemia in US adults aged 50-84y. Further studies are needed to better understand the potential effect of antibiotic replacement in the treatment of various syndromes, including the potential impact of the recent US FDA guidelines on restriction of fluoroquinolone use, as well as the potential effect of changes in the practices for prescribing of penicillins on the rates of sepsis-related hospitalization and mortality.

  View details for DOI 10.1186/s12889-019-7431-8

  View details for PubMedID 31426780

  View details for PubMedCentralID PMC6701127

• Enhancing Situational Awareness to Prevent Infectious Disease Outbreaks from Becoming Catastrophic. Current topics in microbiology and immunology Lipsitch, M., Santillana, M. 2019; 424: 59-74

  Abstract

  Catastrophic epidemics, if they occur, will very likely start from localized and far smaller (non-catastrophic) outbreaks that grow into much greater threats. One key bulwark against this outcome is the ability of governments and the health sector more generally to make informed decisions about control measures based on accurate understanding of the current and future extent of the outbreak. Situation reporting is the activity of periodically summarizing the state of the outbreak in a (usually) public way. We delineate key classes of decisions whose quality depends on high-quality situation reporting, key quantities for which estimates are needed to inform these decisions, and the traditional and novel sources of data that can aid in estimating these quantities. We emphasize the important role of situation reports as providing public, shared planning assumptions that allow decision makers to harmonize the response while making explicit the uncertainties that underlie the scenarios outlined for planning. In this era of multiple data sources and complex factors informing the interpretation of these data sources, we describe four principles for situation reporting: (1) Situation reporting should be thematic, concentrating on essential areas of evidence needed for decisions. (2) Situation reports should adduce evidence from multiple sources to address each area of evidence, along with expert assessments of key parameters. (3) Situation reports should acknowledge uncertainty and attempt to estimate its magnitude for each assessment. (4) Situation reports should contain carefully curated visualizations along with text and tables.

  View details for DOI 10.1007/82_2019_172

  View details for PubMedID 31292726

• Antimicrobial resistance prevalence, rates of hospitalization with septicemia and rates of mortality with sepsis in adults in different US states. International journal of antimicrobial agents Goldstein, E., MacFadden, D. R., Karaca, Z., Steiner, C. A., Viboud, C., Lipsitch, M. 2019; 54 (1): 23-34

  Abstract

  Rates of hospitalization with sepsis/septicemia and associated mortality in the US have risen significantly during the last two decades. Antibiotic resistance may contribute to the rates of sepsis-related outcomes through lack of clearance of bacterial infections following antibiotic treatment during different stages of infection. However, there is limited information about the relationship between prevalence of resistance to various antibiotics in different bacteria and rates of sepsis-related outcomes.For different age groups of adults (18-49y, 50-64y, 65-74y, 75-84y, 85+y) and combinations of antibiotics/bacteria, we evaluated associations between state-specific prevalence (percentage) of resistant samples for a given combination of antibiotics/bacteria among catheter-associated urinary tract infections (CAUTIs) in the CDC Antibiotic Resistance Patient Safety Atlas data between 2011-2014, and rates of hospitalization with septicemia (ICD-9 codes 038.xx present on the discharge diagnosis) reported to the Healthcare Cost and Utilization Project (HCUP), as well as rates of mortality with sepsis (ICD-10 codes A40-41.xx present on death certificate).Among the different combinations of antibiotics/bacteria, prevalence of resistance to fluoroquinolones in Escherichia coli had the strongest association with septicemia hospitalization rates for individuals aged over 50y, and with sepsis mortality rates for individuals aged 18-84y. There were several positive correlations between prevalence of resistance for different combinations of antibiotics/bacteria and septicemia hospitalization/sepsis mortality rates in adults.These findings, and those from work on the relationship between antibiotic use and sepsis rates, support the association between use of/resistance to certain antibiotics and rates of sepsis-related outcomes, indicating the potential utility of antibiotic replacement.

  View details for DOI 10.1016/j.ijantimicag.2019.03.004

  View details for PubMedID 30851403

  View details for PubMedCentralID PMC6571064

• The Relative Impact of Community and Hospital Antibiotic Use on the Selection of Extended-spectrum Beta-lactamase-producing Escherichia coli. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America MacFadden, D. R., Fisman, D. N., Hanage, W. P., Lipsitch, M. 2019; 69 (1): 182-188

  Abstract

  Antibiotic stewardship programs have traditionally focused on reducing hospital antibiotic use. However, reducing community antibiotic prescribing could have substantial impacts in both hospital and community settings. We developed a deterministic model of transmission of extended-spectrum beta-lactamase-producing Escherichia coli in both the community and hospitals. We fit the model to existing, national-level antibiotic use and resistance prevalence data from Sweden. Across a range of conditions, a given relative change in antibiotic use in the community had a greater impact on resistance prevalence in both the community and hospitals than an equivalent relative change in hospital use. However, on a per prescription basis, changes in antibiotic use in hospitals had the greatest impact. The magnitude of changes in prevalence were modest, even with large changes in antimicrobial use. These data support the expansion of stewardship programs/interventions beyond the walls of hospitals, but also suggest that such efforts would benefit hospitals themselves.

  View details for DOI 10.1093/cid/ciy978

  View details for PubMedID 30462185

  View details for PubMedCentralID PMC6771767

• Response to comment on 'The distribution of antibiotic use and its association with antibiotic resistance'. eLife Olesen, S. W., Lipsitch, M., Grad, Y. H. 2019; 8

  Abstract

  We are writing to reply to the comment by Pouwels et al., 2019 about our recent study (Olesen et al., 2018) on antibiotic use and antibiotic resistance.

  View details for DOI 10.7554/eLife.47124

  View details for PubMedID 31050649

  View details for PubMedCentralID PMC6499536

• Challenges of Vaccine Effectiveness and Waning Studies. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Lipsitch, M. 2019; 68 (10): 1631-1633

  View details for DOI 10.1093/cid/ciy773

  View details for PubMedID 30204853

  View details for PubMedCentralID PMC6495011

• Resistance diagnostics as a public health tool to combat antibiotic resistance: A model-based evaluation. PLoS biology McAdams, D., Wollein Waldetoft, K., Tedijanto, C., Lipsitch, M., Brown, S. P. 2019; 17 (5): e3000250

  Abstract

  Rapid point-of-care resistance diagnostics (POC-RD) are a key tool in the fight against antibiotic resistance. By tailoring drug choice to infection genotype, doctors can improve treatment efficacy while limiting costs of inappropriate antibiotic prescription. Here, we combine epidemiological theory and data to assess the potential of resistance diagnostics (RD) innovations in a public health context, as a means to limit or even reverse selection for antibiotic resistance. POC-RD can be used to impose a nonbiological fitness cost on resistant strains by enabling diagnostic-informed treatment and targeted interventions that reduce resistant strains' opportunities for transmission. We assess this diagnostic-imposed fitness cost in the context of a spectrum of bacterial population biologies and find that POC-RD have a greater potential against obligate pathogens than opportunistic pathogens already subject to selection under "bystander" antibiotic exposure during asymptomatic carriage (e.g., the pneumococcus). We close by generalizing the notion of RD-informed strategies to incorporate carriage surveillance information and illustrate that coupling transmission-control interventions to the discovery of resistant strains in carriage can potentially select against resistance in a broad range of opportunistic pathogens.

  View details for DOI 10.1371/journal.pbio.3000250

  View details for PubMedID 31095567

  View details for PubMedCentralID PMC6522007

• On the evolutionary ecology of multidrug resistance in bacteria. PLoS pathogens Lehtinen, S., Blanquart, F., Lipsitch, M., Fraser, C. 2019; 15 (5): e1007763

  Abstract

  Resistance against different antibiotics appears on the same bacterial strains more often than expected by chance, leading to high frequencies of multidrug resistance. There are multiple explanations for this observation, but these tend to be specific to subsets of antibiotics and/or bacterial species, whereas the trend is pervasive. Here, we consider the question in terms of strain ecology: explaining why resistance to different antibiotics is often seen on the same strain requires an understanding of the competition between strains with different resistance profiles. This work builds on models originally proposed to explain another aspect of strain competition: the stable coexistence of antibiotic sensitivity and resistance observed in a number of bacterial species. We first identify a partial structural similarity in these models: either strain or host population structure stratifies the pathogen population into evolutionarily independent sub-populations and introduces variation in the fitness effect of resistance between these sub-populations, thus creating niches for sensitivity and resistance. We then generalise this unified underlying model to multidrug resistance and show that models with this structure predict high levels of association between resistance to different drugs and high multidrug resistance frequencies. We test predictions from this model in six bacterial datasets and find them to be qualitatively consistent with observed trends. The higher than expected frequencies of multidrug resistance are often interpreted as evidence that these strains are out-competing strains with lower resistance multiplicity. Our work provides an alternative explanation that is compatible with long-term stability in resistance frequencies.

  View details for DOI 10.1371/journal.ppat.1007763

  View details for PubMedID 31083687

  View details for PubMedCentralID PMC6532944

• THE AUTHORS REPLY. American journal of epidemiology Lewnard, J. A., Tedijanto, C., Cowling, B. J., Lipsitch, M. 2019; 188 (4): 807-808

  View details for DOI 10.1093/aje/kwz018

  View details for PubMedID 30689694

  View details for PubMedCentralID PMC6676939

• Herd immunity alters the conditions for performing dose schedule comparisons: an individual-based model of pneumococcal carriage. BMC infectious diseases Yang, A., Cai, F., Lipsitch, M. 2019; 19 (1): 227

  Abstract

  There is great interest in the use of reduced dosing schedules for pneumococcal conjugate vaccines, a strategy premised on maintaining an acceptable level of protection against disease and carriage of the organism. We asked about the practicality of measuring differential effectiveness against carriage in a population with and without widespread use of the vaccine for infants.We adapted an existing transmission-dynamic, individual-based stochastic model fitted to the prevaccine epidemiology of pneumococcal carriage in the United States, and compared the observed vaccine-type carriage prevalence in different arms of a simulated trial with one, two, or three infant doses plus a 12-month booster. Using these simulations, we calculated vaccine efficacy that would be estimated at different times post-enrollment in the trial and calculated required sample sizes to see a difference in carriage prevalence.In a pneumococcal conjugate vaccine (PCV)-naïve population, the difference in vaccine-type (VT) pneumococcal carriage prevalence between trial arms was less than 7% and varied with sampling time. In a population already receiving routine PCV administration, VT pneumococcal prevalence is nearly indistinguishable between trial arms. Relative efficacy of different dosing schedules was strongly dependent on the time between enrollment and sampling, with maximal prevalence differences reached 1-3 years post-enrollment. Moreover, vaccine efficacy estimates were typically slightly higher in trials in communities already receiving vaccination. Despite this, much larger sample sizes-by more than an order of magnitude-are required for a vaccine trial conducted in a population receiving routine PCV administration as compared to in a PCV-naïve population.These findings highlight some underappreciated aspects of clinical trials of pneumococcal conjugate vaccines with efficacy endpoints, such as the context- and time-dependence of efficacy estimates. They support the wisdom of conducting comparative dose schedule trials of conjugate vaccine effects on carriage in vaccine-naïve populations.

  View details for DOI 10.1186/s12879-019-3833-6

  View details for PubMedID 30836941

  View details for PubMedCentralID PMC6402138

• Analysis of a meningococcal meningitis outbreak in Niger - potential effectiveness of reactive prophylaxis. PLoS neglected tropical diseases Hitchings, M. D., Coldiron, M. E., Grais, R. F., Lipsitch, M. 2019; 13 (3): e0007077

  Abstract

  Seasonal epidemics of bacterial meningitis in the African Meningitis Belt carry a high burden of disease and mortality. Reactive mass vaccination is used as a control measure during epidemics, but the time taken to gain immunity from the vaccine reduces the flexibility and effectiveness of these campaigns. Targeted reactive antibiotic prophylaxis could be used to supplement reactive mass vaccination and further reduce the incidence of meningitis, and the potential effectiveness and efficiency of these strategies should be explored.Data from an outbreak of meningococcal meningitis in Niger, caused primarily by Neisseria meningitidis serogroup C, is used to estimate clustering of meningitis cases at the household and village level. In addition, reactive antibiotic prophylaxis and reactive vaccination strategies are simulated to estimate their potential effectiveness and efficiency, with a focus on the threshold and spatial unit used to declare an epidemic and initiate the intervention. There is village-level clustering of suspected meningitis cases after an epidemic has been declared in a health area. Risk of suspected meningitis among household contacts of a suspected meningitis case is no higher than among members of the same village. Village-wide antibiotic prophylaxis can target subsequent cases in villages: across of range of parameters pertaining to how the intervention is performed, up to 220/672 suspected cases during the season are potentially preventable. On the other hand, household prophylaxis targets very few cases. In general, the village-wide strategy is not very sensitive to the method used to declare an epidemic. Finally, village-wide antibiotic prophylaxis is potentially more efficient than mass vaccination of all individuals at the beginning of the season, and than the equivalent reactive vaccination strategy.Village-wide antibiotic prophylaxis should be considered and tested further as a response against outbreaks of meningococcal meningitis in the Meningitis Belt, as a supplement to reactive mass vaccination.

  View details for DOI 10.1371/journal.pntd.0007077

  View details for PubMedID 30856166

  View details for PubMedCentralID PMC6428357

• Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose. Scientific reports Langwig, K. E., Gomes, M. G., Clark, M. D., Kwitny, M., Yamada, S., Wargo, A. R., Lipsitch, M. 2019; 9 (1): 3203

  Abstract

  Understanding the causes of vaccine failure is important for predicting disease dynamics in vaccinated populations and planning disease interventions. Pathogen exposure dose and heterogeneity in host susceptibility have both been implicated as important factors that may reduce overall vaccine efficacy and cause vaccine failure. Here, we explore the effect of pathogen dose and heterogeneity in host susceptibility in reducing efficacy of vaccines. Using simulation-based methods, we find that increases in pathogen exposure dose decrease vaccine efficacy, but this effect is modified by heterogeneity in host susceptibility. In populations where the mode of vaccine action is highly polarized, vaccine efficacy decreases more slowly with exposure dose than in populations with less variable protection. We compared these theoretical results to empirical estimates from a systematic literature review of vaccines tested over multiple exposure doses. We found that few studies (nine of 5,389) tested vaccine protection against infection over multiple pathogen challenge doses, with seven studies demonstrating a decrease in vaccine efficacy with increasing exposure dose. Our research demonstrates that pathogen dose has potential to be an important determinant of vaccine failure, although the limited empirical data highlight a need for additional studies to test theoretical predictions on the plausibility of reduced host susceptibility and high pathogen dose as mechanisms responsible for reduced vaccine efficacy in high transmission settings.

  View details for DOI 10.1038/s41598-019-39698-x

  View details for PubMedID 30824732

  View details for PubMedCentralID PMC6397254

• Population genomics of pneumococcal carriage in Massachusetts children following introduction of PCV-13. Microbial genomics Mitchell, P. K., Azarian, T., Croucher, N. J., Callendrello, A., Thompson, C. M., Pelton, S. I., Lipsitch, M., Hanage, W. P. 2019; 5 (2)

  Abstract

  The 13-valent pneumococcal conjugate vaccine (PCV-13) was introduced in the United States in 2010. Using a large paediatric carriage sample collected from shortly after the introduction of PCV-7 to several years after the introduction of PCV-13, we investigate alterations in the composition of the pneumococcal population following the introduction of PCV-13, evaluating the extent to which the post-vaccination non-vaccine type (NVT) population mirrors that from prior to vaccine introduction and the effect of PCV-13 on vaccine type lineages. Draft genome assemblies from 736 newly sequenced and 616 previously published pneumococcal carriage isolates from children in Massachusetts between 2001 and 2014 were analysed. Isolates were classified into one of 22 sequence clusters (SCs) on the basis of their core genome sequence. We calculated the SC diversity for each sampling period as the probability that any two randomly drawn isolates from that period belong to different SCs. The sampling period immediately after the introduction of PCV-13 (2011) was found to have higher diversity than preceding (2007) or subsequent (2014) sampling periods {Simpson's D 2007: 0.915 [95 % confidence interval (CI) 0.901, 0.929]; 2011:  0.935 [0.927, 0.942]; 2014 :  0.912 [0.901, 0.923]}. Amongst NVT isolates, we found the distribution of SCs in 2011 to be significantly different from that in 2007 or 2014 (Fisher's exact test P=0.018, 0.0078), but did not find a difference comparing 2007 to 2014 (Fisher's exact test P=0.24), indicating greater similarity between samples separated by a longer time period than between samples from closer time periods. We also found changes in the accessory gene content of the NVT population between 2007 and 2011 to have been reduced by 2014. Amongst the new serotypes targeted by PCV-13, four were present in our sample. The proportion of our sample composed of PCV-13-only vaccine serotypes 19A, 6C and 7F decreased between 2007 and 2014, but no such reduction was seen for serotype 3. We did, however, observe differences in the genetic composition of the pre- and post-PCV-13 serotype 3 population. Our isolates were collected during discrete sampling periods from a small geographical area, which may limit the generalizability of our findings. Pneumococcal diversity increased immediately following the introduction of PCV-13, but subsequently returned to pre-vaccination levels. This is reflected in the distribution of NVT lineages, and, to a lesser extent, their accessory gene frequencies. As such, there may be a period during which the population is particularly disrupted by vaccination before returning to a more stable distribution. The persistence and shifting genetic composition of serotype 3 is a concern and warrants further investigation.

  View details for DOI 10.1099/mgen.0.000252

  View details for PubMedID 30777813

  View details for PubMedCentralID PMC6421351

• Analyzing Vaccine Trials in Epidemics With Mild and Asymptomatic Infection. American journal of epidemiology Kahn, R., Hitchings, M., Wang, R., Bellan, S. E., Lipsitch, M. 2019; 188 (2): 467-474

  Abstract

  Vaccine efficacy against susceptibility to infection (VES), regardless of symptoms, is an important endpoint of vaccine trials for pathogens with a high proportion of asymptomatic infection, because such infections may contribute to onward transmission and long-term sequelae, such as congenital Zika syndrome. However, estimating VES is resource-intensive. We aimed to identify approaches for accurately estimating VES when limited information is available and resources are constrained. We modeled an individually randomized vaccine trial by generating a network of individuals and simulating an epidemic. The disease natural history followed a "susceptible-exposed-infectious/symptomatic (or infectious/asymptomatic)-recovered" model. We then used 7 approaches to estimate VES, and we also estimated vaccine efficacy against progression to symptoms (VEP). A corrected relative risk and an interval-censored Cox model accurately estimate VES and only require serological testing of participants once, while a Cox model using only symptomatic infections returns biased estimates. Only acquiring serological endpoints in a 10% sample and imputing the remaining infection statuses yields unbiased VES estimates across values of the basic reproduction number (R0) and accurate estimates of VEP for higher R0 values. Identifying resource-preserving methods for accurately estimating VES and VEP is important in designing trials for diseases with a high proportion of asymptomatic infection.

  View details for DOI 10.1093/aje/kwy239

  View details for PubMedID 30329134

  View details for PubMedCentralID PMC6357804

• Postexposure Effects of Vaccines on Infectious Diseases. Epidemiologic reviews Gallagher, T., Lipsitch, M. 2019; 41 (1): 13-27

  Abstract

  We searched the PubMed database for clinical trials and observational human studies about postexposure vaccination effects, targeting infections with approved vaccines and vaccines licensed outside the United States against dengue, hepatitis E, malaria, and tick-borne encephalitis. Studies of animal models, serologic testing, and pipeline vaccines were excluded. Eligible studies were evaluated by definition of exposure; attempts to distinguish pre- and postexposure effects were rated on a scale of 1 to 4. We screened 4,518 articles and ultimately identified for this review 14 clinical trials and 31 observational studies spanning 7 of the 28 vaccine-preventable diseases. For secondary attack rate, the following medians were found for postexposure vaccination effectiveness: hepatitis A, 85% (interquartile range (IQR), 28; n = 5 sources); hepatitis B, 85% (IQR, 22; n = 5 sources); measles, 83% (IQR, 21; n = 8 sources); varicella, 67% (IQR: 48; n = 9 sources); smallpox, 45% (IQR, 39; n = 4 sources); and mumps, 38% (IQR, 7; n = 2 sources). For case fatality proportions resulting from rabies and smallpox, the median vaccine postexposure efficacies were 100% (IQR, 0; n = 6 sources) and 63% (IQR, 50; n = 8 sources), respectively. Many available vaccines can modify or preclude disease if administered after exposure. This postexposure effectiveness could be important to consider during vaccine trials and while developing new vaccines.

  View details for DOI 10.1093/epirev/mxz014

  View details for PubMedID 31680134

  View details for PubMedCentralID PMC7159179

• Azithromycin Susceptibility Among Neisseria gonorrhoeae Isolates and Seasonal Macrolide Use. The Journal of infectious diseases Olesen, S. W., Torrone, E. A., Papp, J. R., Kirkcaldy, R. D., Lipsitch, M., Grad, Y. H. 2019; 219 (4): 619-623

  Abstract

  Rising azithromycin nonsusceptibility among Neisseria gonorrhoeae isolates threatens current treatment recommendations, but the cause of this rise is not well understood. We performed an ecological study of seasonal patterns in macrolide use and azithromycin resistance in N. gonorrhoeae, finding that population-wide macrolide use is associated with increased azithromycin nonsusceptibility. These results, indicative of bystander selection, have implications for antibiotic prescribing guidelines.

  View details for DOI 10.1093/infdis/jiy551

  View details for PubMedID 30239814

  View details for PubMedCentralID PMC6350947

• Models of immune selection for multi-locus antigenic diversity of pathogens. Nature reviews. Immunology Georgieva, M., Buckee, C. O., Lipsitch, M. 2019; 19 (1): 55-62

  Abstract

  It is well accepted that pathogens can evade recognition and elimination by the host immune system by varying their antigenic targets. Thus, it has become a truism that host immunity is a major driver and determinant of the antigenic diversity of pathogens. However, it remains puzzling how host immunity selects for antigenic diversity at the level of the pathogen population, given that hosts have acquired immune responses to multiple antigens of most pathogens - sometimes through multiple effectors of both humoral and cellular immunity. In this Opinion article, we address this puzzle and the related question of why pathogens often have diversity at multiple antigenic loci. Here, we describe five hypotheses to explain the polymorphism of multiple antigens in a single pathogen species and highlight research relevant to our current models of thinking about multi-locus antigenic diversity.

  View details for DOI 10.1038/s41577-018-0092-5

  View details for PubMedID 30479379

  View details for PubMedCentralID PMC6352731

• NIPAH VACCINE TRIALS- ASSESSING THE FEASIBILITY BASED ON PREVIOUS OUTBREAKS IN BANGLADESH Nikolay, B., Salje, H., Lipsitch, M., Luby, S. P., Cauchemez, S., Gurley, E. S. AMER SOC TROP MED & HYGIENE. 2019: 265–66

  View details for Web of Science ID 000507364503221

• Panproteome-wide analysis of antibody responses to whole cell pneumococcal vaccination. eLife Campo, J. J., Le, T. Q., Pablo, J. V., Hung, C., Teng, A. A., Tettelin, H., Tate, A., Hanage, W. P., Alderson, M. R., Liang, X., Malley, R., Lipsitch, M., Croucher, N. J. 2018; 7

  Abstract

  Pneumococcal whole cell vaccines (WCVs) could cost-effectively protect against a greater strain diversity than current capsule-based vaccines. Immunoglobulin G (IgG) responses to a WCV were characterised by applying longitudinally-sampled sera, available from 35 adult placebo-controlled phase I trial participants, to a panproteome microarray. Despite individuals maintaining distinctive antibody 'fingerprints', responses were consistent across vaccinated cohorts. Seventy-two functionally distinct proteins were associated with WCV-induced increases in IgG binding. These shared characteristics with naturally immunogenic proteins, being enriched for transporters and cell wall metabolism enzymes, likely unusually exposed on the unencapsulated WCV's surface. Vaccine-induced responses were specific to variants of the diverse PclA, PspC and ZmpB proteins, whereas PspA- and ZmpA-induced antibodies recognised a broader set of alleles. Temporal variation in IgG levels suggested a mixture of anamnestic and novel responses. These reproducible increases in IgG binding to a limited, but functionally diverse, set of conserved proteins indicate WCV could provide species-wide immunity. Clinical trial registration: The trial was registered with ClinicalTrials.gov with Identifier NCT01537185; the results are available from https://clinicaltrials.gov/ct2/show/results/NCT01537185.

  View details for DOI 10.7554/eLife.37015

  View details for PubMedID 30592459

  View details for PubMedCentralID PMC6344088

• The distribution of antibiotic use and its association with antibiotic resistance. eLife Olesen, S. W., Barnett, M. L., MacFadden, D. R., Brownstein, J. S., Hernández-Díaz, S., Lipsitch, M., Grad, Y. H. 2018; 7

  Abstract

  Antibiotic use is a primary driver of antibiotic resistance. However, antibiotic use can be distributed in different ways in a population, and the association between the distribution of use and antibiotic resistance has not been explored. Here, we tested the hypothesis that repeated use of antibiotics has a stronger association with population-wide antibiotic resistance than broadly-distributed, low-intensity use. First, we characterized the distribution of outpatient antibiotic use across US states, finding that antibiotic use is uneven and that repeated use of antibiotics makes up a minority of antibiotic use. Second, we compared antibiotic use with resistance for 72 pathogen-antibiotic combinations across states. Finally, having partitioned total use into extensive and intensive margins, we found that intense use had a weaker association with resistance than extensive use. If the use-resistance relationship is causal, these results suggest that reducing total use and selection intensity will require reducing broadly distributed, low-intensity use.

  View details for DOI 10.7554/eLife.39435

  View details for PubMedID 30560781

  View details for PubMedCentralID PMC6307856

• Microbiome as a tool and a target in the effort to address antimicrobial resistance PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Relman, D. A., Lipsitch, M. 2018; 115 (51): 12902–10

  View details for DOI 10.1073/pnas.1717163115

  View details for Web of Science ID 000453529800043

• Microbiome as a tool and a target in the effort to address antimicrobial resistance. Proceedings of the National Academy of Sciences of the United States of America Relman, D. A., Lipsitch, M. 2018; 115 (51): 12902–10

  Abstract

  Reciprocal, intimate relationships between the human microbiome and the host immune system are shaped by past microbial encounters and prepare the host for future ones. Antibiotics and other antimicrobials leave their mark on both the microbiome and host immunity. Antimicrobials alter the structure of the microbiota, expand the host-specific pool of antimicrobial-resistance genes and organisms, degrade the protective effects of the microbiota against invasion by pathogens, and may impair vaccine efficacy. Through these effects on the microbiome they may affect immune responses. Vaccines that exert protective or therapeutic effects against pathogens may reduce the use of antimicrobials, the development and spread of antimicrobial resistance, and the harmful impacts of these drugs on the microbiome. Other strategies involving manipulation of the microbiome to deplete antibiotic-resistant organisms or to enhance immune responses to vaccines may prove valuable in addressing antimicrobial resistance as well. This article describes the intersections of immunity, microbiome and antimicrobial exposure, and the use of vaccines and other alternative strategies for the control and management of antimicrobial resistance.

  View details for PubMedID 30559176

• Toward economic evaluation of the value of vaccines and other health technologies in addressing AMR. Proceedings of the National Academy of Sciences of the United States of America Sevilla, J. P., Bloom, D. E., Cadarette, D., Jit, M., Lipsitch, M. 2018; 115 (51): 12911-12919

  Abstract

  We discuss the need to make economic evaluations of vaccines antimicrobial resistance (AMR)-sensitive and ways to do so. Such AMR-sensitive evaluations can play a role in value-for-money comparisons of different vaccines within a national immunization program, or in comparisons of vaccine-centric and non-vaccine-centric technologies within an anti-AMR program. In general terms, incremental cost-effectiveness ratios and rates of return and their associated decision rules are unaltered by consideration of AMR-related value. The decision metrics need to have their various health, cost, and socioeconomic terms disaggregated into resistance-related subcategories, which in turn have to be measured carefully before they are reaggregated. The fundamental scientific challenges lie primarily in quantifying the causal impact of health technologies on resistance-related health outcomes, and secondarily in ascertaining the economic value of those outcomes. We emphasize the importance of evaluating vaccines in the context of other potentially complementary and substitutable nonvaccine technologies. Complementarity implies that optimal spending on each set of interventions is positive, and substitutability implies that the ratio of spending will depend on relative value for money. We exemplify this general point through a qualitative discussion of the complementarities and (especially the) substitutability between pneumococcal conjugate vaccines and antimicrobial stewardship and between research and development (R&D) of a gonorrhea vaccine versus R&D of a gonorrhea antibiotic. We propose a roadmap for future work, which includes quantifying the causal effects of vaccination and other health technologies on short-term and long-term resistance-related outcomes, measuring the health-sector costs and broader socioeconomic consequences of resistance-related mortality and morbidity, and evaluating vaccines in the context of nonvaccine complements and substitutes.

  View details for DOI 10.1073/pnas.1717161115

  View details for PubMedID 30559203

  View details for PubMedCentralID PMC6305008

• Estimating the proportion of bystander selection for antibiotic resistance among potentially pathogenic bacterial flora. Proceedings of the National Academy of Sciences of the United States of America Tedijanto, C., Olesen, S. W., Grad, Y. H., Lipsitch, M. 2018; 115 (51): E11988-E11995

  Abstract

  Bystander selection-the selective pressure for resistance exerted by antibiotics on microbes that are not the target pathogen of treatment-is critical to understanding the total impact of broad-spectrum antibiotic use on pathogenic bacterial species that are often carried asymptomatically. However, to our knowledge, this effect has never been quantified. We quantify bystander selection for resistance for a range of clinically relevant antibiotic-species pairs as the proportion of all antibiotic exposures received by a species for conditions in which that species was not the causative pathogen ("proportion of bystander exposures"). Data sources include the 2010-2011 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, the Human Microbiome Project, and additional carriage and etiological data from existing literature. For outpatient prescribing in the United States, we find that this proportion over all included antibiotic classes is over 80% for eight of nine organisms of interest. Low proportions of bystander exposure are often associated with infrequent bacterial carriage or concentrated prescribing of a particular antibiotic for conditions caused by the species of interest. Applying our results, we roughly estimate that pneumococcal conjugate vaccination programs result in nearly the same proportional reduction in total antibiotic exposures of Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli, despite the latter two organisms not being targeted by the vaccine. These results underscore the importance of considering antibiotic exposures of bystanders, in addition to the target pathogen, in measuring the impact of antibiotic resistance interventions.

  View details for DOI 10.1073/pnas.1810840115

  View details for PubMedID 30559213

  View details for PubMedCentralID PMC6304942

• Measurement of Vaccine Direct Effects Under the Test-Negative Design. American journal of epidemiology Lewnard, J. A., Tedijanto, C., Cowling, B. J., Lipsitch, M. 2018; 187 (12): 2686-2697

  Abstract

  Test-negative designs are commonplace in assessments of influenza vaccination effectiveness, estimating this value from the exposure odds ratio of vaccination among individuals treated for acute respiratory illness who test positive for influenza virus infection. This approach is widely believed to recover the vaccine direct effect by correcting for differential health-care-seeking behavior among vaccinated and unvaccinated persons. However, the relationship of the measured odds ratio to true vaccine effectiveness is poorly understood. We derived the odds ratio under circumstances of real-world test-negative studies. The odds ratio recovers the vaccine direct effect when 2 conditions are met: 1) Individuals' vaccination decisions are uncorrelated with exposure or susceptibility to the test-positive or test-negative conditions, and 2) vaccination confers "all-or-nothing" protection (whereby certain individuals have no protection while others are perfectly protected). Biased effect-size estimates arise if either condition is unmet. Such bias might suggest misleading associations of vaccine effectiveness with time since vaccination or the force of infection of influenza. The test-negative design could also fail to correct for differential health-care-seeking behavior among vaccinated and unvaccinated persons without stringent criteria for enrollment and testing. Our findings demonstrate a need to reassess how data from test-negative studies can inform policy decisions.

  View details for DOI 10.1093/aje/kwy163

  View details for PubMedID 30099505

  View details for PubMedCentralID PMC6269249

• Can antibiotic resistance be reduced by vaccinating against respiratory disease? The Lancet. Respiratory medicine Atkins, K. E., Lipsitch, M. 2018; 6 (11): 820-821

  View details for DOI 10.1016/S2213-2600(18)30328-X

  View details for PubMedID 30076121

• Use of an individual-based model of pneumococcal carriage for planning a randomized trial of a whole-cell vaccine. PLoS computational biology Cai, F. Y., Fussell, T., Cobey, S., Lipsitch, M. 2018; 14 (10): e1006333

  Abstract

  For encapsulated bacteria such as Streptococcus pneumoniae, asymptomatic carriage is more common and longer in duration than disease, and hence is often a more convenient endpoint for clinical trials of vaccines against these bacteria. However, using a carriage endpoint entails specific challenges. Carriage is almost always measured as prevalence, whereas the vaccine may act by reducing incidence or duration. Thus, to determine sample size requirements, its impact on prevalence must first be estimated. The relationship between incidence and prevalence (or duration and prevalence) is convex, saturating at 100% prevalence. For this reason, the proportional effect of a vaccine on prevalence is typically less than its proportional effect on incidence or duration. This relationship is further complicated in the presence of multiple pathogen strains. In addition, host immunity to carriage accumulates rapidly with frequent exposures in early years of life, creating potentially complex interactions with the vaccine's effect. We conducted a simulation study to predict the impact of an inactivated whole cell pneumococcal vaccine-believed to reduce carriage duration-on carriage prevalence in different age groups and trial settings. We used an individual-based model of pneumococcal carriage that incorporates relevant immunological processes, both vaccine-induced and naturally acquired. Our simulations showed that for a wide range of vaccine efficacies, sampling time and age at vaccination are important determinants of sample size. There is a window of favorable sampling times during which the required sample size is relatively low, and this window is prolonged with a younger age at vaccination, and in a trial setting with lower transmission intensity. These results illustrate the ability of simulation studies to inform the planning of vaccine trials with carriage endpoints, and the methods we present here can be applied to trials evaluating other pneumococcal vaccine candidates or comparing alternative dosing schedules for the existing conjugate vaccines.

  View details for DOI 10.1371/journal.pcbi.1006333

  View details for PubMedID 30273332

  View details for PubMedCentralID PMC6181404

• Impact of Antimicrobial Treatment for Acute Otitis Media on Carriage Dynamics of Penicillin-Susceptible and Penicillin-Nonsusceptible Streptococcus pneumoniae. The Journal of infectious diseases Lewnard, J. A., Tähtinen, P. A., Laine, M. K., Lindholm, L., Jalava, J., Huovinen, P., Lipsitch, M., Ruohola, A. 2018; 218 (9): 1356-1366

  Abstract

  Despite concerns that antimicrobial treatment of prevalent infections may select for drug-resistant bacteria, the effects of antimicrobial treatment on colonization dynamics have not been well quantified.We measured impacts of antimicrobial treatment on nasopharyngeal carriage of penicillin-susceptible Streptococcus pneumoniae (PSSP) and penicillin-nonsusceptible (PNSP) lineages at the end of treatment and 15, 30, and 60 days after treatment in a previously conducted randomized, double-blinded, placebo-controlled trial of amoxicillin-clavulanate for stringently defined acute otitis media.In intention-to-treat analyses, immediate treatment with amoxicillin-clavulanate reduced PSSP carriage prevalence by 88% (95% confidence interval [CI], 76%-96%) at the end of treatment and by 27% (-3%-49%) after 60 days but did not alter PNSP carriage prevalence. By the end of treatment, 7% of children who carried PSSP at enrollment remained colonized in the amoxicillin-clavulanate arm, compared with 61% of PSSP carriers who received placebo; impacts of amoxicillin-clavulanate persisted at least 60 days after treatment among children who carried PSSP at enrollment. Amoxicillin-clavulanate therapy reduced PSSP acquisition by >80% over 15 days. Among children who carried PNSP at enrollment, no impacts on carriage prevalence of S. pneumoniae, PSSP, or PNSP were evident at follow-up visits.Although the absolute risk of carrying PNSP was unaffected by treatment, antimicrobial therapy conferred a selective impact on colonizing pneumococci by accelerating clearance and delaying acquisition of PSSP.

  View details for DOI 10.1093/infdis/jiy343

  View details for PubMedID 29873739

  View details for PubMedCentralID PMC6151080

• Why Do Exceptionally Dangerous Gain-of-Function Experiments in Influenza? Methods in molecular biology (Clifton, N.J.) Lipsitch, M. 2018; 1836: 589-608

  Abstract

  This chapter makes the case against performing exceptionally dangerous gain-of-function experiments that are designed to create potentially pandemic and novel strains of influenza, for example, by enhancing the airborne transmissibility in mammals of highly virulent avian influenza strains. This is a question of intense debate over the last 5 years, though the history of such experiments goes back at least to the synthesis of viable influenza A H1N1 (1918) based on material preserved from the 1918 pandemic. This chapter makes the case that experiments to create potential pandemic pathogens (PPPs) are nearly unique in that they present biosafety risks that extend well beyond the experimenter or laboratory performing them; an accidental release could, as the name suggests, lead to global spread of a virulent virus, a biosafety incident on a scale never before seen. In such cases, biosafety considerations should be uppermost in the consideration of alternative approaches to experimental objectives and design, rather than being settled after the fact, as is appropriately done for most research involving pathogens. The extensive recent discussion of the magnitude of risks from such experiments is briefly reviewed. The chapter argues that, while there are indisputably certain questions that can be answered only by gain-of-function experiments in highly pathogenic strains, these questions are narrow and unlikely to meaningfully advance public health goals such as vaccine production and pandemic prediction. Alternative approaches to experimental influenza virology and characterization of existing strains are in general completely safe, higher throughput, more generalizable, and less costly than creation of PPP in the laboratory and can thereby better inform public health. Indeed, virtually every finding of recent PPP experiments that has been cited for its public health value was predated by similar findings using safe methodologies. The chapter concludes that the unique scientific and public health value of PPP experiments is inadequate to justify the unique risks they entail and that researchers would be well-advised to turn their talents to other methodologies that will be safe and more rewarding scientifically.

  View details for DOI 10.1007/978-1-4939-8678-1_29

  View details for PubMedID 30151594

  View details for PubMedCentralID PMC7119956

• Opinion: Risk to study nonparticipants: A procedural approach. Proceedings of the National Academy of Sciences of the United States of America Eyal, N., Lipsitch, M., Bärnighausen, T., Wikler, D. 2018; 115 (32): 8051-8053

  View details for DOI 10.1073/pnas.1810920115

  View details for PubMedID 30087210

  View details for PubMedCentralID PMC6094093

• Choices in vaccine trial design in epidemics of emerging infections. PLoS medicine Kahn, R., Rid, A., Smith, P. G., Eyal, N., Lipsitch, M. 2018; 15 (8): e1002632

  Abstract

  In a Policy Forum, Marc Lipsitch and colleagues discuss trial design issues in infectious disease outbreaks.

  View details for DOI 10.1371/journal.pmed.1002632

  View details for PubMedID 30086139

  View details for PubMedCentralID PMC6080746

• Competing Effects of Indirect Protection and Clustering on the Power of Cluster-Randomized Controlled Vaccine Trials. American journal of epidemiology Hitchings, M. D., Lipsitch, M., Wang, R., Bellan, S. E. 2018; 187 (8): 1763-1771

  Abstract

  Power considerations for trials evaluating vaccines against infectious diseases are complicated by indirect protective effects of vaccination. While cluster-randomized controlled trials (cRCTs) are less statistically efficient than individually randomized controlled trials (iRCTs), a cRCT's ability to measure direct and indirect vaccine effects may mitigate the loss of efficiency due to clustering. Within cRCTs, the number and size of clusters affects 3 determinants of power: the effect size being measured, disease incidence, and intracluster correlation. We simulated trials conducted in a collection of small communities to assess how indirect protection and clustering affected the power of cRCTs and iRCTs during an emerging epidemic. Across diverse parameters, we found that within the same trial population, cRCTs were never more powerful than iRCTs, although the difference can be small. We also identified 2 effects that attenuated the loss of cRCT power traditionally associated with increased cluster size. First, if enrollment of fewer, larger clusters was performed to achieve higher vaccine coverage within vaccinated communities, this increased the effect to be measured and, consequently, power. Second, the greater rate of imported transmission in larger communities may increase the attack rate and similarly mitigate loss of power relative to a trial in many, smaller communities.

  View details for DOI 10.1093/aje/kwy047

  View details for PubMedID 29522080

  View details for PubMedCentralID PMC6070038

• Trends in outpatient antibiotic use and prescribing practice among US older adults, 2011-15: observational study. BMJ (Clinical research ed.) Olesen, S. W., Barnett, M. L., MacFadden, D. R., Lipsitch, M., Grad, Y. H. 2018; 362: k3155

  Abstract

  To identify temporal trends in outpatient antibiotic use and antibiotic prescribing practice among older adults in a high income country.Observational study using United States Medicare administrative claims in 2011-15.Medicare, a US national healthcare program for which 98% of older adults are eligible.4.5 million fee-for-service Medicare beneficiaries aged 65 years old and older.Overall rates of antibiotic prescription claims, rates of potentially appropriate and inappropriate prescribing, rates for each of the most frequently prescribed antibiotics, and rates of antibiotic claims associated with specific diagnoses. Trends in antibiotic use were estimated by multivariable regression adjusting for beneficiaries' demographic and clinical covariates.The number of antibiotic claims fell from 1364.7 to 1309.3 claims per 1000 beneficiaries per year in 2011-14 (adjusted reduction of 2.1% (95% confidence interval 2.0% to 2.2%)), but then rose to 1364.3 claims per 1000 beneficiaries per year in 2015 (adjusted reduction of 0.20% over 2011-15 (0.09% to 0.30%)). Potentially inappropriate antibiotic claims fell from 552.7 to 522.1 per 1000 beneficiaries over 2011-14, an adjusted reduction of 3.9% (3.7% to 4.1%). Individual antibiotics had heterogeneous changes in use. For example, azithromycin claims per beneficiary decreased by 18.5% (18.2% to 18.8%) while levofloxacin claims increased by 27.7% (27.2% to 28.3%). Azithromycin use associated with each of the potentially appropriate and inappropriate respiratory diagnoses decreased, while levofloxacin use associated with each of those diagnoses increased.Among US Medicare beneficiaries, overall antibiotic use and potentially inappropriate use in 2011-15 remained steady or fell modestly, but individual drugs had divergent changes in use. Trends in drug use across indications were stronger than trends in use for individual indications, suggesting that guidelines and concerns about antibiotic resistance were not major drivers of change in antibiotic use.

  View details for DOI 10.1136/bmj.k3155

  View details for PubMedID 30054353

  View details for PubMedCentralID PMC6062849

• The evolution of antibiotic resistance in a structured host population. Journal of the Royal Society, Interface Blanquart, F., Lehtinen, S., Lipsitch, M., Fraser, C. 2018; 15 (143)

  Abstract

  The evolution of antibiotic resistance in opportunistic pathogens such as Streptococcus pneumoniae, Escherichia coli or Staphylococcus aureus is a major public health problem, as infection with resistant strains leads to prolonged hospital stay and increased risk of death. Here, we develop a new model of the evolution of antibiotic resistance in a commensal bacterial population adapting to a heterogeneous host population composed of untreated and treated hosts, and structured in different host classes with different antibiotic use. Examples of host classes include age groups and geographic locations. Explicitly modelling the antibiotic treatment reveals that the emergence of a resistant strain is favoured by more frequent but shorter antibiotic courses, and by higher transmission rates. In addition, in a structured host population, localized transmission in host classes promotes both local adaptation of the bacterial population and the global maintenance of coexistence between sensitive and resistant strains. When transmission rates are heterogeneous across host classes, resistant strains evolve more readily in core groups of transmission. These findings have implications for the better management of antibiotic resistance: reducing the rate at which individuals receive antibiotics is more effective to reduce resistance than reducing the duration of treatment. Reducing the rate of treatment in a targeted class of the host population allows greater reduction in resistance, but determining which class to target is difficult in practice.

  View details for DOI 10.1098/rsif.2018.0040

  View details for PubMedID 29925579

  View details for PubMedCentralID PMC6030642

• Multidrug-resistant Neisseria gonorrhoeae: implications for future treatment strategies. The Lancet. Infectious diseases MacFadden, D. R., Lipsitch, M., Olesen, S. W., Grad, Y. 2018; 18 (6): 599

  View details for DOI 10.1016/S1473-3099(18)30274-3

  View details for PubMedID 29856349

• On the Role of Different Age Groups and Pertussis Vaccines During the 2012 Outbreak in Wisconsin. Open forum infectious diseases Goldstein, E., Worby, C. J., Lipsitch, M. 2018; 5 (5): ofy082

  Abstract

  There is limited information on the roles of different age groups in propagating pertussis outbreaks, and on the impact of vaccination on pertussis transmission in the community.The relative roles of different age groups in propagating the 2012 pertussis outbreak in Wisconsin were evaluated using the relative risk (RR) statistic that measures the change in the group's proportion among all detected cases before vs after the epidemic peak. The impact of vaccination in different age groups against infection (that is potentially different from the protective effect against detectable disease) was evaluated using the odds ratios (ORs), within each age group, for being vaccinated vs undervaccinated before vs after the outbreak's peak.The RR statistic suggests that children aged 13-14 years played the largest relative role during the outbreak's ascent (with estimates consistent across the 3 regions in Wisconsin that were studied), followed by children aged 7-8, 9-10, and 11-12 years. Young children and older teenagers and adults played more limited relative roles during the outbreak. Results of the vaccination status analysis for the fifth dose of DTaP (for children aged 7-8 years: OR, 0.44; 95% confidence interval [CI], 0.23-0.86; for children aged 9-10 years: OR, 0.51; 95% CI, 0.27-0.95); and for Tdap for children aged 13-14 years (OR, 0.38, 95% CI, 0.16-0.89) are consistent with protective effect against infection.While our epidemiological findings for the fifth dose of DTaP and for Tdap are consistent with protective effect against infection, further studies, including those estimating vaccine effectiveness against infection/transmission to others particularly for pertussis vaccines for adolescents, are needed to evaluate the impact of vaccination on the spread of pertussis in the community.

  View details for DOI 10.1093/ofid/ofy082

  View details for PubMedID 29942818

  View details for PubMedCentralID PMC5961225

• The impact of serotype-specific vaccination on phylodynamic parameters of Streptococcus pneumoniae and the pneumococcal pan-genome. PLoS pathogens Azarian, T., Grant, L. R., Arnold, B. J., Hammitt, L. L., Reid, R., Santosham, M., Weatherholtz, R., Goklish, N., Thompson, C. M., Bentley, S. D., O'Brien, K. L., Hanage, W. P., Lipsitch, M. 2018; 14 (4): e1006966

  Abstract

  In the United States, the introduction of the heptavalent pneumococcal conjugate vaccine (PCV) largely eliminated vaccine serotypes (VT); non-vaccine serotypes (NVT) subsequently increased in carriage and disease. Vaccination also disrupts the composition of the pneumococcal pangenome, which includes mobile genetic elements and polymorphic non-capsular antigens important for virulence, transmission, and pneumococcal ecology. Antigenic proteins are of interest for future vaccines; yet, little is known about how the they are affected by PCV use. To investigate the evolutionary impact of vaccination, we assessed recombination, evolution, and pathogen demographic history of 937 pneumococci collected from 1998-2012 among Navajo and White Mountain Apache Native American communities. We analyzed changes in the pneumococcal pangenome, focusing on metabolic loci and 19 polymorphic protein antigens. We found the impact of PCV on the pneumococcal population could be observed in reduced diversity, a smaller pangenome, and changing frequencies of accessory clusters of orthologous groups (COGs). Post-PCV7, diversity rebounded through clonal expansion of NVT lineages and inferred in-migration of two previously unobserved lineages. Accessory COGs frequencies trended toward pre-PCV7 values with increasing time since vaccine introduction. Contemporary frequencies of protein antigen variants are better predicted by pre-PCV7 values (1998-2000) than the preceding period (2006-2008), suggesting balancing selection may have acted in maintaining variant frequencies in this population. Overall, we present the largest genomic analysis of pneumococcal carriage in the United States to date, which includes a snapshot of a true vaccine-naïve community prior to the introduction of PCV7. These data improve our understanding of pneumococcal evolution and emphasize the need to consider pangenome composition when inferring the impact of vaccination and developing future protein-based pneumococcal vaccines.

  View details for DOI 10.1371/journal.ppat.1006966

  View details for PubMedID 29617440

  View details for PubMedCentralID PMC5902063

• Impact of stochastically generated heterogeneity in hazard rates on individually randomized vaccine efficacy trials. Clinical trials (London, England) Kahn, R., Hitchings, M., Bellan, S., Lipsitch, M. 2018; 15 (2): 207-211

  Abstract

  Background/aims Network structure and individuals' level of exposure to a pathogen can impact results from efficacy evaluation studies of interventions against infectious diseases. Heterogeneity in infection risk can cause randomized groups to increasingly differ as a trial progresses and as more high-risk individuals become infected (described in prior work as the "frailty" phenomenon). Here, we show the impact this phenomenon can have on an individually randomized trial of a leaky vaccine in which all participants are exchangeable a priori. Methods We model a vaccine trial by generating a network of individuals grouped into communities, which are connected to a larger main population. We then simulate an epidemic, deterministically and with time-varying transmission rates in the main population and stochastically in the communities. The disease natural history follows a susceptible-exposed-infectious-recovered model. Simulation results are used to estimate vaccine efficacy [Formula: see text] with a Cox proportional hazards model. Results We find downward bias in [Formula: see text] associated with low connectivity between communities in the study population and high force of infection, even when all participants in the trial are exchangeable at the time of randomization. This phenomenon arises because the stochastic dynamics in such a setting randomly lead to community-level variation in the force of infection. Stratifying a Cox model by community alleviates this bias with no loss of power. Conclusion Understanding and accounting for the impact of heterogeneous hazard rates can allow for more accurate estimates of [Formula: see text] in epidemic settings.

  View details for DOI 10.1177/1740774517752671

  View details for PubMedID 29374974

  View details for PubMedCentralID PMC5891371

• Preprints: An underutilized mechanism to accelerate outbreak science. PLoS medicine Johansson, M. A., Reich, N. G., Meyers, L. A., Lipsitch, M. 2018; 15 (4): e1002549

  Abstract

  In an Essay, Michael Johansson and colleagues advocate the posting of research studies addressing infectious disease outbreaks as preprints.

  View details for DOI 10.1371/journal.pmed.1002549

  View details for PubMedID 29614073

  View details for PubMedCentralID PMC5882117

• Weak Epistasis May Drive Adaptation in Recombining Bacteria. Genetics Arnold, B. J., Gutmann, M. U., Grad, Y. H., Sheppard, S. K., Corander, J., Lipsitch, M., Hanage, W. P. 2018; 208 (3): 1247-1260

  Abstract

  The impact of epistasis on the evolution of multi-locus traits depends on recombination. While sexually reproducing eukaryotes recombine so frequently that epistasis between polymorphisms is not considered to play a large role in short-term adaptation, many bacteria also recombine, some to the degree that their populations are described as "panmictic" or "freely recombining." However, whether this recombination is sufficient to limit the ability of selection to act on epistatic contributions to fitness is unknown. We quantify homologous recombination in five bacterial pathogens and use these parameter estimates in a multilocus model of bacterial evolution with additive and epistatic effects. We find that even for highly recombining species (e.g., Streptococcus pneumoniae or Helicobacter pylori), selection on weak interactions between distant mutations is nearly as efficient as for an asexual species, likely because homologous recombination typically transfers only short segments. However, for strong epistasis, bacterial recombination accelerates selection, with the dynamics dependent on the amount of recombination and the number of loci. Epistasis may thus play an important role in both the short- and long-term adaptive evolution of bacteria, and, unlike in eukaryotes, is not limited to strong effect sizes, closely linked loci, or other conditions that limit the impact of recombination.

  View details for DOI 10.1534/genetics.117.300662

  View details for PubMedID 29330348

  View details for PubMedCentralID PMC5844334

• Serotype-specific immune responses to pneumococcal conjugate vaccine among children are significantly correlated by individual: Analysis of randomized controlled trial data. Vaccine Lipsitch, M., Li, L. M., Patterson, S., Trammel, J., Juergens, C., Gruber, W. C., Scott, D. A., Dagan, R. 2018; 36 (4): 473-478

  Abstract

  The magnitude of an individual's serotype-specific immunoglobulin G (IgG) response to a pneumococcal conjugate vaccine (PCV) has been associated with the vaccine's protective efficacy against carriage of pneumococci of that serotype, though the relationship with other serotypes needs to be understood.Using immunogenicity data collected during a trial comparing the 7-valent (PCV7) and 13-valent (PCV13) vaccines, we measured associations between serotype-specific IgG levels, and used multiple regressions to identify demographic predictors of response.Vaccine-induced IgG levels were moderately positively correlated with one another, with pairwise correlation coefficients of 0.40-0.70. Principal component analysis of vaccine-serotype responses yielded one principal component indicating general immune responsiveness, and a second principal component mainly describing responses to serotype 14, which was the least correlated with the other responses. Overall, demographic variables explained only 17.0 and 20.4% of the geometric mean PCV7 and PCV13 responses, respectively. In both groups, older age at the first vaccine dose and shorter time from vaccination to antibody measurement were independently associated with stronger geometric mean responses.Improved understanding of the nature and causes of variation in immune response may aid in optimizing vaccination schedules and identifying robust correlates of protection.

  View details for DOI 10.1016/j.vaccine.2017.12.015

  View details for PubMedID 29248266

  View details for PubMedCentralID PMC5767551

• On the Relative Role of Different Age Groups During Epidemics Associated With Respiratory Syncytial Virus. The Journal of infectious diseases Goldstein, E., Nguyen, H. H., Liu, P., Viboud, C., Steiner, C. A., Worby, C. J., Lipsitch, M. 2018; 217 (2): 238-244

  Abstract

  While circulation of respiratory syncytial virus (RSV) results in high rates of hospitalization, particularly among young children and elderly individuals, little is known about the role of different age groups in propagating annual RSV epidemics.We evaluate the roles played by individuals in different age groups during RSV epidemics in the United States between 2001 and 2012, using the previously defined relative risk (RR) statistic estimated from the hospitalization data from the Healthcare Cost and Utilization Project. Transmission modeling was used to examine the robustness of our inference method.Children aged 3-4 years and 5-6 years each had the highest RR estimate for 5 of 11 seasons included in this study, with RSV hospitalization rates in infants being generally higher during seasons when children aged 5-6 years had the highest RR estimate. Children aged 2 years had the highest RR estimate during one season. RR estimates in infants and individuals aged ≥11 years were mostly lower than in children aged 1-10 years. Highest RR values aligned with groups for which vaccination had the largest impact on epidemic dynamics in most model simulations.Our estimates suggest the prominent relative roles of children aged ≤10 years (particularly among those aged 3-6 years) in propagating RSV epidemics. These results, combined with further modeling work, should help inform RSV vaccination policies.

  View details for DOI 10.1093/infdis/jix575

  View details for PubMedID 29112722

  View details for PubMedCentralID PMC5853559

• Simulations for designing and interpreting intervention trials in infectious diseases. BMC medicine Halloran, M. E., Auranen, K., Baird, S., Basta, N. E., Bellan, S. E., Brookmeyer, R., Cooper, B. S., DeGruttola, V., Hughes, J. P., Lessler, J., Lofgren, E. T., Longini, I. M., Onnela, J. P., Özler, B., Seage, G. R., Smith, T. A., Vespignani, A., Vynnycky, E., Lipsitch, M. 2017; 15 (1): 223

  Abstract

  Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods.Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects.Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.

  View details for DOI 10.1186/s12916-017-0985-3

  View details for PubMedID 29287587

  View details for PubMedCentralID PMC5747936

• Frequency-dependent selection in vaccine-associated pneumococcal population dynamics. Nature ecology & evolution Corander, J., Fraser, C., Gutmann, M. U., Arnold, B., Hanage, W. P., Bentley, S. D., Lipsitch, M., Croucher, N. J. 2017; 1 (12): 1950-1960

  Abstract

  Many bacterial species are composed of multiple lineages distinguished by extensive variation in gene content. These often cocirculate in the same habitat, but the evolutionary and ecological processes that shape these complex populations are poorly understood. Addressing these questions is particularly important for Streptococcus pneumoniae, a nasopharyngeal commensal and respiratory pathogen, because the changes in population structure associated with the recent introduction of partial-coverage vaccines have substantially reduced pneumococcal disease. Here we show that pneumococcal lineages from multiple populations each have a distinct combination of intermediate-frequency genes. Functional analysis suggested that these loci may be subject to negative frequency-dependent selection (NFDS) through interactions with other bacteria, hosts or mobile elements. Correspondingly, these genes had similar frequencies in four populations with dissimilar lineage compositions. These frequencies were maintained following substantial alterations in lineage prevalences once vaccination programmes began. Fitting a multilocus NFDS model of post-vaccine population dynamics to three genomic datasets using Approximate Bayesian Computation generated reproducible estimates of the influence of NFDS on pneumococcal evolution, the strength of which varied between loci. Simulations replicated the stable frequency of lineages unperturbed by vaccination, patterns of serotype switching and clonal replacement. This framework highlights how bacterial ecology affects the impact of clinical interventions.

  View details for DOI 10.1038/s41559-017-0337-x

  View details for PubMedID 29038424

  View details for PubMedCentralID PMC5708525

• Vaccine Effects on Heterogeneity in Susceptibility and Implications for Population Health Management. mBio Langwig, K. E., Wargo, A. R., Jones, D. R., Viss, J. R., Rutan, B. J., Egan, N. A., Sá-Guimarães, P., Kim, M. S., Kurath, G., Gomes, M. G., Lipsitch, M. 2017; 8 (6)

  Abstract

  Heterogeneity in host susceptibility is a key determinant of infectious disease dynamics but is rarely accounted for in assessment of disease control measures. Understanding how susceptibility is distributed in populations, and how control measures change this distribution, is integral to predicting the course of epidemics with and without interventions. Using multiple experimental and modeling approaches, we show that rainbow trout have relatively homogeneous susceptibility to infection with infectious hematopoietic necrosis virus and that vaccination increases heterogeneity in susceptibility in a nearly all-or-nothing fashion. In a simple transmission model with an R0 of 2, the highly heterogeneous vaccine protection would cause a 35 percentage-point reduction in outbreak size over an intervention inducing homogenous protection at the same mean level. More broadly, these findings provide validation of methodology that can help to reduce biases in predictions of vaccine impact in natural settings and provide insight into how vaccination shapes population susceptibility.IMPORTANCE Differences among individuals influence transmission and spread of infectious diseases as well as the effectiveness of control measures. Control measures, such as vaccines, may provide leaky protection, protecting all hosts to an identical degree, or all-or-nothing protection, protecting some hosts completely while leaving others completely unprotected. This distinction can have a dramatic influence on disease dynamics, yet this distribution of protection is frequently unaccounted for in epidemiological models and estimates of vaccine efficacy. Here, we apply new methodology to experimentally examine host heterogeneity in susceptibility and mode of vaccine action as distinct components influencing disease outcome. Through multiple experiments and new modeling approaches, we show that the distribution of vaccine effects can be robustly estimated. These results offer new experimental and inferential methodology that can improve predictions of vaccine effectiveness and have broad applicability to human, wildlife, and ecosystem health.

  View details for DOI 10.1128/mBio.00796-17

  View details for PubMedID 29162706

  View details for PubMedCentralID PMC5698548

• Pan-serotype Reduction in Progression of Streptococcus pneumoniae to Otitis Media After Rollout of Pneumococcal Conjugate Vaccines. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Lewnard, J. A., Givon-Lavi, N., Weinberger, D. M., Lipsitch, M., Dagan, R. 2017; 65 (11): 1853-1861

  Abstract

  Reductions in otitis media (OM) burden following rollout of pneumococcal conjugate vaccines (PCVs) have exceeded predictions of vaccine impact. In settings with active surveillance, reductions in OM caused by vaccine-targeted pneumococcal serotypes have co-occurred with reductions in OM caused by other pathogens carried in the upper-respiratory tract of children. To understand these changes, we investigated the progression of vaccine-targeted and non-vaccine pneumococcal serotypes from carriage to OM before and after vaccine rollout.Nasopharyngeal carriage prevalence of pneumococcus was monitored in prospective studies of Bedouin and Jewish children <3 years old in southern Israel between 2004 and 2016. Incidence of OM necessitating middle-ear fluid culture (predominantly complex OM including recurrent, spontaneously-draining, non-responsive, and chronic cases) was monitored via prospective, population-based active surveillance. We estimated rates of pneumococcal serotype-specific progression from carriage to disease before and after rollout of PCV7/13, measured as OM incidence per carrier. We pooled serotype-specific estimates using Bayesian random-effects models.On average, rates of progression declined 92% (95% credible interval: 79-97%) and 80% (46-93%) for PCV7/13 serotypes among Bedouin and Jewish children <12 months old, respectively, and 32% (-58-71%) and 61% (-5-86%) among children aged 12-35m. For non-vaccine serotypes, rates of progression among Bedouin and Jewish children aged <12m declined 74% (55-85%) and 43% (4-68%), respectively.Vaccine-targeted and non-vaccine pneumococcal serotypes showed lower rates of progression to complex OM after rollout of PCV7/13. Early-life OM episodes historically associated with vaccine-serotype pneumococci may impact the susceptibility of children to OM progression.

  View details for DOI 10.1093/cid/cix673

  View details for PubMedID 29020218

  View details for PubMedCentralID PMC6248775

• Immunization, Antibiotic Use, and Pneumococcal Colonization Over a 15-Year Period PEDIATRICS Lee, G. M., Kleinman, K., Pelton, S., Lipsitch, M., Huang, S. S., Lakoma, M., Dutta-Linn, M., Rett, M., Hanage, W. P., Finkelstein, J. A. 2017; 140 (5)

  View details for DOI 10.1542/peds.2017-0001

  View details for Web of Science ID 000414119600012

• Displacement of sexual partnerships in trials of sexual behavior interventions: A model-based assessment of consequences. Epidemics McCormick, A. W., Abuelezam, N. N., Fussell, T., Seage, G. R., Lipsitch, M. 2017; 20: 94-101

  Abstract

  We investigated the impact of the displacement of sexual activity from adherent recipients of an intervention to others within or outside a trial population on the results from hypothetical trials of different sexual behavior interventions. A short-term model of HIV-prevention interventions that lead to female rejection of male partnership requests showed the impact of displacement expected at the start of a trial. An agent-based model, with sexual mixing and other South African specific demographics, evaluated consequences of displacement for sexual behavior interventions targeting young females in South Africa. This model measured the cumulative incidence among adherent, non-adherent, control and non-enrolled females in a hypothetical trial of HIV prevention. When males made more than one attempt to seek a partnership, interventions reduced short-term HIV infection risk among adherent females, but increased it among non-adherent females as well as controls, non-enrolled (females eligible for the trial but not chosen to participate) and ineligible females (females that did not qualify for the trial due to age). The impact of displacement depends on the intervention and the adherence. In both models, the risk to individuals who are not members of the adherent intervention group will increase with displacement leading to a biased calculation for the effect estimates for the trial. Likewise, intent-to-treat effect estimates become nonlinear functions of the proportion adherent.

  View details for DOI 10.1016/j.epidem.2017.03.007

  View details for PubMedID 28416219

  View details for PubMedCentralID PMC5610917

• Vaccine testing for emerging infections: the case for individual randomisation. Journal of medical ethics Eyal, N., Lipsitch, M. 2017; 43 (9): 625-631

  Abstract

  During the 2014-2015 Ebola outbreak in Guinea, Liberia and Sierra Leone, many opposed the use of individually randomised controlled trials to test candidate Ebola vaccines. For a raging fatal disease, they explained, it is unethical to relegate some study participants to control arms. In Zika and future emerging infections, similar opposition may hinder urgent vaccine research, so it is best to address these questions now. This article lays out the ethical case for individually randomised control in testing vaccines against many emerging infections, including lethal infections in low-income countries, even when at no point in the trial do the controls receive the countermeasures being tested. When individual randomisation is feasible-and it often will be-it tends to save more lives than alternative designs would. And for emerging infections, individual randomisation also tends as such to improve care, access to the experimental vaccine and prospects for all participants relative to their opportunities absent the trial, and no less than alternative designs would. That obtains even under placebo control and without equipoise-requiring which would undermine individual randomisation and the alternative designs that opponents proffered. Our arguments expound four often-neglected factors: benefits to non-participants, benefits to participants once a trial is over including post-trial access to the study intervention, participants' prospects before randomisation to arms and the near-inevitable disparity between arms in any randomised controlled trial.

  View details for DOI 10.1136/medethics-2015-103220

  View details for PubMedID 28396558

  View details for PubMedCentralID PMC5577361

• Host population structure and treatment frequency maintain balancing selection on drug resistance. Journal of the Royal Society, Interface Cobey, S., Baskerville, E. B., Colijn, C., Hanage, W., Fraser, C., Lipsitch, M. 2017; 14 (133)

  Abstract

  It is a truism that antimicrobial drugs select for resistance, but explaining pathogen- and population-specific variation in patterns of resistance remains an open problem. Like other common commensals, Streptococcus pneumoniae has demonstrated persistent coexistence of drug-sensitive and drug-resistant strains. Theoretically, this outcome is unlikely. We modelled the dynamics of competing strains of S. pneumoniae to investigate the impact of transmission dynamics and treatment-induced selective pressures on the probability of stable coexistence. We find that the outcome of competition is extremely sensitive to structure in the host population, although coexistence can arise from age-assortative transmission models with age-varying rates of antibiotic use. Moreover, we find that the selective pressure from antibiotics arises not so much from the rate of antibiotic use per se but from the frequency of treatment: frequent antibiotic therapy disproportionately impacts the fitness of sensitive strains. This same phenomenon explains why serotypes with longer durations of carriage tend to be more resistant. These dynamics may apply to other potentially pathogenic, microbial commensals and highlight how population structure, which is often omitted from models, can have a large impact.

  View details for DOI 10.1098/rsif.2017.0295

  View details for PubMedID 28835542

  View details for PubMedCentralID PMC5582124

• Improving vaccine trials in infectious disease emergencies. Science (New York, N.Y.) Lipsitch, M., Eyal, N. 2017; 357 (6347): 153-156

  Abstract

  Unprecedented global effort is under way to facilitate the testing of countermeasures in infectious disease emergencies. Better understanding of the various options for trial design is needed in advance of outbreaks, as is preliminary global agreement on the most suitable designs for the various scenarios. What would enhance the speed, validity, and ethics of clinical studies of such countermeasures? Focusing on studies of vaccine efficacy and effectiveness in emergencies, we highlight three needs: for formal randomized trials-even in most emergencies; for individually randomized trials-even in many emergencies; and for six areas of innovation in trial methodology. These needs should inform current updates of protocols and roadmaps.

  View details for DOI 10.1126/science.aam8334

  View details for PubMedID 28706038

  View details for PubMedCentralID PMC5568786

• Systematic analysis of protein identity between Zika virus and other arthropod-borne viruses. Bulletin of the World Health Organization Chang, H. H., Huber, R. G., Bond, P. J., Grad, Y. H., Camerini, D., Maurer-Stroh, S., Lipsitch, M. 2017; 95 (7): 517-525I

  Abstract

  To analyse the proportions of protein identity between Zika virus and dengue, Japanese encephalitis, yellow fever, West Nile and chikungunya viruses as well as polymorphism between different Zika virus strains.We used published protein sequences for the Zika virus and obtained protein sequences for the other viruses from the National Center for Biotechnology Information (NCBI) protein database or the NCBI virus variation resource. We used BLASTP to find regions of identity between viruses. We quantified the identity between the Zika virus and each of the other viruses, as well as within-Zika virus polymorphism for all amino acid k-mers across the proteome, with k ranging from 6 to 100. We assessed accessibility of protein fragments by calculating the solvent accessible surface area for the envelope and nonstructural-1 (NS1) proteins.In total, we identified 294 Zika virus protein fragments with both low proportion of identity with other viruses and low levels of polymorphisms among Zika virus strains. The list includes protein fragments from all Zika virus proteins, except NS3. NS4A has the highest number (190 k-mers) of protein fragments on the list.We provide a candidate list of protein fragments that could be used when developing a sensitive and specific serological test to detect previous Zika virus infections.

  View details for DOI 10.2471/BLT.16.182105

  View details for PubMedID 28670016

  View details for PubMedCentralID PMC5487971

• Population effect of influenza vaccination under co-circulation of non-vaccine variants and the case for a bivalent A/H3N2 vaccine component. Epidemics Worby, C. J., Wallinga, J., Lipsitch, M., Goldstein, E. 2017; 19: 74-82

  Abstract

  Some past epidemics of different influenza subtypes (particularly A/H3N2) in the US saw co-circulation of vaccine-type and variant strains. There is evidence that natural infection with one influenza subtype offers short-term protection against infection with another influenza subtype (henceforth, cross-immunity). This suggests that such cross-immunity for strains within a subtype is expected to be strong. Therefore, while vaccination effective against one strain may reduce transmission of that strain, this may also lead to a reduction of the vaccine-type strain's ability to suppress spread of a variant strain. It remains unclear what the joint effect of vaccination and cross-immunity is for co-circulating influenza strains within a subtype, and what is the potential benefit of a bivalent vaccine that protects against both strains. We simulated co-circulation of vaccine-type and variant strains under a variety of scenarios. In each scenario, we considered the case when the vaccine efficacy against the variant strain is lower than the efficacy against the vaccine-type strain (monovalent vaccine), as well the case when vaccine is equally efficacious against both strains (bivalent vaccine). Administration of a bivalent vaccine results in a significant reduction in the overall incidence of infection compared to administration of a monovalent vaccine, even with lower coverage by the bivalent vaccine. Additionally, we found that with greater cross-immunity, increasing coverage levels for the monovalent vaccine becomes less beneficial, while introducing the bivalent vaccine becomes more beneficial. Our work exhibits the limitations of influenza vaccines that have low efficacy against non-vaccine strains, and demonstrates the benefits of vaccines that offer good protection against multiple influenza strains. The results elucidate the need for guarding against the potential co-circulation of non-vaccine strains for an influenza subtype, at least during select seasons, possibly through inclusion of multiple strains within a subtype (particularly A/H3N2) in a vaccine.

  View details for DOI 10.1016/j.epidem.2017.02.008

  View details for PubMedID 28262588

  View details for PubMedCentralID PMC5533618

• Underprotection of Unpredictable Statistical Lives Compared to Predictable Ones. Risk analysis : an official publication of the Society for Risk Analysis Lipsitch, M., Evans, N. G., Cotton-Barratt, O. 2017; 37 (5): 893-904

  Abstract

  Existing ethical discussion considers the differences in care for identified versus statistical lives. However, there has been little attention to the different degrees of care that are taken for different kinds of statistical lives. Here we argue that for a given number of statistical lives at stake, there will sometimes be different, and usually greater, care taken to protect predictable statistical lives, in which the number of lives that will be lost can be predicted fairly accurately, than for unpredictable statistical lives, where the lives are at stake because of a low-probability event, such that most likely no one will be affected by the decision but with low probability some lives will be at stake. One reason for this difference is the statistical challenge of estimating low probabilities, and in particular the tendency of common approaches to underestimate these probabilities. Another is the existence of rational incentives to treat unpredictable risks as if the probabilities were lower than they are. Some of these factors apply outside the pure economic context, to institutions, individuals, and governments. We argue that there is no ethical reason to treat unpredictable statistical lives differently from predictable statistical lives. Moreover, lives that are unpredictable from the perspective of an individual agent may become predictable when aggregated to the level of a societal decision. Underprotection of unpredictable statistical lives is a form of market failure that may need to be corrected by altering regulation, introducing compulsory liability insurance, or other social policies.

  View details for DOI 10.1111/risa.12658

  View details for PubMedID 27393181

  View details for PubMedCentralID PMC5222861

• Using simulation to aid trial design: Ring-vaccination trials. PLoS neglected tropical diseases Hitchings, M. D., Grais, R. F., Lipsitch, M. 2017; 11 (3): e0005470

  Abstract

  The 2014-6 West African Ebola epidemic highlights the need for rigorous, rapid clinical trial methods for vaccines. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination.We present a stochastic, compartmental model for a ring vaccination trial. After identification of an index case, a ring of contacts is recruited and either vaccinated immediately or after 21 days. The primary outcome of the trial is total vaccine effect, counting cases only from a pre-specified window in which the immediate arm is assumed to be fully protected and the delayed arm is not protected. Simulation results are used to calculate necessary sample size and estimated vaccine effect. Under baseline assumptions about vaccine properties, monthly incidence in unvaccinated rings and trial design, a standard sample-size calculation neglecting dynamic effects estimated that 7,100 participants would be needed to achieve 80% power to detect a difference in attack rate between arms, while incorporating dynamic considerations in the model increased the estimate to 8,900. This approach replaces assumptions about parameters at the ring level with assumptions about disease dynamics and vaccine characteristics at the individual level, so within this framework we were able to describe the sensitivity of the trial power and estimated effect to various parameters. We found that both of these quantities are sensitive to properties of the vaccine, to setting-specific parameters over which investigators have little control, and to parameters that are determined by the study design.Incorporating simulation into the trial design process can improve robustness of sample size calculations. For this specific trial design, vaccine effectiveness depends on properties of the ring vaccination design and on the measurement window, as well as the epidemiologic setting.

  View details for DOI 10.1371/journal.pntd.0005470

  View details for PubMedID 28328984

  View details for PubMedCentralID PMC5378415

• Monitoring the fitness of antiviral-resistant influenza strains during an epidemic: a mathematical modelling study. The Lancet. Infectious diseases Leung, K., Lipsitch, M., Yuen, K. Y., Wu, J. T. 2017; 17 (3): 339-347

  Abstract

  Antivirals (eg, oseltamivir) are important for mitigating influenza epidemics. In 2007, an oseltamivir-resistant influenza seasonal A H1N1 strain emerged and spread to global fixation within 1 year. This event showed that antiviral-resistant (AVR) strains can be intrinsically more transmissible than their contemporaneous antiviral-sensitive (AVS) counterpart. Surveillance of AVR fitness is therefore essential. Our objective was to develop a simple method for estimating AVR fitness from surveillance data.We defined the fitness of AVR strains as their reproductive number relative to their co-circulating AVS counterparts. We developed a simple method for real-time estimation of AVR fitness from surveillance data. This method requires only information on generation time without other specific details regarding transmission dynamics. We first used simulations to validate this method by showing that it yields unbiased and robust fitness estimates in most epidemic scenarios. We then applied this method to two retrospective case studies and one hypothetical case study.We estimated that the oseltamivir-resistant A H1N1 strain that emerged in 2007 was 4% (95% credible interval [CrI] 3-5) more transmissible than its oseltamivir-sensitive predecessor and the oseltamivir-resistant pandemic A H1N1 strain that emerged and circulated in Japan during 2013-14 was 24% (95% CrI 17-30) less transmissible than its oseltamivir-sensitive counterpart. We show that in the event of large-scale antiviral interventions during a pandemic with co-circulation of AVS and AVR strains, our method can be used to inform optimal use of antivirals by monitoring intrinsic AVR fitness and drug pressure on the AVS strain.We developed a simple method that can be easily integrated into contemporary influenza surveillance systems to provide reliable estimates of AVR fitness in real time.Research Fund for the Control of Infectious Disease (09080792) and a commissioned grant from the Health and Medical Research Fund from the Government of the Hong Kong Special Administrative Region, Harvard Center for Communicable Disease Dynamics from the National Institute of General Medical Sciences (grant number U54 GM088558), Area of Excellence Scheme of the Hong Kong University Grants Committee (grant number AoE/M-12/06).

  View details for DOI 10.1016/S1473-3099(16)30465-0

  View details for PubMedID 27914853

  View details for PubMedCentralID PMC5470942

• Association of Pneumococcal Protein Antigen Serology With Age and Antigenic Profile of Colonizing Isolates. The Journal of infectious diseases Azarian, T., Grant, L. R., Georgieva, M., Hammitt, L. L., Reid, R., Bentley, S. D., Goldblatt, D., Santosham, M., Weatherholtz, R., Burbidge, P., Goklish, N., Thompson, C. M., Hanage, W. P., O'Brien, K. L., Lipsitch, M. 2017; 215 (5): 713-722

  Abstract

  Several Streptococcus pneumoniae proteins play a role in pathogenesis and are being investigated as vaccine targets. It is largely unknown whether naturally acquired antibodies reduce the risk of colonization with strains expressing a particular antigenic variant.Serum immunoglobulin G (IgG) titers to 28 pneumococcal protein antigens were measured among 242 individuals aged <6 months-78 years in Native American communities between 2007 and 2009. Nasopharyngeal swabs were collected >- 30 days after serum collection, and the antigen variant in each pneumococcal isolate was determined using genomic data. We assessed the association between preexisting variant-specific antibody titers and subsequent carriage of pneumococcus expressing a particular antigen variant.Antibody titers often increased across pediatric groups before decreasing among adults. Individuals with low titers against group 3 pneumococcal surface protein C (PspC) variants were more likely to be colonized with pneumococci expressing those variants. For other antigens, variant-specific IgG titers do not predict colonization.We observed an inverse association between variant-specific antibody concentration and homologous pneumococcal colonization for only 1 protein. Further assessment of antibody repertoires may elucidate the nature of antipneumococcal antibody-mediated mucosal immunity while informing vaccine development.

  View details for DOI 10.1093/infdis/jiw628

  View details for PubMedID 28035010

  View details for PubMedCentralID PMC6005115

• Reply to Allan-Blitz and Klausner. The Journal of infectious diseases Grad, Y. H., Lipsitch, M. 2017; 215 (3): 491-492

  View details for DOI 10.1093/infdis/jiw552

  View details for PubMedID 28003355

  View details for PubMedCentralID PMC5873214

• Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage. Proceedings of the National Academy of Sciences of the United States of America Lehtinen, S., Blanquart, F., Croucher, N. J., Turner, P., Lipsitch, M., Fraser, C. 2017; 114 (5): 1075-1080

  Abstract

  Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance.

  View details for DOI 10.1073/pnas.1617849114

  View details for PubMedID 28096340

  View details for PubMedCentralID PMC5293062

• Diverse evolutionary patterns of pneumococcal antigens identified by pangenome-wide immunological screening. Proceedings of the National Academy of Sciences of the United States of America Croucher, N. J., Campo, J. J., Le, T. Q., Liang, X., Bentley, S. D., Hanage, W. P., Lipsitch, M. 2017; 114 (3): E357-E366

  Abstract

  Characterizing the immune response to pneumococcal proteins is critical in understanding this bacterium's epidemiology and vaccinology. Probing a custom-designed proteome microarray with sera from 35 healthy US adults revealed a continuous distribution of IgG affinities for 2,190 potential antigens from the species-wide pangenome. Reproducibly elevated IgG binding was elicited by 208 "antibody binding targets" (ABTs), which included 109 variants of the diverse pneumococcal surface proteins A and C (PspA and PspC) and zinc metalloprotease A and B (ZmpA and ZmpB) proteins. Functional analysis found ABTs were enriched in motifs for secretion and cell surface association, with extensive representation of cell wall synthesis machinery, adhesins, transporter solute-binding proteins, and degradative enzymes. ABTs were associated with stronger evidence for evolving under positive selection, although this varied between functional categories, as did rates of diversification through recombination. Particularly rapid variation was observed at some immunogenic accessory loci, including a phage protein and a phase-variable glycosyltransferase ubiquitous among the diverse set of genomic islands encoding the serine-rich PsrP glycoprotein. Nevertheless, many antigens were conserved in the core genome, and strains' antigenic profiles were generally stable. No strong evidence was found for any epistasis between antigens driving population dynamics, or redundancy between functionally similar accessory ABTs, or age stratification of antigen profiles. These results highlight the paradox of why substantial variation is observed in only a subset of epitopes. This result may indicate only some interactions between immunoglobulins and ABTs clear pneumococcal colonization or that acquired immunity to pneumococci is an accumulation of individually weak responses to ABTs evolving under different levels of functional constraint.

  View details for DOI 10.1073/pnas.1613937114

  View details for PubMedID 28053228

  View details for PubMedCentralID PMC5255586

• Immunization, Antibiotic Use, and Pneumococcal Colonization Over a 15-Year Period. Pediatrics Lee, G. M., Kleinman, K. n., Pelton, S. n., Lipsitch, M. n., Huang, S. S., Lakoma, M. n., Dutta-Linn, M. n., Rett, M. n., Hanage, W. P., Finkelstein, J. A. 2017; 140 (5)

  Abstract

  Rates of invasive pneumococcal disease have declined since widespread introduction of pneumococcal conjugate vaccines (PCVs) in the United States. We evaluated the impact of immunization status and recent antibiotic use on an individual child's risk of colonization.This study extends previously reported data from children <7 years of age seen for well child or acute care visits in Massachusetts communities. Nasopharyngeal swabs were collected during 6 surveillance seasons from 2000 to 2014. Parent surveys and medical record reviews confirmed immunization status and recent antibiotic use. We estimated the proportions of children colonized with PCV7-included, additional PCV13-included, and non-PCV13 serotypes. Risk factors for colonization with additional PCV13-included and non-PCV13 serotypes were assessed by using generalized linear mixed models adjusted for clustering by community.Among 6537 children, 19A emerged as the predominant serotype in 2004, with substantial reductions in 2014. Among non-PCV serotypes, 15B/C, 35B, 23B, 11A, and 23A were most common in 2014. We observed greater odds for both additional PCV13 and non-PCV13 colonization in younger children, those with more child care exposure, and those with a concomitant respiratory tract infection. Adjusted odds for additional PCV13 colonization was lower (odds ratio 0.48 [95% confidence interval 0.31-0.75]) among children up-to-date for PCV13 vaccines. Recent antibiotic use was associated with higher odds of additional PCV13 colonization but substantially lower odds of non-PCV13 colonization.Despite the success of pneumococcal vaccines in reducing colonization and disease due to targeted serotypes, ongoing community-based surveillance will be critical to evaluate the impact of interventions on pneumococcal colonization and disease.

  View details for PubMedID 28978716

  View details for PubMedCentralID PMC5654389

• Temporally Varying Relative Risks for Infectious Diseases: Implications for Infectious Disease Control. Epidemiology (Cambridge, Mass.) Goldstein, E., Pitzer, V. E., O'Hagan, J. J., Lipsitch, M. 2017; 28 (1): 136-144

  Abstract

  Risks for disease in some population groups relative to others (relative risks) are usually considered to be consistent over time, although they are often modified by other, nontemporal factors. For infectious diseases, in which overall incidence often varies substantially over time, the patterns of temporal changes in relative risks can inform our understanding of basic epidemiologic questions. For example, recent studies suggest that temporal changes in relative risks of infection over the course of an epidemic cycle can both be used to identify population groups that drive infectious disease outbreaks, and help elucidate differences in the effect of vaccination against infection (that is relevant to transmission control) compared with its effect against disease episodes (that reflects individual protection). Patterns of change in the age groups affected over the course of seasonal outbreaks can provide clues to the types of pathogens that could be responsible for diseases for which an infectious cause is suspected. Changing apparent efficacy of vaccines during trials may provide clues to the vaccine's mode of action and/or indicate risk heterogeneity in the trial population. Declining importance of unusual behavioral risk factors may be a signal of increased local transmission of an infection. We review these developments and the related public health implications.

  View details for DOI 10.1097/EDE.0000000000000571

  View details for PubMedID 27748685

  View details for PubMedCentralID PMC5131868

• Fractional dosing of yellow fever vaccine to extend supply: a modelling study. Lancet (London, England) Wu, J. T., Peak, C. M., Leung, G. M., Lipsitch, M. 2016; 388 (10062): 2904-2911

  Abstract

  The ongoing yellow fever epidemic in Angola strains the global vaccine supply, prompting WHO to adopt dose sparing for its vaccination campaign in Kinshasa, Democratic Republic of the Congo, in July-August, 2016. Although a 5-fold fractional-dose vaccine is similar to standard-dose vaccine in safety and immunogenicity, efficacy is untested. There is an urgent need to ensure the robustness of fractional-dose vaccination by elucidation of the conditions under which dose fractionation would reduce transmission.We estimate the effective reproductive number for yellow fever in Angola using disease natural history and case report data. With simple mathematical models of yellow fever transmission, we calculate the infection attack rate (the proportion of population infected over the course of an epidemic) with various levels of transmissibility and 5-fold fractional-dose vaccine efficacy for two vaccination scenarios, ie, random vaccination in a hypothetical population that is completely susceptible, and the Kinshasa vaccination campaign in July-August, 2016, with different age cutoff for fractional-dose vaccines.We estimate the effective reproductive number early in the Angola outbreak was between 5·2 and 7·1. If vaccine action is all-or-nothing (ie, a proportion of vaccine recipients receive complete protection [VE] and the remainder receive no protection), n-fold fractionation can greatly reduce infection attack rate as long as VE exceeds 1/n. This benefit threshold becomes more stringent if vaccine action is leaky (ie, the susceptibility of each vaccine recipient is reduced by a factor that is equal to the vaccine efficacy). The age cutoff for fractional-dose vaccines chosen by WHO for the Kinshasa vaccination campaign (2 years) provides the largest reduction in infection attack rate if the efficacy of 5-fold fractional-dose vaccines exceeds 20%.Dose fractionation is an effective strategy for reduction of the infection attack rate that would be robust with a large margin for error in case fractional-dose VE is lower than expected.NIH-MIDAS, HMRF-Hong Kong.

  View details for DOI 10.1016/S0140-6736(16)31838-4

  View details for PubMedID 27837923

  View details for PubMedCentralID PMC5161610

• Observational studies and the difficult quest for causality: lessons from vaccine effectiveness and impact studies. International journal of epidemiology Lipsitch, M., Jha, A., Simonsen, L. 2016; 45 (6): 2060-2074

  Abstract

  Although randomized placebo-controlled trials (RCT) are critical to establish efficacy of vaccines at the time of licensure, important remaining questions about vaccine effectiveness (VE)-used here to include individual-level measures and population-wide impact of vaccine programmes-can only be answered once the vaccine is in use, from observational studies. However, such studies are inherently at risk for bias. Using a causal framework and illustrating with examples, we review newer approaches to detecting and avoiding confounding and selection bias in three major classes of observational study design: cohort, case-control and ecological studies. Studies of influenza VE, especially in seniors, are an excellent demonstration of the challenges of detecting and reducing such bias, and so we use influenza VE as a running example. We take a fresh look at the time-trend studies often dismissed as 'ecological'. Such designs are the only observational study design that can measure the overall effect of a vaccination programme [indirect (herd) as well as direct effects], and are in fact already an important part of the evidence base for several vaccines currently in use. Despite the great strides towards more robust observational study designs, challenges lie ahead for evaluating best practices for achieving robust unbiased results from observational studies. This is critical for evaluation of national and global vaccine programme effectiveness.

  View details for DOI 10.1093/ije/dyw124

  View details for PubMedID 27453361

  View details for PubMedCentralID PMC5841615

• Genomic Epidemiology of Gonococcal Resistance to Extended-Spectrum Cephalosporins, Macrolides, and Fluoroquinolones in the United States, 2000-2013. The Journal of infectious diseases Grad, Y. H., Harris, S. R., Kirkcaldy, R. D., Green, A. G., Marks, D. S., Bentley, S. D., Trees, D., Lipsitch, M. 2016; 214 (10): 1579-1587

  Abstract

  Treatment of Neisseria gonorrhoeae infection is empirical and based on population-wide susceptibilities. Increasing antimicrobial resistance underscores the potential importance of rapid diagnostic tests, including sequence-based tests, to guide therapy. However, the usefulness of sequence-based diagnostic tests depends on the prevalence and dynamics of the resistance mechanisms.We define the prevalence and dynamics of resistance markers to extended-spectrum cephalosporins, macrolides, and fluoroquinolones in 1102 resistant and susceptible clinical N. gonorrhoeae isolates collected from 2000 to 2013 via the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project.Reduced extended-spectrum cephalosporin susceptibility is predominantly clonal and associated with the mosaic penA XXXIV allele and derivatives (sensitivity 98% for cefixime and 91% for ceftriaxone), but alternative resistance mechanisms have sporadically emerged. Reduced azithromycin susceptibility has arisen through multiple mechanisms and shows limited clonal spread; the basis for resistance in 36% of isolates with reduced azithromycin susceptibility is unclear. Quinolone-resistant N. gonorrhoeae has arisen multiple times, with extensive clonal spread.Quinolone-resistant N. gonorrhoeae and reduced cefixime susceptibility appear amenable to development of sequence-based diagnostic tests, whereas the undefined mechanisms of resistance to ceftriaxone and azithromycin underscore the importance of phenotypic surveillance. The identification of multidrug-resistant isolates highlights the need for additional measures to respond to the threat of untreatable gonorrhea.

  View details for DOI 10.1093/infdis/jiw420

  View details for PubMedID 27638945

  View details for PubMedCentralID PMC5091375

• Viral factors in influenza pandemic risk assessment. eLife Lipsitch, M., Barclay, W., Raman, R., Russell, C. J., Belser, J. A., Cobey, S., Kasson, P. M., Lloyd-Smith, J. O., Maurer-Stroh, S., Riley, S., Beauchemin, C. A., Bedford, T., Friedrich, T. C., Handel, A., Herfst, S., Murcia, P. R., Roche, B., Wilke, C. O., Russell, C. A. 2016; 5

  Abstract

  The threat of an influenza A virus pandemic stems from continual virus spillovers from reservoir species, a tiny fraction of which spark sustained transmission in humans. To date, no pandemic emergence of a new influenza strain has been preceded by detection of a closely related precursor in an animal or human. Nonetheless, influenza surveillance efforts are expanding, prompting a need for tools to assess the pandemic risk posed by a detected virus. The goal would be to use genetic sequence and/or biological assays of viral traits to identify those non-human influenza viruses with the greatest risk of evolving into pandemic threats, and/or to understand drivers of such evolution, to prioritize pandemic prevention or response measures. We describe such efforts, identify progress and ongoing challenges, and discuss three specific traits of influenza viruses (hemagglutinin receptor binding specificity, hemagglutinin pH of activation, and polymerase complex efficiency) that contribute to pandemic risk.

  View details for DOI 10.7554/eLife.18491

  View details for PubMedID 27834632

  View details for PubMedCentralID PMC5156527

• Comment on "Gain-of-Function Research and the Relevance to Clinical Practice". The Journal of infectious diseases Lipsitch, M. 2016; 214 (8): 1284-5

  View details for DOI 10.1093/infdis/jiw348

  View details for PubMedID 27503367

  View details for PubMedCentralID PMC7107370

• Zika vaccine trials. Science (New York, N.Y.) Lipsitch, M., Cowling, B. J. 2016; 353 (6304): 1094-5

  View details for DOI 10.1126/science.aai8126

  View details for PubMedID 27609872

• How Can Vaccines Contribute to Solving the Antimicrobial Resistance Problem? mBio Lipsitch, M., Siber, G. R. 2016; 7 (3)

  Abstract

  There is a growing appreciation for the role of vaccines in confronting the problem of antimicrobial resistance (AMR). Vaccines can reduce the prevalence of resistance by reducing the need for antimicrobial use and can reduce its impact by reducing the total number of cases. By reducing the number of pathogens that may be responsible for a particular clinical syndrome, vaccines can permit the use of narrower-spectrum antibiotics for empirical therapy. These effects may be amplified by herd immunity, extending protection to unvaccinated persons in the population. Because much selection for resistance is due to selection on bystander members of the normal flora, vaccination can reduce pressure for resistance even in pathogens not included in the vaccine. Some vaccines have had disproportionate effects on drug-resistant lineages within the target species, a benefit that could be more deliberately exploited in vaccine design. We describe the effects of current vaccines in controlling AMR, survey some vaccines in development with the potential to do so further, and discuss strategies to amplify these benefits. We conclude with a discussion of research and policy priorities to more fully enlist vaccines in the battle against AMR.

  View details for DOI 10.1128/mBio.00428-16

  View details for PubMedID 27273824

  View details for PubMedCentralID PMC4959668

• Infectious Diseases Society of America and Gain-of-Function Experiments With Pathogens Having Pandemic Potential JOURNAL OF INFECTIOUS DISEASES Frank, G. M., Adalja, A., Barbour, A., Casadevall, A., Dormitzer, P. R., Duchin, J., Hayden, F. G., Hirsch, M. S., Hynes, N. A., Lipsitch, M., Pavia, A. T., Relman, D. A. 2016; 213 (9): 1359–61

  View details for PubMedID 26416656

• Improving Control of Antibiotic-Resistant Gonorrhea by Integrating Research Agendas Across Disciplines: Key Questions Arising From Mathematical Modeling. The Journal of infectious diseases Grad, Y. H., Goldstein, E., Lipsitch, M., White, P. J. 2016; 213 (6): 883-90

  Abstract

  The rise in gonococcal antibiotic resistance and the threat of untreatable infection are focusing attention on strategies to limit the spread of drug-resistant gonorrhea. Mathematical models provide a framework to link the natural history of infection and patient behavior to epidemiological outcomes and can be used to guide research and enhance the public health impact of interventions. While limited knowledge of key disease parameters and networks of spread has impeded development of operational models of gonococcal transmission, new tools in gonococcal surveillance may provide useful data to aid tracking and modeling. Here, we highlight critical questions in the management of gonorrhea that can be addressed by mathematical models and identify key data needs. Our overarching aim is to articulate a shared agenda across gonococcus-related fields from microbiology to epidemiology that will catalyze a comprehensive evidence-based clinical and public health strategy for management of gonococcal infections and antimicrobial resistance.

  View details for DOI 10.1093/infdis/jiv517

  View details for PubMedID 26518045

  View details for PubMedCentralID PMC4760416

• Identifying the effect of patient sharing on between-hospital genetic differentiation of methicillin-resistant Staphylococcus aureus GENOME MEDICINE Chang, H., Dordel, J., Donker, T., Worby, C. J., Feil, E. J., Hanage, W. P., Bentley, S. D., Huang, S. S., Lipsitch, M. 2016; 8

  Abstract

  Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common healthcare-associated pathogens. To examine the role of inter-hospital patient sharing on MRSA transmission, a previous study collected 2,214 samples from 30 hospitals in Orange County, California and showed by spa typing that genetic differentiation decreased significantly with increased patient sharing. In the current study, we focused on the 986 samples with spa type t008 from the same population.We used genome sequencing to determine the effect of patient sharing on genetic differentiation between hospitals. Genetic differentiation was measured by between-hospital genetic diversity, F ST , and the proportion of nearly identical isolates between hospitals.Surprisingly, we found very similar genetic diversity within and between hospitals, and no significant association between patient sharing and genetic differentiation measured by F ST . However, in contrast to F ST , there was a significant association between patient sharing and the proportion of nearly identical isolates between hospitals. We propose that the proportion of nearly identical isolates is more powerful at determining transmission dynamics than traditional estimators of genetic differentiation (F ST ) when gene flow between populations is high, since it is more responsive to recent transmission events. Our hypothesis was supported by the results from coalescent simulations.Our results suggested that there was a high level of gene flow between hospitals facilitated by patient sharing, and that the proportion of nearly identical isolates is more sensitive to population structure than F ST when gene flow is high.

  View details for DOI 10.1186/s13073-016-0274-3

  View details for Web of Science ID 000369910400001

  View details for PubMedID 26873713

  View details for PubMedCentralID PMC4752745

• Impact of Host Heterogeneity on the Efficacy of Interventions to Reduce Staphylococcus aureus Carriage. Infection control and hospital epidemiology Chang, Q., Lipsitch, M., Hanage, W. P. 2016; 37 (2): 197-204

  Abstract

  Staphylococcus aureus is a common cause of bacterial infections worldwide. It is most commonly carried in and transmitted from the anterior nares. Hosts are known to vary in their proclivity for S. aureus nasal carriage and may be divided into persistent carriers, intermittent carriers, and noncarriers, depending on duration of carriage. Mathematical models of S. aureus to predict outcomes of interventions have, however, typically assumed that all individuals are equally susceptible to colonization.To characterize biases created by assuming a homogeneous host population in estimating efficacy of control interventions.Mathematical model.We developed a model of S. aureus carriage in the healthcare setting under the homogeneous assumption as well as a heterogeneous model to account for the 3 types of S. aureus carriers. In both models, we calculated the equilibrium carriage prevalence to predict the impact of control measures (reducing contact and decolonization).The homogeneous model almost always underestimates S. aureus transmissibility and overestimates the impact of intervention strategies in lowering carriage prevalence compared to the heterogeneous model. This finding is generally consistent regardless of changes in model setting that vary the proportions of various carriers in the population and the duration of carriage for these carrier types.Not accounting for host heterogeneity leads to systematic and substantial biases in predictions of the effects of intervention strategies. Further understanding of the clinical impacts of heterogeneity through modeling can help to target control measures and allocate resources more efficiently.

  View details for DOI 10.1017/ice.2015.269

  View details for PubMedID 26598029

  View details for PubMedCentralID PMC4760641

• Infective endocarditis and cancer in the elderly. European journal of epidemiology García-Albéniz, X., Hsu, J., Lipsitch, M., Logan, R. W., Hernández-Díaz, S., Hernán, M. A. 2016; 31 (1): 41-9

  Abstract

  Little is known about the magnitude of the association between infective endocarditis and cancer, and about the natural history of cancer patients with concomitant diagnosis of infective endocarditis. We used the SEER-Medicare linked database to identify individuals aged 65 years or more diagnosed with colorectal, lung, breast, or prostate cancer, and without any cancer diagnosis (5% random Medicare sample from SEER areas) between 1992 and 2009. We identified infective endocarditis from the ICD-9 diagnosis of each admission recorded in the Medpar file and its incidence rate 90 days around cancer diagnosis. We also estimated the overall survival and CRC-specific survival after a concomitant diagnosis of infective endocarditis. The peri-diagnostic incidence of infective endocarditis was 19.8 cases per 100,000 person-months for CRC, 5.7 cases per 100,000 person-months for lung cancer, 1.9 cases per 100,000 person-months for breast cancer, 4.1 cases per 100,000 person-months for prostate cancer and 2.4 cases per 100,000 person-months for individuals without cancer. Two-year overall survival was 46.4% (95% CI 39.5, 54.5%) for stage I-III CRC patients with concomitant endocarditis and 73.1% (95 % CI 72.9, 73.3%) for those without it. In this elderly population, the incidence of infective endocarditis around CRC diagnosis was substantially higher than around the diagnosis of lung, breast and prostate cancers. A concomitant diagnosis of infective endocarditis in patients with CRC diagnosis is associated with shorter survival.

  View details for DOI 10.1007/s10654-015-0111-9

  View details for PubMedID 26683995

  View details for PubMedCentralID PMC5354127

• On the relative role of different age groups in influenza epidemics. Epidemics Worby, C. J., Chaves, S. S., Wallinga, J., Lipsitch, M., Finelli, L., Goldstein, E. 2015; 13: 10-16

  Abstract

  The identification of key "driver" groups in influenza epidemics is of much interest for the implementation of effective public health response strategies, including vaccination programs. However, the relative importance of different age groups in propagating epidemics is uncertain. During a communicable disease outbreak, some groups may be disproportionately represented during the outbreak's ascent due to increased susceptibility and/or contact rates. Such groups or subpopulations can be identified by considering the proportion of cases within the subpopulation occurring before (Bp) and after the epidemic peak (Ap) to calculate the subpopulation's relative risk, RR=Bp/Ap. We estimated RR for several subpopulations (age groups) using data on laboratory-confirmed US influenza hospitalizations during epidemics between 2009-2014. Additionally, we simulated various influenza outbreaks in an age-stratified population, relating the RR to the impact of vaccination in each subpopulation on the epidemic's initial effective reproductive number R_e(0). We found that children aged 5-17 had the highest estimates of RR during the five largest influenza A outbreaks, though the relative magnitude of RR in this age group compared to other age groups varied, being highest for the 2009 A/H1N1 pandemic. For the 2010-2011 and 2012-2013 influenza B epidemics, adults aged 18-49, and 0-4 year-olds had the highest estimates of RR respectively. For 83% of simulated epidemics, the group with the highest RR was also the group for which initial distribution of a given quantity of vaccine would result in the largest reduction of R_e(0). In the largest 40% of simulated outbreaks, the group with the highest RR and the largest vaccination impact was children 5-17. While the relative importance of different age groups in propagating influenza outbreaks varies, children aged 5-17 play the leading role during the largest influenza A epidemics. Extra vaccination efforts for this group may contribute to reducing the epidemic's impact in the whole community.

  View details for DOI 10.1016/j.epidem.2015.04.003

  View details for PubMedID 26097505

  View details for PubMedCentralID PMC4469206

• The ethics of biosafety considerations in gain-of-function research resulting in the creation of potential pandemic pathogens. Journal of medical ethics Evans, N. G., Lipsitch, M., Levinson, M. 2015; 41 (11): 901-8

  Abstract

  This paper proposes an ethical framework for evaluating biosafety risks of gain-of-function (GOF) experiments that create novel strains of influenza expected to be virulent and transmissible in humans, so-called potential pandemic pathogens (PPPs). Such research raises ethical concerns because of the risk that accidental release from a laboratory could lead to extensive or even global spread of a virulent pathogen. Biomedical research ethics has focused largely on human subjects research, while biosafety concerns about accidental infections, seen largely as a problem of occupational health, have been ignored. GOF/PPP research is an example of a small but important class of research where biosafety risks threaten public health, well beyond the small number of persons conducting the research.We argue that bioethical principles that ordinarily apply only to human subjects research should also apply to research that threatens public health, even if, as in GOF/PPP studies, the research involves no human subjects. Specifically we highlight the Nuremberg Code's requirements of 'fruitful results for the good of society, unprocurable by other methods', and proportionality of risk and humanitarian benefit, as broad ethical principles that recur in later documents on research ethics and should also apply to certain types of research not involving human subjects. We address several potential objections to this view, and conclude with recommendations for bringing these ethical considerations into policy development.

  View details for DOI 10.1136/medethics-2014-102619

  View details for PubMedID 26320212

  View details for PubMedCentralID PMC4623968

• Population genomic datasets describing the post-vaccine evolutionary epidemiology of Streptococcus pneumoniae. Scientific data Croucher, N. J., Finkelstein, J. A., Pelton, S. I., Parkhill, J., Bentley, S. D., Lipsitch, M., Hanage, W. P. 2015; 2: 150058

  Abstract

  Streptococcus pneumoniae is common nasopharyngeal commensal bacterium and important human pathogen. Vaccines against a subset of pneumococcal antigenic diversity have reduced rates of disease, without changing the frequency of asymptomatic carriage, through altering the bacterial population structure. These changes can be studied in detail through using genome sequencing to characterise systematically-sampled collections of carried S. pneumoniae. This dataset consists of 616 annotated draft genomes of isolates collected from children during routine visits to primary care physicians in Massachusetts between 2001, shortly after the seven valent polysaccharide conjugate vaccine was introduced, and 2007. Also made available are a core genome alignment and phylogeny describing the overall population structure, clusters of orthologous protein sequences, software for inferring serotype from Illumina reads, and whole genome alignments for the analysis of closely-related sets of pneumococci. These data can be used to study both bacterial evolution and the epidemiology of a pathogen population under selection from vaccine-induced immunity.

  View details for DOI 10.1038/sdata.2015.58

  View details for PubMedID 26528397

  View details for PubMedCentralID PMC4622223

• Enhancing disease surveillance with novel data streams: challenges and opportunities. EPJ data science Althouse, B. M., Scarpino, S. V., Meyers, L. A., Ayers, J. W., Bargsten, M., Baumbach, J., Brownstein, J. S., Castro, L., Clapham, H., Cummings, D. A., Del Valle, S., Eubank, S., Fairchild, G., Finelli, L., Generous, N., George, D., Harper, D. R., Hébert-Dufresne, L., Johansson, M. A., Konty, K., Lipsitch, M., Milinovich, G., Miller, J. D., Nsoesie, E. O., Olson, D. R., Paul, M., Polgreen, P. M., Priedhorsky, R., Read, J. M., Rodríguez-Barraquer, I., Smith, D. J., Stefansen, C., Swerdlow, D. L., Thompson, D., Vespignani, A., Wesolowski, A. 2015; 4 (1)

  Abstract

  Novel data streams (NDS), such as web search data or social media updates, hold promise for enhancing the capabilities of public health surveillance. In this paper, we outline a conceptual framework for integrating NDS into current public health surveillance. Our approach focuses on two key questions: What are the opportunities for using NDS and what are the minimal tests of validity and utility that must be applied when using NDS? Identifying these opportunities will necessitate the involvement of public health authorities and an appreciation of the diversity of objectives and scales across agencies at different levels (local, state, national, international). We present the case that clearly articulating surveillance objectives and systematically evaluating NDS and comparing the performance of NDS to existing surveillance data and alternative NDS data is critical and has not sufficiently been addressed in many applications of NDS currently in the literature.

  View details for DOI 10.1140/epjds/s13688-015-0054-0

  View details for PubMedID 27990325

  View details for PubMedCentralID PMC5156315

• Effect of Serotype on Pneumococcal Competition in a Mouse Colonization Model. mBio Trzciński, K., Li, Y., Weinberger, D. M., Thompson, C. M., Cordy, D., Bessolo, A., Malley, R., Lipsitch, M. 2015; 6 (5): e00902-15

  Abstract

  Competitive interactions between Streptococcus pneumoniae strains during host colonization could influence the serotype distribution in nasopharyngeal carriage and pneumococcal disease. We evaluated the competitive fitness of strains of serotypes 6B, 14, 19A, 19F, 23F, and 35B in a mouse model of multiserotype carriage. Isogenic variants were constructed using clinical strains as the capsule gene donors. Animals were intranasally inoculated with a mixture of up to six pneumococcal strains of different serotypes, with separate experiments involving either clinical isolates or isogenic capsule-switch variants of clinical strain TIGR4. Upper-respiratory-tract samples were repeatedly collected from animals in order to monitor changes in the serotype ratios using quantitative PCR. A reproducible hierarchy of capsular types developed in the airways of mice inoculated with multiple strains. Serotype ranks in this hierarchy were similar among pneumococcal strains of different genetic backgrounds in different strains of mice and were not altered when tested under a range of host conditions. This rank correlated with the measure of the metabolic cost of capsule synthesis and in vitro measure of pneumococcal cell surface charge, both parameters considered to be predictors of serotype-specific fitness in carriage. This study demonstrates the presence of a robust competitive hierarchy of pneumococcal serotypes in vivo that is driven mainly, but not exclusively, by the capsule itself.Streptococcus pneumoniae (pneumococcus) is the leading cause of death due to respiratory bacterial infections but also a commensal frequently carried in upper airways. Available vaccines induce immune responses against polysaccharides coating pneumococcal cells, but with over 90 different capsular types (serotypes) identified, they can only target strains of the selected few serotypes most prevalent in disease. Vaccines not only protect vaccinated individuals against disease but also protect by reducing carriage of vaccine-targeted strains to induce herd effects across whole populations. Unfortunately, reduction in the circulation of vaccine-type strains is offset by increase in carriage and disease from nonvaccine strains, indicating the importance of competitive interactions between pneumococci in shaping the population structure of this pathogen. Here, we showed that the competitive ability of pneumococcal strains to colonize the host strongly depends on the type of capsular polysaccharide expressed by pneumococci and only to a lesser degree on strain or host genetic backgrounds or on variation in host immune responses.

  View details for DOI 10.1128/mBio.00902-15

  View details for PubMedID 26374118

  View details for PubMedCentralID PMC4600102

• Estimating the hospitalization burden associated with influenza and respiratory syncytial virus in New York City, 2003-2011. Influenza and other respiratory viruses Goldstein, E., Greene, S. K., Olson, D. R., Hanage, W. P., Lipsitch, M. 2015; 9 (5): 225-33

  Abstract

  Hospitalization burden associated with influenza and respiratory syncytial virus (RSV) is uncertain due to ambiguity in the inference methodologies employed for its estimation.Utilization of a new method to quantitate the above burden.Weekly hospitalization rates for several principal diagnoses from 2003 to 2011 in New York City by age group were regressed linearly against incidence proxies for the major influenza subtypes and RSV adjusting for temporal trends and seasonal baselines.Average annual rates of influenza-associated respiratory hospitalizations per 100 000 were estimated to be 129 [95% CI (79, 179)] for age <1, 36·3 (21·6, 51·4) for ages 1-4, 10·6 (7·5, 13·7) for ages 5-17, 25·6 (21·3, 29·8) for ages 18-49, 65·5 (54·0, 76·9) for ages 50-64, 125 (105, 147) for ages 65-74, and 288 (244, 331) for ages ≥75. Additionally, influenza had a significant contribution to hospitalization rates with a principal diagnosis of septicemia for ages 5-17 [0·76 (0·1, 1·4)], 18-49 [1·02 (0·3, 1·7)], 50-64 [4·0 (1·7, 6·3)], 65-74 [8·8 (2·2, 15·6)], and ≥75 [38·7 (25·7, 52·9)]. RSV had a significant contribution to the rates of respiratory hospitalizations for age <1 [1900 (1740, 2060)], ages 1-4 [117 (70, 167)], and ≥75 [175 (44, 312)] [including chronic lower respiratory disease, 90 (43, 140)] as well as pneumonia & influenza hospitalizations for ages 18-49 [6·2 (1·1, 11·3)] and circulatory hospitalizations for ages ≥75 [199 (13, 375)].The high burden of RSV hospitalizations among young children and seniors age ≥75 suggests the need for additional control measures such as vaccination to mitigate the impact of annual RSV epidemics. Our estimates for influenza-associated hospitalizations provide further evidence of the burden of morbidity associated with influenza, supporting current guidelines regarding influenza vaccination and antiviral treatment.

  View details for DOI 10.1111/irv.12325

  View details for PubMedID 25980600

  View details for PubMedCentralID PMC4548992

• Examining the role of different age groups, and of vaccination during the 2012 Minnesota pertussis outbreak. Scientific reports Worby, C. J., Kenyon, C., Lynfield, R., Lipsitch, M., Goldstein, E. 2015; 5: 13182

  Abstract

  There is limited information on the roles of different age groups during pertussis outbreaks. Little is known about vaccine effectiveness against pertussis infection (both clinically apparent and subclinical), which is different from effectiveness against reportable pertussis disease, with the former influencing the impact of vaccination on pertussis transmission in the community. For the 2012 pertussis outbreak in Minnesota, we estimated odds ratios for case counts in pairs of population groups before vs. after the epidemic's peak. We found children aged 11-12y, 13-14y and 8-10y experienced the greatest rates of depletion of susceptible individuals during the outbreak's ascent, with all ORs for each of those age groups vs. groups outside this age range significantly above 1, with the highest ORs for ages 11-12y. Receipt of the fifth dose of DTaP was associated with a decreased relative role during the outbreak's ascent compared to non-receipt [OR 0.16 (0.01, 0.84) for children aged 5, 0.13 (0.003, 0.82) for ages 8-10y, indicating a protective effect of DTaP against pertussis infection. No analogous effect of Tdap was detected. Our results suggest that children aged 8-14y played a key role in propagating this outbreak. The impact of immunization with Tdap on pertussis infection requires further investigation.

  View details for DOI 10.1038/srep13182

  View details for PubMedID 26278132

  View details for PubMedCentralID PMC4538373

• Potential Biases in Estimating Absolute and Relative Case-Fatality Risks during Outbreaks. PLoS neglected tropical diseases Lipsitch, M., Donnelly, C. A., Fraser, C., Blake, I. M., Cori, A., Dorigatti, I., Ferguson, N. M., Garske, T., Mills, H. L., Riley, S., Van Kerkhove, M. D., Hernán, M. A. 2015; 9 (7): e0003846

  Abstract

  Estimating the case-fatality risk (CFR)-the probability that a person dies from an infection given that they are a case-is a high priority in epidemiologic investigation of newly emerging infectious diseases and sometimes in new outbreaks of known infectious diseases. The data available to estimate the overall CFR are often gathered for other purposes (e.g., surveillance) in challenging circumstances. We describe two forms of bias that may affect the estimation of the overall CFR-preferential ascertainment of severe cases and bias from reporting delays-and review solutions that have been proposed and implemented in past epidemics. Also of interest is the estimation of the causal impact of specific interventions (e.g., hospitalization, or hospitalization at a particular hospital) on survival, which can be estimated as a relative CFR for two or more groups. When observational data are used for this purpose, three more sources of bias may arise: confounding, survivorship bias, and selection due to preferential inclusion in surveillance datasets of those who are hospitalized and/or die. We illustrate these biases and caution against causal interpretation of differential CFR among those receiving different interventions in observational datasets. Again, we discuss ways to reduce these biases, particularly by estimating outcomes in smaller but more systematically defined cohorts ascertained before the onset of symptoms, such as those identified by forward contact tracing. Finally, we discuss the circumstances in which these biases may affect non-causal interpretation of risk factors for death among cases.

  View details for DOI 10.1371/journal.pntd.0003846

  View details for PubMedID 26181387

  View details for PubMedCentralID PMC4504518

• Carriage burden, multiple colonization and antibiotic pressure promote emergence of resistant vaccine escape pneumococci. Philosophical transactions of the Royal Society of London. Series B, Biological sciences Mitchell, P. K., Lipsitch, M., Hanage, W. P. 2015; 370 (1670): 20140342

  Abstract

  Pneumococcal conjugate vaccines target the limited subset of the more than 90 known serotypes of Streptococcus pneumoniae responsible for the greatest burden of pneumococcal disease and antibiotic resistance. Following the introduction of these vaccines, serotypes not targeted were able to expand and resistance became more common within these types. Here we use a stochastic dynamic model of pediatric pneumococcal carriage to evaluate potential influences on the emergence of new resistant lineages following the introduction of a vaccine targeting more common resistant types. Antibiotic pressure was the strongest driver, with no emergence at low levels and universal emergence at high levels. At intermediate levels of antibiotic pressure, higher carriage burden and a greater degree of dual carriage promoted emergence. This may have implications for current plans to introduce childhood pneumococcal vaccination in several high-burden countries.

  View details for DOI 10.1098/rstb.2014.0342

  View details for PubMedID 25918447

  View details for PubMedCentralID PMC4424439

• How could preventive therapy affect the prevalence of drug resistance? Causes and consequences. Philosophical transactions of the Royal Society of London. Series B, Biological sciences Kunkel, A., Colijn, C., Lipsitch, M., Cohen, T. 2015; 370 (1670): 20140306

  Abstract

  Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects.

  View details for DOI 10.1098/rstb.2014.0306

  View details for PubMedID 25918446

  View details for PubMedCentralID PMC4424438

• Identification of pneumococcal colonization determinants in the stringent response pathway facilitated by genomic diversity. BMC genomics Li, Y., Croucher, N. J., Thompson, C. M., Trzciński, K., Hanage, W. P., Lipsitch, M. 2015; 16 (1): 369

  Abstract

  Understanding genetic determinants of a microbial phenotype generally involves creating and comparing isogenic strains differing at the locus of interest, but the naturally existing genomic and phenotypic diversity of microbial populations has rarely been exploited. Here we report use of a diverse collection of 616 carriage isolates of Streptococcus pneumoniae and their genome sequences to help identify a novel determinant of pneumococcal colonization.A spontaneously arising laboratory variant (SpnYL101) of a capsule-switched TIGR4 strain (TIGR4:19F) showed reduced ability to establish mouse nasal colonization and lower resistance to non-opsonic neutrophil-mediated killing in vitro, a phenotype correlated with in vivo success. Whole genome sequencing revealed 5 single nucleotide polymorphisms (SNPs) affecting 4 genes in SpnYL101 relative to its ancestor. To evaluate the effect of variation in each gene, we performed an in silico screen of 616 previously published genome sequences to identify pairs of closely-related, serotype-matched isolates that differ at the gene of interest, and compared their resistance to neutrophil-killing. This method allowed rapid examination of multiple candidate genes and found phenotypic differences apparently associated with variation in SP_1645, a RelA/ SpoT homolog (RSH) involved in the stringent response. To establish causality, the alleles corresponding to SP_1645 were switched between the TIGR4:19F and SpnYL101. The wild-type SP_1645 conferred higher resistance to neutrophil-killing and competitiveness in mouse colonization. Using a similar strategy, variation in another RSH gene (TIGR4 locus tag SP_1097) was found to alter resistance to neutrophil-killing.These results indicate that analysis of naturally existing genomic diversity complements traditional genetics approaches to accelerate genotype-phenotype analysis.

  View details for DOI 10.1186/s12864-015-1573-6

  View details for PubMedID 25956132

  View details for PubMedCentralID PMC4424882

• Vaccine testing. Ebola and beyond. Science (New York, N.Y.) Lipsitch, M., Eyal, N., Halloran, M. E., Hernán, M. A., Longini, I. M., Perencevich, E. N., Grais, R. F. 2015; 348 (6230): 46-8

  View details for DOI 10.1126/science.aaa3178

  View details for PubMedID 25838371

  View details for PubMedCentralID PMC4408019

• Inference of seasonal and pandemic influenza transmission dynamics. Proceedings of the National Academy of Sciences of the United States of America Yang, W., Lipsitch, M., Shaman, J. 2015; 112 (9): 2723-8

  Abstract

  The inference of key infectious disease epidemiological parameters is critical for characterizing disease spread and devising prevention and containment measures. The recent emergence of surveillance records mined from big data such as health-related online queries and social media, as well as model inference methods, permits the development of new methodologies for more comprehensive estimation of these parameters. We use such data in conjunction with Bayesian inference methods to study the transmission dynamics of influenza. We simultaneously estimate key epidemiological parameters, including population susceptibility, the basic reproductive number, attack rate, and infectious period, for 115 cities during the 2003-2004 through 2012-2013 seasons, including the 2009 pandemic. These estimates discriminate key differences in the epidemiological characteristics of these outbreaks across 10 y, as well as spatial variations of influenza transmission dynamics among subpopulations in the United States. In addition, the inference methods appear to compensate for observational biases and underreporting inherent in the surveillance data.

  View details for DOI 10.1073/pnas.1415012112

  View details for PubMedID 25730851

  View details for PubMedCentralID PMC4352784

• Antibiotics in agriculture and the risk to human health: how worried should we be? Evolutionary applications Chang, Q., Wang, W., Regev-Yochay, G., Lipsitch, M., Hanage, W. P. 2015; 8 (3): 240-7

  Abstract

  The use of antibiotics in agriculture is routinely described as a major contributor to the clinical problem of resistant disease in human medicine. While a link is plausible, there are no data conclusively showing the magnitude of the threat emerging from agriculture. Here, we define the potential mechanisms by which agricultural antibiotic use could lead to human disease and use case studies to critically assess the potential risk from each. The three mechanisms considered are as follows 1: direct infection with resistant bacteria from an animal source, 2: breaches in the species barrier followed by sustained transmission in humans of resistant strains arising in livestock, and 3: transfer of resistance genes from agriculture into human pathogens. Of these, mechanism 1 is the most readily estimated, while significant is small in comparison with the overall burden of resistant disease. Several cases of mechanism 2 are known, and we discuss the likely livestock origins of resistant clones of Staphylococcus aureus and Enterococcus faecium, but while it is easy to show relatedness the direction of transmission is hard to assess in robust fashion. More difficult yet to study is the contribution of mechanism 3, which may be the most important of all.

  View details for DOI 10.1111/eva.12185

  View details for PubMedID 25861382

  View details for PubMedCentralID PMC4380918

• Sequence tag-based analysis of microbial population dynamics. Nature methods Abel, S., Abel zur Wiesch, P., Chang, H. H., Davis, B. M., Lipsitch, M., Waldor, M. K. 2015; 12 (3): 223-6, 3 p following 226

  Abstract

  We describe sequence tag-based analysis of microbial populations (STAMP) for characterization of pathogen population dynamics during infection. STAMP analyzes the frequency changes of genetically 'barcoded' organisms to quantify population bottlenecks and infer the founding population size. Analyses of intraintestinal Vibrio cholerae revealed infection-stage and region-specific host barriers to infection and showed unexpected V. cholerae migration counter to intestinal flow. STAMP provides a robust, widely applicable analytical framework for high-confidence characterization of in vivo microbial dissemination.

  View details for DOI 10.1038/nmeth.3253

  View details for PubMedID 25599549

  View details for PubMedCentralID PMC4344388

• Origin and proliferation of multiple-drug resistance in bacterial pathogens. Microbiology and molecular biology reviews : MMBR Chang, H. H., Cohen, T., Grad, Y. H., Hanage, W. P., O'Brien, T. F., Lipsitch, M. 2015; 79 (1): 101-16

  Abstract

  Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including experimental, epidemiological, population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR.

  View details for DOI 10.1128/MMBR.00039-14

  View details for PubMedID 25652543

  View details for PubMedCentralID PMC4402963

• Selective and genetic constraints on pneumococcal serotype switching. PLoS genetics Croucher, N. J., Kagedan, L., Thompson, C. M., Parkhill, J., Bentley, S. D., Finkelstein, J. A., Lipsitch, M., Hanage, W. P. 2015; 11 (3): e1005095

  Abstract

  Streptococcus pneumoniae isolates typically express one of over 90 immunologically distinguishable polysaccharide capsules (serotypes), which can be classified into "serogroups" based on cross-reactivity with certain antibodies. Pneumococci can alter their serotype through recombinations affecting the capsule polysaccharide synthesis (cps) locus. Twenty such "serotype switching" events were fully characterised using a collection of 616 whole genome sequences from systematic surveys of pneumococcal carriage. Eleven of these were within-serogroup switches, representing a highly significant (p < 0.0001) enrichment based on the observed serotype distribution. Whereas the recombinations resulting in between-serogroup switches all spanned the entire cps locus, some of those that caused within-serogroup switches did not. However, higher rates of within-serogroup switching could not be fully explained by either more frequent, shorter recombinations, nor by genetic linkage to genes involved in β-lactam resistance. This suggested the observed pattern was a consequence of selection for preserving serogroup. Phenotyping of strains constructed to express different serotypes in common genetic backgrounds was used to test whether genotypes were physiologically adapted to particular serogroups. These data were consistent with epistatic interactions between the cps locus and the rest of the genome that were specific to serotype, but not serogroup, meaning they were unlikely to account for the observed distribution of capsule types. Exclusion of these genetic and physiological hypotheses suggested future work should focus on alternative mechanisms, such as host immunity spanning multiple serotypes within the same serogroup, which might explain the observed pattern.

  View details for DOI 10.1371/journal.pgen.1005095

  View details for PubMedID 25826208

  View details for PubMedCentralID PMC4380333

• Stability of the pneumococcal population structure in Massachusetts as PCV13 was introduced BMC INFECTIOUS DISEASES Chang, Q., Stevenson, A. E., Croucher, N. J., Lee, G. M., Pelton, S. I., Lipsitch, M., Finkelstein, J. A., Hanage, W. P. 2015; 15

  Abstract

  The success of 7-valent pneumococcal conjugate vaccination (PCV-7) introduced to the US childhood immunization schedule in 2000 was partially offset by increases in invasive pneumococcal disease (IPD) and pneumococcal carriage due to non-vaccine serotypes, in particular 19A, in the years that followed. A 13-valent conjugate vaccine (PCV-13) was introduced in 2010. As part of an ongoing study of the response of the Massachusetts pneumococcal population to conjugate vaccination, we report the findings from the samples collected in 2011, as PCV-13 was introduced.We used multilocus sequence typing (MLST) to analyze 367 pneumococcal isolates carried by Massachusetts children (aged 3 months-7 years) collected during the winter of 2010-11 and used eBURST software to compare the pneumococcal population structure with that found in previous years.One hundred and four distinct sequence types (STs) were found, including 24 that had not been previously recorded. Comparison with a similar sample collected in 2009 revealed no significant overall difference in the ST composition (p = 0.39, classification index). However, we describe clonal dynamics within the important replacement serotypes 19A, 15B/C, and 6C, and clonal expansion of ST 433 and ST 432, which are respectively serotype 22F and 21 clones.While little overall change in serotypes or STs was evident, multiple changes in the frequency of individual STs and or serotypes may plausibly be ascribed to the introduction of PCV-13. This 2011 sample documents the initial impact of PCV-13 and will be important for comparison with future studies of the evolution of the pneumococcal population in Massachusetts.

  View details for DOI 10.1186/s12879-015-0797-z

  View details for Web of Science ID 000349868300002

  View details for PubMedID 25887323

  View details for PubMedCentralID PMC4336693

• Erratum for lipsitch and inglesby, moratorium on research intended to create novel potential pandemic pathogens. mBio Lipsitch, M., Inglesby, T. V. 2015; 6 (1)

  View details for DOI 10.1128/mBio.02534-14

  View details for PubMedID 25670775

  View details for PubMedCentralID PMC4337581

• Reply to "Studies on influenza virus transmission between ferrets: the public health risks revisited". mBio Lipsitch, M., Inglesby, T. V. 2015; 6 (1)

  View details for DOI 10.1128/mBio.00041-15

  View details for PubMedID 25616376

  View details for PubMedCentralID PMC4323416

• Gain-of-function experiments: time for a real debate. Nature reviews. Microbiology Duprex, W. P., Fouchier, R. A., Imperiale, M. J., Lipsitch, M., Relman, D. A. 2015; 13 (1): 58-64

  Abstract

  According to the WHO, dual use research of concern (DURC) is "life sciences research that is intended for benefit, but which might easily be misapplied to do harm". Recent studies, particularly those on influenza viruses, have led to renewed attention on DURC, as there is an ongoing debate over whether the benefits of gain-of-function (GOF) experiments that result in an increase in the transmission and/or pathogenicity of potential pandemic pathogens (PPPs) are outweighed by concerns over biosecurity and biosafety. In this Viewpoint article, proponents and opponents of GOF experiments discuss the benefits and risks associated with these studies, as well as the implications of the current debate for the scientific community and the general public, and suggest how the current discussion should move forward.

  View details for DOI 10.1038/nrmicro3405

  View details for PubMedID 25482289

• Moratorium on research intended to create novel potential pandemic pathogens. mBio Lipsitch, M., Inglesby, T. V. 2014; 5 (6)

  View details for DOI 10.1128/mBio.02366-14

  View details for PubMedID 25505122

  View details for PubMedCentralID PMC4271556

• The distribution of pairwise genetic distances: a tool for investigating disease transmission. Genetics Worby, C. J., Chang, H. H., Hanage, W. P., Lipsitch, M. 2014; 198 (4): 1395-404

  Abstract

  Whole-genome sequencing of pathogens has recently been used to investigate disease outbreaks and is likely to play a growing role in real-time epidemiological studies. Methods to analyze high-resolution genomic data in this context are still lacking, and inferring transmission dynamics from such data typically requires many assumptions. While recent studies have proposed methods to infer who infected whom based on genetic distance between isolates from different individuals, the link between epidemiological relationship and genetic distance is still not well understood. In this study, we investigated the distribution of pairwise genetic distances between samples taken from infected hosts during an outbreak. We proposed an analytically tractable approximation to this distribution, which provides a framework to evaluate the likelihood of particular transmission routes. Our method accounts for the transmission of a genetically diverse inoculum, a possibility overlooked in most analyses. We demonstrated that our approximation can provide a robust estimation of the posterior probability of transmission routes in an outbreak and may be used to rule out transmission events at a particular probability threshold. We applied our method to data collected during an outbreak of methicillin-resistant Staphylococcus aureus, ruling out several potential transmission links. Our study sheds light on the accumulation of mutations in a pathogen during an epidemic and provides tools to investigate transmission dynamics, avoiding the intensive computation necessary in many existing methods.

  View details for DOI 10.1534/genetics.114.171538

  View details for PubMedID 25313129

  View details for PubMedCentralID PMC4256759

• A new approach to the analysis of antibiotic resistance data from hospitals. Microbial drug resistance (Larchmont, N.Y.) Ascioglu, S., Samore, M. H., Lipsitch, M. 2014; 20 (6): 583-90

  Abstract

  We aimed to develop a new approach to the analysis of antimicrobial resistance data from the hospitals, which allows simultaneous analysis of both individual- and population-level determinants of bacterial resistance. This was a retrospective cohort study that included adult patients who stayed in the hospital >2 days. We analyzed data using shared frailty Cox models and tested our approach using a priori hypotheses based on biology and epidemiology of antibiotic resistance. For gram-negative bacteria, the use of the major selecting antibiotic by an individual was the main risk factor for acquiring resistant species. Hazard ratios (HRs) were strikingly high for ceftazidime-resistant Enterobacter species (HR=11.17; 95% confidence interval [CI]: 5.67-22.02), ciprofloxacin-resistant Pseudomonas aeruginosa (HR=4.41; 95% CI: 2.14-9.08), and imipenem-resistant P. aeruginosa (HR=7.92; 95% CI: 4.35-14.43). Ward-level use was significant for vancomycin-resistant enterococci (VRE) (HR=1.40; 95% CI: 1.07-1.83) and for imipenem-resistant P. aeruginosa (HR=1.40; 95% CI: 1.08-1.83). Previous incidence of infection in the same ward increased the risk of acquiring methicillin-resistant Staphylococcus aureus (HR=1.22; 95% CI: 1.15-1.30) and VRE (HR=1.53; 95% CI: 1.38-1.70). Our results were consistent with our hypotheses and showed that combining population- and individual-level data is crucial for the exploration of antimicrobial resistance development.

  View details for DOI 10.1089/mdr.2013.0173

  View details for PubMedID 25055133

• In Vitro selection of Neisseria gonorrhoeae mutants with elevated MIC values and increased resistance to cephalosporins. Antimicrobial agents and chemotherapy Johnson, S. R., Grad, Y., Ganakammal, S. R., Burroughs, M., Frace, M., Lipsitch, M., Weil, R., Trees, D. 2014; 58 (11): 6986-9

  Abstract

  Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA have been isolated from ceftriaxone treatment failures. Such isolates exhibit significantly higher MIC values to third-generation cephalosporins. Here we report the in vitro isolation of two mutants with elevated MICs to cephalosporins. The first possesses a point mutation in the transpeptidase region of the mosaic penA gene, and the second contains an insertion mutation in pilQ.

  View details for DOI 10.1128/AAC.03082-14

  View details for PubMedID 25199775

  View details for PubMedCentralID PMC4249396

• Improving pandemic influenza risk assessment. eLife Russell, C. A., Kasson, P. M., Donis, R. O., Riley, S., Dunbar, J., Rambaut, A., Asher, J., Burke, S., Davis, C. T., Garten, R. J., Gnanakaran, S., Hay, S. I., Herfst, S., Lewis, N. S., Lloyd-Smith, J. O., Macken, C. A., Maurer-Stroh, S., Neuhaus, E., Parrish, C. R., Pepin, K. M., Shepard, S. S., Smith, D. L., Suarez, D. L., Trock, S. C., Widdowson, M. A., George, D. B., Lipsitch, M., Bloom, J. D. 2014; 3: e03883

  Abstract

  Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.

  View details for DOI 10.7554/eLife.03883

  View details for PubMedID 25321142

  View details for PubMedCentralID PMC4199076

• Can limited scientific value of potential pandemic pathogen experiments justify the risks? mBio Lipsitch, M. 2014; 5 (5): e02008-14

  View details for DOI 10.1128/mBio.02008-14

  View details for PubMedID 25316701

  View details for PubMedCentralID PMC4205796

• The association of meningococcal disease with influenza in the United States, 1989-2009. PloS one Jacobs, J. H., Viboud, C., Tchetgen, E. T., Schwartz, J., Steiner, C., Simonsen, L., Lipsitch, M. 2014; 9 (9): e107486

  Abstract

  Prior influenza infection is a risk factor for invasive meningococcal disease. Quantifying the fraction of meningococcal disease attributable to influenza could improve understanding of viral-bacterial interaction and indicate additional health benefits to influenza immunization.A time series analysis of the association of influenza and meningococcal disease using hospitalizations in 9 states from 1989-2009 included in the State Inpatient Databases from the Agency for Healthcare Research and Quality and the proportion of positive influenza tests by subtype reported to the Centers for Disease Control. The model accounts for the autocorrelation of meningococcal disease and influenza between weeks, temporal trends, co-circulating respiratory syncytial virus, and seasonality. The influenza-subtype-attributable fraction was estimated using the model coefficients. We analyzed the synchrony of seasonal peaks in hospitalizations for influenza, respiratory syncytial virus, and meningococcal disease.In 19 of 20 seasons, influenza peaked≤2 weeks before meningococcal disease, and peaks were highly correlated in time (ρ = 0.95; P <.001). H3N2 and H1N1 peaks were highly synchronized with meningococcal disease while pandemic H1N1, B, and respiratory syncytial virus were not. Over 20 years, 12.8% (95% CI, 9.1-15.0) of meningococcal disease can be attributable to influenza in the preceding weeks with H3N2 accounting for 5.2% (95% CI, 3.0-6.5), H1N1 4.3% (95% CI, 2.6-5.6), B 3.0% (95% CI, 0.8-4.9) and pH1N1 0.2% (95% CI, 0-0.4). During the height of influenza season, weekly attributable fractions reach 59%. While vaccination against meningococcal disease is the most important prevention strategy, influenza vaccination could provide further protection, particularly in young children where the meningococcal disease vaccine is not recommended or protective against the most common serogroup.

  View details for DOI 10.1371/journal.pone.0107486

  View details for PubMedID 25265409

  View details for PubMedCentralID PMC4180274

• Within-host whole-genome deep sequencing and diversity analysis of human respiratory syncytial virus infection reveals dynamics of genomic diversity in the absence and presence of immune pressure. Journal of virology Grad, Y. H., Newman, R., Zody, M., Yang, X., Murphy, R., Qu, J., Malboeuf, C. M., Levin, J. Z., Lipsitch, M., DeVincenzo, J. 2014; 88 (13): 7286-93

  Abstract

  Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children and an important respiratory pathogen in the elderly and immunocompromised. While population-wide molecular epidemiology studies have shown multiple cocirculating RSV genotypes and revealed antigenic and genetic change over successive seasons, little is known about the extent of viral diversity over the course of an individual infection, the origins of novel variants, or the effect of immune pressure on viral diversity and potential immune-escape mutations. To investigate viral population diversity in the presence and absence of selective immune pressures, we studied whole-genome deep sequencing of RSV in upper airway samples from an infant with severe combined immune deficiency syndrome and persistent RSV infection. The infection continued over several months before and after bone marrow transplant (BMT) from his RSV-immune father. RSV diversity was characterized in 26 samples obtained over 78 days. Diversity increased after engraftment, as defined by T-cell presence, and populations reflected variation mostly within the G protein, the major surface antigen. Minority populations with known palivizumab resistance mutations emerged after its administration. The viral population appeared to diversify in response to selective pressures, showing a statistically significant growth in diversity in the presence of pressure from immunity. Defining escape mutations and their dynamics will be useful in the design and application of novel therapeutics and vaccines. These data can contribute to future studies of the relationship between within-host and population-wide RSV phylodynamics.Human RSV is an important cause of respiratory disease in infants, the elderly, and the immunocompromised. RSV circulating in a community appears to change season by season, but the amount of diversity generated during an individual infection and the impact of immunity on this viral diversity has been unclear. To address this question, we described within-host RSV diversity by whole-genome deep sequencing in a unique clinical case of an RSV-infected infant with severe combined immunodeficiency and effectively no adaptive immunity who then gained adaptive immunity after undergoing bone marrow transplantation. We found that viral diversity increased in the presence of adaptive immunity and was primarily within the G protein, the major surface antigen. These data will be useful in designing RSV treatments and vaccines and to help understand the relationship between the dynamics of viral diversification within individual hosts and the viral populations circulating in a community.

  View details for DOI 10.1128/JVI.00038-14

  View details for PubMedID 24741088

  View details for PubMedCentralID PMC4054443

• A modified Janus cassette (Sweet Janus) to improve allelic replacement efficiency by high-stringency negative selection in Streptococcus pneumoniae. PloS one Li, Y., Thompson, C. M., Lipsitch, M. 2014; 9 (6): e100510

  Abstract

  The Janus cassette permits marker-free allelic replacement or knockout in streptomycin-resistant Streptococcus pneumoniae (pneumococcus) through sequential positive and negative selection. Spontaneous revertants of Janus can lead to high level of false-positives during negative selection, which necessitate a time-consuming post-selection screening process. We hypothesized that an additional counter-selectable marker in Janus would decrease the revertant frequency and reduce false-positives, since simultaneous reversion of both counter-selectable makers is much less likely. Here we report a modified cassette, Sweet Janus (SJ), in which the sacB gene from Bacillus subtilis conferring sucrose sensitivity is added to Janus. By using streptomycin and sucrose simultaneously as selective agents, the frequency of SJ double revertants was about 105-fold lower than the frequency of Janus revertants. Accordingly, the frequency of false-positives in the SJ-mediated negative selection was about 100-fold lower than what was seen for Janus. Thus, SJ enhances negative selection stringency and can accelerate allelic replacement in pneumococcus, especially when transformation frequency is low due to strain background or suboptimal transformation conditions. Results also suggested the sacB gene alone can function as a counter-selectable marker in the Gram-positive pneumococcus, which will have the advantage of not requiring a streptomycin-resistant strain for allelic replacement.

  View details for DOI 10.1371/journal.pone.0100510

  View details for PubMedID 24959661

  View details for PubMedCentralID PMC4068995

• Development, calibration and performance of an HIV transmission model incorporating natural history and behavioral patterns: application in South Africa. PloS one McCormick, A. W., Abuelezam, N. N., Rhode, E. R., Hou, T., Walensky, R. P., Pei, P. P., Becker, J. E., DiLorenzo, M. A., Losina, E., Freedberg, K. A., Lipsitch, M., Seage, G. R. 2014; 9 (5): e98272

  Abstract

  Understanding HIV transmission dynamics is critical to estimating the potential population-wide impact of HIV prevention and treatment interventions. We developed an individual-based simulation model of the heterosexual HIV epidemic in South Africa and linked it to the previously published Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International Model, which simulates the natural history and treatment of HIV. In this new model, the CEPAC Dynamic Model (CDM), the probability of HIV transmission per sexual encounter between short-term, long-term and commercial sex worker partners depends upon the HIV RNA and disease stage of the infected partner, condom use, and the circumcision status of the uninfected male partner. We included behavioral, demographic and biological values in the CDM and calibrated to HIV prevalence in South Africa pre-antiretroviral therapy. Using a multi-step fitting procedure based on Bayesian melding methodology, we performed 264,225 simulations of the HIV epidemic in South Africa and identified 3,750 parameter sets that created an epidemic and had behavioral characteristics representative of a South African population pre-ART. Of these parameter sets, 564 contributed 90% of the likelihood weight to the fit, and closely reproduced the UNAIDS HIV prevalence curve in South Africa from 1990-2002. The calibration was sensitive to changes in the rate of formation of short-duration partnerships and to the partnership acquisition rate among high-risk individuals, both of which impacted concurrency. Runs that closely fit to historical HIV prevalence reflect diverse ranges for individual parameter values and predict a wide range of possible steady-state prevalence in the absence of interventions, illustrating the value of the calibration procedure and utility of the model for evaluating interventions. This model, which includes detailed behavioral patterns and HIV natural history, closely fits HIV prevalence estimates.

  View details for DOI 10.1371/journal.pone.0098272

  View details for PubMedID 24867402

  View details for PubMedCentralID PMC4035281

• Ethical alternatives to experiments with novel potential pandemic pathogens. PLoS medicine Lipsitch, M., Galvani, A. P. 2014; 11 (5): e1001646

  Abstract

  Please see later in the article for the Editors' Summary

  View details for DOI 10.1371/journal.pmed.1001646

  View details for PubMedID 24844931

  View details for PubMedCentralID PMC4028196

• Within-host bacterial diversity hinders accurate reconstruction of transmission networks from genomic distance data. PLoS computational biology Worby, C. J., Lipsitch, M., Hanage, W. P. 2014; 10 (3): e1003549

  Abstract

  The prospect of using whole genome sequence data to investigate bacterial disease outbreaks has been keenly anticipated in many quarters, and the large-scale collection and sequencing of isolates from cases is becoming increasingly feasible. While sequence data can provide many important insights into disease spread and pathogen adaptation, it remains unclear how successfully they may be used to estimate individual routes of transmission. Several studies have attempted to reconstruct transmission routes using genomic data; however, these have typically relied upon restrictive assumptions, such as a shared topology of the phylogenetic tree and a lack of within-host diversity. In this study, we investigated the potential for bacterial genomic data to inform transmission network reconstruction. We used simulation models to investigate the origins, persistence and onward transmission of genetic diversity, and examined the impact of such diversity on our estimation of the epidemiological relationship between carriers. We used a flexible distance-based metric to provide a weighted transmission network, and used receiver-operating characteristic (ROC) curves and network entropy to assess the accuracy and uncertainty of the inferred structure. Our results suggest that sequencing a single isolate from each case is inadequate in the presence of within-host diversity, and is likely to result in misleading interpretations of transmission dynamics--under many plausible conditions, this may be little better than selecting transmission links at random. Sampling more frequently improves accuracy, but much uncertainty remains, even if all genotypes are observed. While it is possible to discriminate between clusters of carriers, individual transmission routes cannot be resolved by sequence data alone. Our study demonstrates that bacterial genomic distance data alone provide only limited information on person-to-person transmission dynamics.

  View details for DOI 10.1371/journal.pcbi.1003549

  View details for PubMedID 24675511

  View details for PubMedCentralID PMC3967931

• The US 2009 A(H1N1) influenza epidemic: quantifying the impact of school openings on the reproductive number. Epidemiology (Cambridge, Mass.) Huang, K. E., Lipsitch, M., Shaman, J., Goldstein, E. 2014; 25 (2): 203-6

  Abstract

  There is limited information on differences in the dynamics of influenza transmission during time periods when schools are open compared with periods when they are closed.Data on school openings, influenza surveillance, and absolute humidity were incorporated into a regression model to estimate the increase in the reproductive number for the 2009 A(H1N1) influenza pandemic associated with the opening of school in 10 US states.The estimate for the average increase in the reproductive number for the 2009 A(H1N1) influenza pandemic associated with the beginning of the school year was 19.5% (95% credible interval = 10%-29%).Whether schools are open or closed can have a major impact on community transmission dynamics of influenza.

  View details for DOI 10.1097/EDE.0000000000000055

  View details for PubMedID 24434751

  View details for PubMedCentralID PMC3960948

• A missing dimension in measures of vaccination impacts. PLoS pathogens Gomes, M. G., Lipsitch, M., Wargo, A. R., Kurath, G., Rebelo, C., Medley, G. F., Coutinho, A. 2014; 10 (3): e1003849

  View details for DOI 10.1371/journal.ppat.1003849

  View details for PubMedID 24603721

  View details for PubMedCentralID PMC3946326

• Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. The Lancet. Infectious diseases Grad, Y. H., Kirkcaldy, R. D., Trees, D., Dordel, J., Harris, S. R., Goldstein, E., Weinstock, H., Parkhill, J., Hanage, W. P., Bentley, S., Lipsitch, M. 2014; 14 (3): 220-6

  Abstract

  The emergence of Neisseria gonorrhoeae with decreased susceptibility to extended spectrum cephalosporins raises the prospect of untreatable gonorrhoea. In the absence of new treatments, efforts to slow the increasing incidence of resistant gonococcus require insight into the factors that contribute to its emergence and spread. We assessed the relatedness between isolates in the USA and reconstructed likely spread of lineages through different sexual networks.We sequenced the genomes of 236 isolates of N gonorrhoeae collected by the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project (GISP) from sentinel public sexually transmitted disease clinics in the USA, including 118 (97%) of the isolates from 2009-10 in GISP with reduced susceptibility to cefixime (cef(RS)) and 118 cefixime-susceptible isolates from GISP matched as closely as possible by location, collection date, and sexual orientation. We assessed the association between antimicrobial resistance genotype and phenotype and correlated phylogenetic clustering with location and sexual orientation.Mosaic penA XXXIV had a high positive predictive value for cef(RS). We found that two of the 118 cef(RS) isolates lacked a mosaic penA allele, and rechecking showed that these two were susceptible to cefixime. Of the 116 remaining cef(RS) isolates, 114 (98%) fell into two distinct lineages that have independently acquired mosaic penA allele XXXIV. A major lineage of cef(RS) strains spread eastward, predominantly through a sexual network of men who have sex with men. Eight of nine inferred transitions between sexual networks were introductions from men who have sex with men into the heterosexual population.Genomic methods might aid efforts to slow the spread of antibiotic-resistant N gonorrhoeae through augmentation of gonococcal outbreak surveillance and identification of populations that could benefit from increased screening for asymptomatic infections.

  View details for DOI 10.1016/S1473-3099(13)70693-5

  View details for PubMedID 24462211

  View details for PubMedCentralID PMC4030102

• Nuanced risk assessment for emerging infectious diseases. Lancet (London, England) Fisman, D. N., Leung, G. M., Lipsitch, M. 2014; 383 (9913): 189-90

  View details for DOI 10.1016/S0140-6736(13)62123-6

  View details for PubMedID 24439726

  View details for PubMedCentralID PMC7137147

• Estimating the per-exposure effect of infectious disease interventions. Epidemiology (Cambridge, Mass.) O'Hagan, J. J., Lipsitch, M., Hernán, M. A. 2014; 25 (1): 134-8

  Abstract

  The average effect of an infectious disease intervention (eg, a vaccine) varies across populations with different degrees of exposure to the pathogen. As a result, many investigators favor a per-exposure effect measure that is considered independent of the population level of exposure and that can be used in simulations to estimate the total disease burden averted by an intervention across different populations. However, while per-exposure effects are frequently estimated, the quantity of interest is often poorly defined, and assumptions in its calculation are typically left implicit. In this article, we build upon work by Halloran and Struchiner (Epidemiology. 1995;6:142-151) to develop a formal definition of the per-exposure effect and discuss conditions necessary for its unbiased estimation. With greater care paid to the parameterization of transmission models, their results can be better understood and can thereby be of greater value to decision-makers.

  View details for DOI 10.1097/EDE.0000000000000003

  View details for PubMedID 24240656

  View details for PubMedCentralID PMC3898464

• Within-host selection is limited by an effective population of Streptococcus pneumoniae during nasopharyngeal colonization. Infection and immunity Li, Y., Thompson, C. M., Trzciński, K., Lipsitch, M. 2013; 81 (12): 4534-43

  Abstract

  Streptococcus pneumoniae (pneumococcus) is a significant pathogen that frequently colonizes the human nasopharynx. Environmental factors, including antimicrobial use and host immunity, exert selection on members of the nasopharyngeal population, and the dynamics of selection are influenced by the effective population size of the selected population, about which little is known. We measured here the variance effective population size (N(e)) of pneumococcus in a mouse colonization model by monitoring the frequency change of two cocolonizing, competitively neutral pneumococcal strains over time. The point estimate of N(e) during nasal carriage in 16 BALB/c mice was 133 (95% confidence interval [CI] = 11 to 203). In contrast, the lower-bound census population exhibited a mean of 5768 (95% CI = 2,515 to 9,021). Therefore, pneumococcal N(e) during nasal carriage is substantially smaller than the census population. The N(e) during day 1 to day 4 of colonization was comparable to the Ne during day 4 to day 8. Similarly, a low Ne was also evident for the colonization of pneumococcus in BALB/c mice exposed to cholera toxin 4 weeks prior to challenge and in another mouse strain (DO11.10 RAG(-/-)). We developed a mathematical model of pneumococcal colonization composed of two subpopulations with differential contribution to future generations. By stochastic simulation, this model can reproduce the pattern of observed pneumococcal N(e) and predicts that the selection coefficients may be difficult to measure in vivo. We hypothesized that such a small N(e) may reduce the effectiveness of within host selection for pneumococcus.

  View details for DOI 10.1128/IAI.00527-13

  View details for PubMedID 24082074

  View details for PubMedCentralID PMC3837969

• Surface charge of Streptococcus pneumoniae predicts serotype distribution. Infection and immunity Li, Y., Weinberger, D. M., Thompson, C. M., Trzciński, K., Lipsitch, M. 2013; 81 (12): 4519-24

  Abstract

  Streptococcus pneumoniae (pneumococcus) frequently colonizes the human nasopharynx and is an important cause of pneumonia, meningitis, sinusitis, and otitis media. The outer cell surface of pneumococcus may assume various degrees of negative charge depending on the polysaccharide capsule, of which more than 90 serotypes have been identified. The negative charge of capsular polysaccharides has been proposed to electrostatically repel pneumococci from phagocytic cells, and avoidance of phagocytosis correlates with higher carriage prevalence. We hypothesized that the surface charge of pneumococcus contributes to its success in nasopharyngeal carriage by modulating resistance to phagocyte-mediated killing. Here, we measured the surface charge (zeta potential) of laboratory-constructed strains that share a genetic background but differ in serotype and of clinical strains that differ in serotype and genetic background. A more negative surface charge correlated with higher resistance to nonopsonic killing by human neutrophils in vitro. In addition, a more negative zeta potential was associated with higher carriage prevalence in human populations before and after the widespread use of the pneumococcal conjugate vaccine PCV7. We also confirmed that capsule is the major determinant of net surface charge in clinical isolates with diverse backgrounds. We noted that exceptions exist to the idea that a higher magnitude of negative charge predicts higher prevalence. The results indicated that zeta potential is strongly influenced by pneumococcal capsule type but is unlikely to be the only important mechanism by which capsule interacts with host.

  View details for DOI 10.1128/IAI.00724-13

  View details for PubMedID 24082068

  View details for PubMedCentralID PMC3837974

• Geographic and temporal trends in antimicrobial nonsusceptibility in Streptococcus pneumoniae in the post-vaccine era in the United States. The Journal of infectious diseases Link-Gelles, R., Thomas, A., Lynfield, R., Petit, S., Schaffner, W., Harrison, L., Farley, M. M., Aragon, D., Nicols, M., Kirley, P. D., Zansky, S., Jorgensen, J., Juni, B. A., Jackson, D., Moore, M. R., Lipsitch, M. 2013; 208 (8): 1266-73

  Abstract

  We examined whether observed increases in antibiotic nonsusceptible nonvaccine serotypes after introduction of pneumococcal conjugate vaccine in the United States in 2000 were driven primarily by vaccine or antibiotic use. Using active surveillance data, we evaluated geographic and temporal differences in serotype distribution and within-serotype differences during 2000-2009. We compared nonsusceptibility to penicillin and erythromycin by geography after standardizing differences across time, place, and serotype by regressing standardized versus crude proportions. A regression slope (RS) approaching zero indicates greater importance of the standardizing factor. Through 2000-2006, geographic differences in nonsusceptibility were better explained by within-serotype prevalence of nonsusceptibility (RS 0.32, 95% confidence interval [CI], .08-.55 for penicillin) than by geographic differences in serotype distribution (RS 0.71, 95% CI, .44-.97). From 2007-2009, serotype distribution differences became more important for penicillin (within-serotype RS 0.52, 95% CI, .11-.93; serotype distribution RS 0.57, 95% CI, .14-1.0). Differential nonsusceptibility, within individual serotypes, accounts for most geographic variation in nonsusceptibility, suggesting selective pressure from antibiotic use, rather than differences in serotype distribution, mainly determines nonsusceptibility patterns. Recent trends suggest geographic differences in serotype distribution may be affecting the prevalence of nonsusceptibility, possibly due to decreases in the number of nonsusceptible serotypes.

  View details for DOI 10.1093/infdis/jit315

  View details for PubMedID 23852588

  View details for PubMedCentralID PMC3778966

• Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance. PloS one Joice, R., Lipsitch, M. 2013; 8 (7): e68940

  Abstract

  The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug-resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens--Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus--in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8%) against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains). Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak.

  View details for DOI 10.1371/journal.pone.0068940

  View details for PubMedID 23935910

  View details for PubMedCentralID PMC3723804

• Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. Nature genetics Ford, C. B., Shah, R. R., Maeda, M. K., Gagneux, S., Murray, M. B., Cohen, T., Johnston, J. C., Gardy, J., Lipsitch, M., Fortune, S. M. 2013; 45 (7): 784-90

  Abstract

  A key question in tuberculosis control is why some strains of M. tuberculosis are preferentially associated with resistance to multiple drugs. We demonstrate that M. tuberculosis strains from lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole-genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug-susceptible lineage 2 strain will harbor multidrug-resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug-resistant tuberculosis should target bacterial as well as treatment-related risk factors.

  View details for DOI 10.1038/ng.2656

  View details for PubMedID 23749189

  View details for PubMedCentralID PMC3777616

• Population genomics of post-vaccine changes in pneumococcal epidemiology NATURE GENETICS Croucher, N. J., Finkelstein, J. A., Pelton, S. I., Mitchell, P. K., Lee, G. M., Parkhill, J., Bentley, S. D., Hanage, W. P., Lipsitch, M. 2013; 45 (6): 656-?

  Abstract

  Whole-genome sequencing of 616 asymptomatically carried Streptococcus pneumoniae isolates was used to study the impact of the 7-valent pneumococcal conjugate vaccine. Comparison of closely related isolates showed the role of transformation in facilitating capsule switching to non-vaccine serotypes and the emergence of drug resistance. However, such recombination was found to occur at significantly different rates across the species, and the evolution of the population was primarily driven by changes in the frequency of distinct genotypes extant before the introduction of the vaccine. These alterations resulted in little overall effect on accessory genome composition at the population level, contrasting with the decrease in pneumococcal disease rates after the vaccine's introduction.

  View details for DOI 10.1038/ng.2625

  View details for Web of Science ID 000319563900013

  View details for PubMedID 23644493

  View details for PubMedCentralID PMC3725542

• Comparative genomics of recent Shiga toxin-producing Escherichia coli O104:H4: short-term evolution of an emerging pathogen. mBio Grad, Y. H., Godfrey, P., Cerquiera, G. C., Mariani-Kurkdjian, P., Gouali, M., Bingen, E., Shea, T. P., Haas, B. J., Griggs, A., Young, S., Zeng, Q., Lipsitch, M., Waldor, M. K., Weill, F. X., Wortman, J. R., Hanage, W. P. 2013; 4 (1): e00452-12

  Abstract

  The large outbreak of diarrhea and hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli O104:H4 in Europe from May to July 2011 highlighted the potential of a rarely identified E. coli serogroup to cause severe disease. Prior to the outbreak, there were very few reports of disease caused by this pathogen and thus little known of its diversity and evolution. The identification of cases of HUS caused by E. coli O104:H4 in France and Turkey after the outbreak and with no clear epidemiological links raises questions about whether these sporadic cases are derived from the outbreak. Here, we report genome sequences of five independent isolates from these cases and results of a comparative analysis with historical and 2011 outbreak isolates. These analyses revealed that the five isolates are not derived from the outbreak strain; however, they are more closely related to the outbreak strain and each other than to isolates identified prior to the 2011 outbreak. Over the short time scale represented by these closely related organisms, the majority of genome variation is found within their mobile genetic elements: none of the nine O104:H4 isolates compared here contain the same set of plasmids, and their prophages and genomic islands also differ. Moreover, the presence of closely related HUS-associated E. coli O104:H4 isolates supports the contention that fully virulent O104:H4 isolates are widespread and emphasizes the possibility of future food-borne E. coli O104:H4 outbreaks.In the summer of 2011, a large outbreak of bloody diarrhea with a high rate of severe complications took place in Europe, caused by a previously rarely seen Escherichia coli strain of serogroup O104:H4. Identification of subsequent infections caused by E. coli O104:H4 raised questions about whether these new cases represented ongoing transmission of the outbreak strain. In this study, we sequenced the genomes of isolates from five recent cases and compared them with historical isolates. The analyses reveal that, in the very short term, evolution of the bacterial genome takes place in parts of the genome that are exchanged among bacteria, and these regions contain genes involved in adaptation to local environments. We show that these recent isolates are not derived from the outbreak strain but are very closely related and share many of the same disease-causing genes, emphasizing the concern that these bacteria may cause future severe outbreaks.

  View details for DOI 10.1128/mBio.00452-12

  View details for PubMedID 23341549

  View details for PubMedCentralID PMC3551546

• Pathogen diversity and hidden regimes of apparent competition. The American naturalist Cobey, S., Lipsitch, M. 2013; 181 (1): 12-24

  Abstract

  Competition through cross-reacting host immune responses, a form of apparent competition, is a major driver of pathogen evolution and diversity. Most models of pathogens have focused on intraspecific interactions to explain observed patterns. Two recent experiments suggested that Haemophilus influenzae, a common nasopharyngeal colonizer of humans, might alter the immune environment in a way that favors otherwise less fit serotypes of another common pathogen, pneumococcus. Using a computational model, we demonstrate that H. influenzae, if it consistently raises the fitness of the less fit serotypes, can strongly promote pneumococcal diversity. However, the effects of H. influenzae are so sensitive to the prevalence of H. influenzae that this species is unlikely to be the main driver of serotype coexistence. Interactions that significantly affect diversity could furthermore be extremely difficult to detect through co-occurrence analysis alone. These results suggest that small differences in strains' adaptations to different immunological regimes, which are shaped by coinfections with other pathogens, can have dramatic effects on strain dynamics and patterns of phenotypic variation. Studies of microbial communities might therefore benefit from the use of varied approaches to infer the presence of indirect interactions.

  View details for DOI 10.1086/668598

  View details for PubMedID 23234842

  View details for PubMedCentralID PMC3716377

• Reply to Guy et al.: Support for a bottleneck in the 2011 Escherichia coli O104:H4 outbreak in Germany. Proceedings of the National Academy of Sciences of the United States of America Grad, Y. H., Lipsitch, M., Griggs, A. D., Haas, B. J., Shea, T. P., McCowan, C., Montmayeur, A., FitzGerald, M., Wortman, J. R., Krogfelt, K. A., Bingen, E., Weill, F. X., Tietze, E., Flieger, A., Lander, E. S., Nusbaum, C., Birren, B. W., Hung, D. T., Hanage, W. P. 2012; 109 (52): E3629-30

  View details for DOI 10.1073/pnas.1209419110

  View details for PubMedID 23479789

  View details for PubMedCentralID PMC3535640

• Distinct effects on diversifying selection by two mechanisms of immunity against Streptococcus pneumoniae. PLoS pathogens Li, Y., Gierahn, T., Thompson, C. M., Trzciński, K., Ford, C. B., Croucher, N., Gouveia, P., Flechtner, J. B., Malley, R., Lipsitch, M. 2012; 8 (11): e1002989

  Abstract

  Antigenic variation to evade host immunity has long been assumed to be a driving force of diversifying selection in pathogens. Colonization by Streptococcus pneumoniae, which is central to the organism's transmission and therefore evolution, is limited by two arms of the immune system: antibody- and T cell- mediated immunity. In particular, the effector activity of CD4(+) T(H)17 cell mediated immunity has been shown to act in trans, clearing co-colonizing pneumococci that do not bear the relevant antigen. It is thus unclear whether T(H)17 cell immunity allows benefit of antigenic variation and contributes to diversifying selection. Here we show that antigen-specific CD4(+) T(H)17 cell immunity almost equally reduces colonization by both an antigen-positive strain and a co-colonized, antigen-negative strain in a mouse model of pneumococcal carriage, thus potentially minimizing the advantage of escape from this type of immunity. Using a proteomic screening approach, we identified a list of candidate human CD4(+) T(H)17 cell antigens. Using this list and a previously published list of pneumococcal Antibody antigens, we bioinformatically assessed the signals of diversifying selection among the identified antigens compared to non-antigens. We found that Antibody antigen genes were significantly more likely to be under diversifying selection than the T(H)17 cell antigen genes, which were indistinguishable from non-antigens. Within the Antibody antigens, epitopes recognized by human antibodies showed stronger evidence of diversifying selection. Taken together, the data suggest that T(H)17 cell-mediated immunity, one form of T cell immunity that is important to limit carriage of antigen-positive pneumococcus, favors little diversifying selection in the targeted antigen. The results could provide new insight into pneumococcal vaccine design.

  View details for DOI 10.1371/journal.ppat.1002989

  View details for PubMedID 23144610

  View details for PubMedCentralID PMC3493470

• Improving the estimation of influenza-related mortality over a seasonal baseline. Epidemiology (Cambridge, Mass.) Goldstein, E., Viboud, C., Charu, V., Lipsitch, M. 2012; 23 (6): 829-38

  Abstract

  Existing methods for estimation of mortality attributable to influenza are limited by methodological and data uncertainty. We have used proxies for disease incidence of the three influenza cocirculating subtypes (A/H3N2, A/H1N1, and B) that combine data on influenza-like illness consultations and respiratory specimen testing to estimate influenza-associated mortality in the United States between 1997 and 2007.Weekly mortality rate for several mortality causes potentially affected by influenza was regressed linearly against subtype-specific influenza incidence proxies, adjusting for temporal trend and seasonal baseline, modeled by periodic cubic splines.Average annual influenza-associated mortality rates per 100,000 individuals were estimated for the following underlying causes of death: for pneumonia and influenza, 1.73 (95% confidence interval = 1.53-1.93); for chronic lower respiratory disease, 1.70 (1.48-1.93); for all respiratory causes, 3.58 (3.04-4.14); for myocardial infarctions, 1.02 (0.85-1.2); for ischemic heart disease, 2.7 (2.23-3.16); for heart disease, 3.82 (3.21-4.4); for cerebrovascular deaths, 0.65 (0.51-0.78); for all circulatory causes, 4.6 (3.79-5.39); for cancer, 0.87 (0.68-1.05); for diabetes, 0.33 (0.26-0.39); for renal disease, 0.19 (0.14-0.24); for Alzheimer disease, 0.41 (0.3-0.52); and for all causes, 11.92 (10.17-13.67). For several underlying causes of death, baseline mortality rates changed after the introduction of the pneumococcal conjugate vaccine.The proposed methodology establishes a linear relation between influenza incidence proxies and excess mortality, rendering temporally consistent model fits, and allowing for the assessment of related epidemiologic phenomena such as changes in mortality baselines.

  View details for DOI 10.1097/EDE.0b013e31826c2dda

  View details for PubMedID 22992574

  View details for PubMedCentralID PMC3516362

• Rethinking biosafety in research on potential pandemic pathogens. mBio Lipsitch, M., Bloom, B. R. 2012; 3 (5)

  Abstract

  If accidentally released, mammalian-transmissible influenza A/H5N1 viruses could pose a greater threat to public health than possibly any other infectious agent currently under study in laboratories, because of such viruses' likely combination of transmissibility and virulence to humans. We advocate explicit risk-benefit assessments before work on such pathogens is permitted or funded, improvement of biosafety practices and enforcement, and harmonization of criteria for permitting such experiments across government agencies, as well as internationally. Such potential pandemic pathogens, as they have been called, jeopardize not only laboratory workers and their contacts, but also the wider population, who should be involved in assessments of when such risks are acceptable in the service of scientific knowledge that may itself bear major public health benefits.

  View details for DOI 10.1128/mBio.00360-12

  View details for PubMedID 23047752

  View details for PubMedCentralID PMC3484391

• Rates of acquisition and clearance of pneumococcal serotypes in the nasopharynges of children in Kilifi District, Kenya. The Journal of infectious diseases Abdullahi, O., Karani, A., Tigoi, C. C., Mugo, D., Kungu, S., Wanjiru, E., Jomo, J., Musyimi, R., Lipsitch, M., Scott, J. A. 2012; 206 (7): 1020-9

  Abstract

  To understand and model the impact of pneumococcal conjugate vaccines at the population level, we need to know the transmission dynamics of individual pneumococcal serotypes. We estimated serotype-specific clearance and acquisition rates of nasopharyngeal colonization among Kenyan children.Children aged 3-59 months who were identified as carriers in a cross-sectional survey were followed-up approximately 1, 2, 4, 8, 16, and 32 days later and monthly thereafter until culture of 2 consecutive swabs yielded an alternative serotype or no pneumococcus. Serotype-specific clearance rates were estimated by exponential regression of interval-censored carriage durations. Duration was estimated as the reciprocal of the clearance rate, and acquisition rates were estimated on the basis of prevalence and duration, assuming an equilibrium state.Of 2840 children sampled between October 2006 and December 2008, 1868 were carriers. The clearance rate was 0.032 episodes/day (95% confidence interval [CI], .030-.034), for a carriage duration of 31.3 days, and the rate varied by serotype (P< .0005). Carriage durations for the 28 serotypes with ≥ 10 carriers ranged from 6.7 to 50 days. Clearance rates increased with year of age, adjusted for serotype (hazard ratio, 1.21; 95% CI, 1.15-1.27). The acquisition rate was 0.061 episodes/day (95% CI, .055-.067), which did not vary with age. Serotype-specific acquisition rates varied from 0.0002 to 0.0022 episodes/day. Serotype-specific acquisition rates correlated with prevalence (r=0.91; P< .00005) and with acquisition rates measured in a separate study involving 1404 newborns in Kilifi (r=0.87; P< .00005).The large sample size and short swabbing intervals provide a precise description of the prevalence, duration, and acquisition of carriage of 28 pneumococcal serotypes. In Kilifi, young children experience approximately 8 episodes of carriage per year. The declining prevalence with age is attributable to increasing clearance rates.

  View details for DOI 10.1093/infdis/jis447

  View details for PubMedID 22829650

  View details for PubMedCentralID PMC3433858

• Searching for sharp drops in the incidence of pandemic A/H1N1 influenza by single year of age. PloS one Jacobs, J. H., Archer, B. N., Baker, M. G., Cowling, B. J., Heffernan, R. T., Mercer, G., Uez, O., Hanshaoworakul, W., Viboud, C., Schwartz, J., Tchetgen Tchetgen, E., Lipsitch, M. 2012; 7 (8): e42328

  Abstract

  During the 2009 H1N1 pandemic (pH1N1), morbidity and mortality sparing was observed among the elderly population; it was hypothesized that this age group benefited from immunity to pH1N1 due to cross-reactive antibodies generated from prior infection with antigenically similar influenza viruses. Evidence from serologic studies and genetic similarities between pH1N1 and historical influenza viruses suggest that the incidence of pH1N1 cases should drop markedly in age cohorts born prior to the disappearance of H1N1 in 1957, namely those at least 52-53 years old in 2009, but the precise range of ages affected has not been delineated.To test for any age-associated discontinuities in pH1N1 incidence, we aggregated laboratory-confirmed pH1N1 case data from 8 jurisdictions in 7 countries, stratified by single year of age, sex (when available), and hospitalization status. Using single year of age population denominators, we generated smoothed curves of the weighted risk ratio of pH1N1 incidence, and looked for sharp drops at varying age bandwidths, defined as a significantly negative second derivative. Analyses stratified by hospitalization status and sex were used to test alternative explanations for observed discontinuities. We found that the risk of laboratory-confirmed infection with pH1N1 declines with age, but that there was a statistically significant leveling off or increase in risk from about 45 to 50 years of age, after which a sharp drop in risk occurs until the late fifties. This trend was more pronounced in hospitalized cases and in women and was independent of the choice in smoothing parameters. The age range at which the decline in risk accelerates corresponds to the cohort born between 1951-1959 (hospitalized) and 1953-1960 (not hospitalized).The reduced incidence of pH1N1 disease in older individuals shows a detailed age-specific pattern consistent with protection conferred by exposure to influenza A/H1N1 viruses circulating before 1957.

  View details for DOI 10.1371/journal.pone.0042328

  View details for PubMedID 22876316

  View details for PubMedCentralID PMC3410923

• Factors related to increasing prevalence of resistance to ciprofloxacin and other antimicrobial drugs in Neisseria gonorrhoeae, United States. Emerging infectious diseases Goldstein, E., Kirkcaldy, R. D., Reshef, D., Berman, S., Weinstock, H., Sabeti, P., Del Rio, C., Hall, G., Hook, E. W., Lipsitch, M. 2012; 18 (8): 1290-7

  Abstract

  Using data from the Gonococcal Isolate Surveillance Project, we studied changes in ciprofloxacin resistance in Neisseria gonorrhoeae isolates in the United States during 2002-2007. Compared with prevalence in heterosexual men, prevalence of ciprofloxacin-resistant N. gonorrhoeae infections showed a more pronounced increase in men who have sex with men (MSM), particularly through an increase in prevalence of strains also resistant to tetracycline and penicillin. Moreover, that multidrug resistance profile among MSM was negatively associated with recent travel. Across the surveillance project sites, first appearance of ciprofloxacin resistance in heterosexual men was positively correlated with such resistance for MSM. The increase in prevalence of ciprofloxacin resistance may have been facilitated by use of fluoroquinolones for treating gonorrhea and other conditions. The prominence of multidrug resistance suggests that using other classes of antimicrobial drugs for purposes other than treating gonorrhea helped increase the prevalence of ciprofloxacin-resistant strains that are also resistant to those drugs.

  View details for DOI 10.3201/eid1808.111202

  View details for PubMedID 22840274

  View details for PubMedCentralID PMC3414012

• Modelling seasonal variations in the age and incidence of Kawasaki disease to explore possible infectious aetiologies. Proceedings. Biological sciences Pitzer, V. E., Burgner, D., Viboud, C., Simonsen, L., Andreasen, V., Steiner, C. A., Lipsitch, M. 2012; 279 (1739): 2736-43

  Abstract

  The average age of infection is expected to vary during seasonal epidemics in a way that is predictable from the epidemiological features, such as the duration of infectiousness and the nature of population mixing. However, it is not known whether such changes can be detected and verified using routinely collected data. We examined the correlation between the weekly number and average age of cases using data on pre-vaccination measles and rotavirus. We show that age-incidence patterns can be observed and predicted for these childhood infections. Incorporating additional information about important features of the transmission dynamics improves the correspondence between model predictions and empirical data. We then explored whether knowledge of the age-incidence pattern can shed light on the epidemiological features of diseases of unknown aetiology, such as Kawasaki disease (KD). Our results indicate KD is unlikely to be triggered by a single acute immunizing infection, but is consistent with an infection of longer duration, a non-immunizing infection or co-infection with an acute agent and one with longer duration. Age-incidence patterns can lend insight into important epidemiological features of infections, providing information on transmission-relevant population mixing for known infections and clues about the aetiology of complex paediatric diseases.

  View details for DOI 10.1098/rspb.2011.2464

  View details for PubMedID 22398170

  View details for PubMedCentralID PMC3367771

• Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model. Epidemiology (Cambridge, Mass.) Lipsitch, M., Abdullahi, O., DʼAmour, A., Xie, W., Weinberger, D. M., Tchetgen Tchetgen, E., Scott, J. A. 2012; 23 (4): 510-9

  Abstract

  There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a nonserotype-specific fashion.We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children 3-59 months of age, following up positive swabs at days 2, 4, 8, 16, and 32 and then monthly thereafter until 2 swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance, and competition parameters for 27 serotypes using a Markov transition model.Point estimates of type-specific acquisition rates ranged from 0.00025/d (type 1) to 0.0031/d (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval = 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes.Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine.

  View details for DOI 10.1097/EDE.0b013e31824f2f32

  View details for PubMedID 22441543

  View details for PubMedCentralID PMC3670084

• Evolution, safety, and highly pathogenic influenza viruses. Science (New York, N.Y.) Lipsitch, M., Plotkin, J. B., Simonsen, L., Bloom, B. 2012; 336 (6088): 1529-31

  Abstract

  Experience with influenza has shown that predictions of virus phenotype or fitness from nucleotide sequence are imperfect and that predicting the timing and course of evolution is extremely difficult. Such uncertainty means that the risk of experiments with mammalian-transmissible, possibly highly virulent influenza viruses remains high even if some aspects of their laboratory biology are reassuring; it also implies limitations on the ability of laboratory observations to guide interpretation of surveillance of strains in the field. Thus, we propose that future experiments with virulent pathogens whose accidental or deliberate release could lead to extensive spread in human populations should be limited by explicit risk-benefit considerations.

  View details for DOI 10.1126/science.1223204

  View details for PubMedID 22723411

  View details for PubMedCentralID PMC3467308

• Patient sharing and population genetic structure of methicillin-resistant Staphylococcus aureus. Proceedings of the National Academy of Sciences of the United States of America Ke, W., Huang, S. S., Hudson, L. O., Elkins, K. R., Nguyen, C. C., Spratt, B. G., Murphy, C. R., Avery, T. R., Lipsitch, M. 2012; 109 (17): 6763-8

  Abstract

  Rates of hospital-acquired infections, specifically methicillin-resistant Staphylococcus aureus (MRSA), are increasingly being used as indicators for quality of hospital hygiene. There has been much effort on understanding the transmission process at the hospital level; however, interhospital population-based transmission remains poorly defined. We evaluated whether the proportion of shared patients between hospitals was correlated with genetic similarity of MRSA strains from those hospitals. Using data collected from 30 of 32 hospitals in Orange County, California, multivariate linear regression showed that for each twofold increase in the proportion of patients shared between 2 hospitals, there was a 7.7% reduction in genetic heterogeneity between the hospitals' MRSA populations (permutation P value = 0.0356). Pairs of hospitals that both served adults had more similar MRSA populations than pairs including a pediatric hospital. These findings suggest that concerted efforts among hospitals that share large numbers of patients may be synergistic to prevent MRSA transmission.

  View details for DOI 10.1073/pnas.1113578109

  View details for PubMedID 22431601

  View details for PubMedCentralID PMC3340079

• Niche and neutral effects of acquired immunity permit coexistence of pneumococcal serotypes. Science (New York, N.Y.) Cobey, S., Lipsitch, M. 2012; 335 (6074): 1376-80

  Abstract

  Over 90 capsular serotypes of Streptococcus pneumoniae, a common nasopharyngeal colonizer and major cause of pneumonia, bacteremia, and meningitis, are known. It is unclear why some serotypes can persist at all: They are more easily cleared from carriage and compete poorly in vivo. Serotype-specific immune responses, which could promote diversity in principle, are weak enough to allow repeated colonizations by the same type. We show that weak serotype-specific immunity and an acquired response not specific to the capsule can together reproduce observed diversity. Serotype-specific immunity stabilizes competition, and acquired immunity to noncapsular antigens reduces fitness differences. Our model can be used to explain the effects of pneumococcal vaccination and indicates general factors that regulate the diversity of pathogens.

  View details for DOI 10.1126/science.1215947

  View details for PubMedID 22383809

  View details for PubMedCentralID PMC3341938

• Pneumococcal Carriage and Antibiotic Resistance in Young Children Before 13-valent Conjugate Vaccine PEDIATRIC INFECTIOUS DISEASE JOURNAL Wroe, P. C., Lee, G. M., Finkelstein, J. A., Pelton, S. I., Hanage, W. P., Lipsitch, M., Stevenson, A. E., Rifas-Shiman, S. L., Kleinman, K., Dutta-Linn, M. M., Hinrichsen, V. L., Lakoma, M., Huang, S. S. 2012; 31 (3): 249-254

  Abstract

  We sought to measure trends in Streptococcus pneumoniae carriage and antibiotic resistance in young children in Massachusetts communities after widespread adoption of heptavalent 7-valent pneumococcal conjugate vaccine (PCV7) and before the introduction of the 13-valent PCV (PCV13).We conducted a cross-sectional study including collection of questionnaire data and nasopharyngeal specimens among children aged <7 years in primary care practices from 8 Massachusetts communities during the winter season of 2008-2009 and compared with similar studies performed in 2001, 2003-2004, and 2006-2007. Antimicrobial susceptibility testing and serotyping were performed on pneumococcal isolates, and risk factors for colonization in recent seasons (2006-2007 and 2008-2009) were evaluated.We collected nasopharyngeal specimens from 1011 children, 290 (29%) of whom were colonized with pneumococcus. Non-PCV7 serotypes accounted for 98% of pneumococcal isolates, most commonly 19A (14%), 6C (11%), and 15B/C (11%). In 2008-2009, newly targeted PCV13 serotypes accounted for 20% of carriage isolates and 41% of penicillin-nonsusceptible S. pneumoniae. In multivariate models, younger age, child care, young siblings, and upper respiratory illness remained predictors of pneumococcal carriage, despite near-complete serotype replacement. Only young age and child care were significantly associated with penicillin-nonsusceptible S. pneumoniae carriage.Serotype replacement post-PCV7 is essentially complete and has been sustained in young children, with the relatively virulent 19A being the most common serotype. Predictors of carriage remained similar despite serotype replacement. PCV13 may reduce 19A and decrease antibiotic-resistant strains, but monitoring for new serotype replacement is warranted.

  View details for DOI 10.1097/INF.0b013e31824214ac

  View details for Web of Science ID 000300706700010

  View details for PubMedID 22173142

  View details for PubMedCentralID PMC3288953

• The prevalence and risk factors for pneumococcal colonization of the nasopharynx among children in Kilifi District, Kenya. PloS one Abdullahi, O., Karani, A., Tigoi, C. C., Mugo, D., Kungu, S., Wanjiru, E., Jomo, J., Musyimi, R., Lipsitch, M., Scott, J. A. 2012; 7 (2): e30787

  Abstract

  Pneumococcal conjugate vaccines (PCV) reduce nasopharyngeal carriage of vaccine-serotype pneumococci but increase in the carriage of non-vaccine serotypes. We studied the epidemiology of carriage among children 3-59 months old before vaccine introduction in Kilifi, Kenya.In a rolling cross-sectional study from October 2006 to December 2008 we approached 3570 healthy children selected at random from the population register of the Kilifi Health and Demographic Surveillance System and 134 HIV-infected children registered at a specialist clinic. A single nasopharyngeal swab was transported in STGG and cultured on gentamicin blood agar. A single colony of pneumococcus was serotyped by Quellung reaction.Families of 2840 children in the population-based sample and 99 in the HIV-infected sample consented to participate; carriage prevalence was 65.8% (95% CI, 64.0-67.5%) and 76% (95% CI, 66-84%) in the two samples, respectively. Carriage prevalence declined progressively with age from 79% at 6-11 months to 51% at 54-59 months (p<0.0005). Carriage was positively associated with coryza (Odds ratio 2.63, 95%CI 2.12-3.25) and cough (1.55, 95%CI 1.26-1.91) and negatively associated with recent antibiotic use (0.53 95%CI 0.34-0.81). 53 different serotypes were identified and 42% of isolates were of serotypes contained in the 10-valent PCV. Common serotypes declined in prevalence with age while less common serotypes did not.Carriage prevalence in children was high, serotypes were diverse, and the majority of strains were of serotypes not represented in the 10-valent PCV. Vaccine introduction in Kenya will provide a natural test of virulence for the many circulating non-vaccine serotypes.

  View details for DOI 10.1371/journal.pone.0030787

  View details for PubMedID 22363489

  View details for PubMedCentralID PMC3282706

• Serotype replacement in disease after pneumococcal vaccination. Lancet (London, England) Weinberger, D. M., Malley, R., Lipsitch, M. 2011; 378 (9807): 1962-73

  Abstract

  Vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) has significantly reduced the burden of pneumococcal disease and has had an important public health benefit. Because this vaccine targets only seven of the more than 92 pneumococcal serotypes, concerns have been raised that non-vaccine serotypes (NVTs) could increase in prevalence and reduce the benefits of vaccination. Indeed, among asymptomatic carriers, the prevalence of NVTs has increased substantially, and consequently, there has been little or no net change in the bacterial carriage prevalence. In many populations, pneumococcal disease caused by NVT has increased, but in most cases this increase has been less than the increase in NVT carriage. We review the evidence for serotype replacement in carriage and disease, and address the surveillance biases that might affect these findings. We then discuss possible reasons for the discrepancy between near-complete replacement in carriage and partial replacement for disease, including differences in invasiveness between vaccine serotypes. We contend that the magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and biases in the disease surveillance systems that could underestimate the true amount of replacement. We conclude by discussing the future potential for serotype replacement in disease and the need for continuing surveillance.

  View details for DOI 10.1016/S0140-6736(10)62225-8

  View details for PubMedID 21492929

  View details for PubMedCentralID PMC3256741

• Is methicillin-resistant Staphylococcus aureus replacing methicillin-susceptible S. aureus? The Journal of antimicrobial chemotherapy Mostofsky, E., Lipsitch, M., Regev-Yochay, G. 2011; 66 (10): 2199-214

  Abstract

  Despite extensive research on the emergence of and treatments for methicillin-resistant Staphylococcus aureus (MRSA), prior studies have not rigorously evaluated the impact of methicillin resistance on the overall incidence of S. aureus infections. Yet, there are direct clinical and research implications of determining whether methicillin-susceptible S. aureus (MSSA) infection rates remain stable in the face of increasing MRSA prevalence or whether MSSA will be replaced over time. A synthesis of prior studies indicates that the emergence of healthcare-associated MRSA (HA-MRSA) and community-associated MRSA (CA-MRSA) has led to an increase in the overall incidence of S. aureus infections, with MRSA principally adding to, rather than replacing, MSSA. However, colonization with CA-MRSA may at least partially replace colonization with MSSA. So far, evidence indicates that MSSA still accounts for many infections. Therefore, eradication of MRSA alone is not sufficient to address the public health burden of S. aureus.

  View details for DOI 10.1093/jac/dkr278

  View details for PubMedID 21737459

  View details for PubMedCentralID PMC3172038

• Estimating incidence curves of several infections using symptom surveillance data. PloS one Goldstein, E., Cowling, B. J., Aiello, A. E., Takahashi, S., King, G., Lu, Y., Lipsitch, M. 2011; 6 (8): e23380

  Abstract

  We introduce a method for estimating incidence curves of several co-circulating infectious pathogens, where each infection has its own probabilities of particular symptom profiles. Our deconvolution method utilizes weekly surveillance data on symptoms from a defined population as well as additional data on symptoms from a sample of virologically confirmed infectious episodes. We illustrate this method by numerical simulations and by using data from a survey conducted on the University of Michigan campus. Last, we describe the data needs to make such estimates accurate.

  View details for DOI 10.1371/journal.pone.0023380

  View details for PubMedID 21887246

  View details for PubMedCentralID PMC3160845

• Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Hernán, M. A., Lipsitch, M. 2011; 53 (3): 277-9

  Abstract

  An independent reanalysis of 11 randomized clinical trials shows that oseltamivir treatment reduces the risk of lower respiratory tract complications requiring antibiotic treatment by 28% overall (95% confidence interval [CI], 11%-42%) and by 37% among patients with confirmed influenza infections (95% CI, 18%-52%).

  View details for DOI 10.1093/cid/cir400

  View details for PubMedID 21677258

  View details for PubMedCentralID PMC3137795

• Predicting the epidemic sizes of influenza A/H1N1, A/H3N2, and B: a statistical method. PLoS medicine Goldstein, E., Cobey, S., Takahashi, S., Miller, J. C., Lipsitch, M. 2011; 8 (7): e1001051

  Abstract

  The epidemic sizes of influenza A/H3N2, A/H1N1, and B infections vary from year to year in the United States. We use publicly available US Centers for Disease Control (CDC) influenza surveillance data between 1997 and 2009 to study the temporal dynamics of influenza over this period.Regional outpatient surveillance data on influenza-like illness (ILI) and virologic surveillance data were combined to define a weekly proxy for the incidence of each strain in the United States. All strains exhibited a negative association between their cumulative incidence proxy (CIP) for the whole season (from calendar week 40 of each year to calendar week 20 of the next year) and the CIP of the other two strains (the complementary CIP) from the start of the season up to calendar week 2 (or 3, 4, or 5) of the next year. We introduce a method to predict a particular strain's CIP for the whole season by following the incidence of each strain from the start of the season until either the CIP of the chosen strain or its complementary CIP exceed certain thresholds. The method yielded accurate predictions, which generally occurred within a few weeks of the peak of incidence of the chosen strain, sometimes after that peak. For the largest seasons in the data, which were dominated by A/H3N2, prediction of A/H3N2 incidence always occurred at least several weeks in advance of the peak.Early circulation of one influenza strain is associated with a reduced total incidence of the other strains, consistent with the presence of interference between subtypes. Routine ILI and virologic surveillance data can be combined using this new method to predict the relative size of each influenza strain's epidemic by following the change in incidence of a given strain in the context of the incidence of cocirculating strains. Please see later in the article for the Editors' Summary.

  View details for DOI 10.1371/journal.pmed.1001051

  View details for PubMedID 21750666

  View details for PubMedCentralID PMC3130020

• Improving the evidence base for decision making during a pandemic: the example of 2009 influenza A/H1N1. Biosecurity and bioterrorism : biodefense strategy, practice, and science Lipsitch, M., Finelli, L., Heffernan, R. T., Leung, G. M., Redd, S. C. 2011; 9 (2): 89-115

  Abstract

  This article synthesizes and extends discussions held during an international meeting on "Surveillance for Decision Making: The Example of 2009 Pandemic Influenza A/H1N1," held at the Center for Communicable Disease Dynamics (CCDD), Harvard School of Public Health, on June 14 and 15, 2010. The meeting involved local, national, and global health authorities and academics representing 7 countries on 4 continents. We define the needs for surveillance in terms of the key decisions that must be made in response to a pandemic: how large a response to mount and which control measures to implement, for whom, and when. In doing so, we specify the quantitative evidence required to make informed decisions. We then describe the sources of surveillance and other population-based data that can presently--or in the future--form the basis for such evidence, and the interpretive tools needed to process raw surveillance data. We describe other inputs to decision making besides epidemiologic and surveillance data, and we conclude with key lessons of the 2009 pandemic for designing and planning surveillance in the future.

  View details for DOI 10.1089/bsp.2011.0007

  View details for PubMedID 21612363

  View details for PubMedCentralID PMC3102310

• Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nature genetics Ford, C. B., Lin, P. L., Chase, M. R., Shah, R. R., Iartchouk, O., Galagan, J., Mohaideen, N., Ioerger, T. R., Sacchettini, J. C., Lipsitch, M., Flynn, J. L., Fortune, S. M. 2011; 43 (5): 482-6

  Abstract

  Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.

  View details for DOI 10.1038/ng.811

  View details for PubMedID 21516081

  View details for PubMedCentralID PMC3101871

• Carried pneumococci in Massachusetts children: the contribution of clonal expansion and serotype switching. The Pediatric infectious disease journal Hanage, W. P., Bishop, C. J., Huang, S. S., Stevenson, A. E., Pelton, S. I., Lipsitch, M., Finkelstein, J. A. 2011; 30 (4): 302-8

  Abstract

  Vaccination against 7 serotypes of Streptococcus pneumoniae has led to the near extinction of vaccine serotypes in both disease and asymptomatic carriage. In carriage, vaccine serotypes have been replaced by nonvaccine serotypes.We used multilocus sequence typing to analyze a sample of 294 isolates of S. pneumoniae carried by Massachusetts children (aged, 3 months-7 years) and examine the results for serotype switching and association with antimicrobial resistance.Eighty-six distinct sequence types (STs) were found, 10 of which exhibited a serotype other than that which would be expected from previous carriage samples. We interpret this as evidence of past or recent serotype switching. Switched variants include ST 320, which is a common and increasing source of multidrug resistance in this community. Switching events within serogroups were more common than expected by chance (P = 0.043 by a Monte Carlo approach). Using multilocus sequence typing data and eBURST analysis, we also describe clonal dynamics within the important replacement serotypes 19A, 15B/C, 35B, and the recently described 6C.Some strains generated by serotype switching are increasingly important parts of the carriage population. In the case of 19A, it appears that the majority of increase is due to ST 320, a recently reported switched variant. This may have consequences for the STs causing invasive pneumococcal disease.

  View details for DOI 10.1097/INF.0b013e318201a154

  View details for PubMedID 21085049

  View details for PubMedCentralID PMC3175614

• Prediction of serotypes causing invasive pneumococcal disease in unvaccinated and vaccinated populations. Epidemiology (Cambridge, Mass.) Weinberger, D. M., Harboe, Z. B., Flasche, S., Scott, J. A., Lipsitch, M. 2011; 22 (2): 199-207

  Abstract

  Before the introduction of the heptavalent pneumococcal conjugate vaccine (Prevnar-7), the relative prevalence of serotypes of Streptococcus pneumoniae was fairly stable worldwide. We sought to develop a statistical tool to predict the relative frequency of different serotypes among disease isolates in the pre- and post-Prevnar-7 eras using the limited amount of data that is widely available.We initially used pre-Prevnar-7 carriage prevalence and estimates of invasiveness derived from case-fatality data as predictors for the relative abundance of serotypes causing invasive pneumococcal disease during the pre- and post-Prevnar-7 eras, using negative binomial regression. We fit the model to pre-Prevnar-7 invasive pneumococcal disease data from England and Wales and used these data to (1) evaluate the performance of the model using several datasets and (2) evaluate the utility of the country-specific carriage data. We then fit an alternative model that used polysaccharide structure, a correlate of prevalence that does not require country-specific information and could be useful in determining the postvaccine population structure, as a predictor.Predictions from the initial model fit data from several pediatric populations in the pre-Prevnar-7 era. After the introduction of Prevnar-7, the model still had a good negative predictive value, though substantial unexplained variation remained. The alternative model had a good negative predictive value but poor positive predictive value. Both models demonstrate that the pneumococcal population follows a somewhat predictable pattern even after vaccination.This approach provides a preliminary framework to evaluate the potential patterns and impact of serotypes causing invasive pneumococcal disease.

  View details for DOI 10.1097/EDE.0b013e3182087634

  View details for PubMedID 21646962

  View details for PubMedCentralID PMC3142570

• Quantifying Child Mortality Reductions Related to Measles Vaccination PLOS ONE Goldhaber-Fiebert, J. D., Lipsitch, M., Mahal, A., Zaslavsky, A. M., Salomon, J. A. 2010; 5 (11)

  Abstract

  This study characterizes the historical relationship between coverage of measles containing vaccines (MCV) and mortality in children under 5 years, with a view toward ongoing global efforts to reduce child mortality.Using country-level, longitudinal panel data, from 44 countries over the period 1960-2005, we analyzed the relationship between MCV coverage and measles mortality with (1) logistic regressions for no measles deaths in a country-year, and (2) linear regressions for the logarithm of the measles death rate. All regressions allowed a flexible, non-linear relationship between coverage and mortality. Covariates included birth rate, death rates from other causes, percent living in urban areas, population density, per-capita GDP, use of the two-dose MCV, year, and mortality coding system. Regressions used lagged covariates, country fixed effects, and robust standard errors clustered by country. The likelihood of no measles deaths increased nonlinearly with higher MCV coverage (ORs: 13.8 [1.6-122.7] for 80-89% to 40.7 [3.2-517.6] for ≥95%), compared to pre-vaccination risk levels. Measles death rates declined nonlinearly with higher MCV coverage, with benefits accruing more slowly above 90% coverage. Compared to no coverage, predicted average reductions in death rates were -79% at 70% coverage, -93% at 90%, and -95% at 95%.40 years of experience with MCV vaccination suggests that extremely high levels of vaccination coverage are needed to produce sharp reductions in measles deaths. Achieving sustainable benefits likely requires a combination of extended vaccine programs and supplementary vaccine efforts.

  View details for DOI 10.1371/journal.pone.0013842

  View details for Web of Science ID 000283838600016

  View details for PubMedID 21079809

  View details for PubMedCentralID PMC2973966

• Quantifying interhospital patient sharing as a mechanism for infectious disease spread. Infection control and hospital epidemiology Huang, S. S., Avery, T. R., Song, Y., Elkins, K. R., Nguyen, C. C., Nutter, S. K., Nafday, A. A., Condon, C. J., Chang, M. T., Chrest, D., Boos, J., Bobashev, G., Wheaton, W., Frank, S. A., Platt, R., Lipsitch, M., Bush, R. M., Eubank, S., Burke, D. S., Lee, B. Y. 2010; 31 (11): 1160-9

  Abstract

  Assessments of infectious disease spread in hospitals seldom account for interfacility patient sharing. This is particularly important for pathogens with prolonged incubation periods or carrier states.We quantified patient sharing among all 32 hospitals in Orange County (OC), California, using hospital discharge data. Same-day transfers between hospitals were considered "direct" transfers, and events in which patients were shared between hospitals after an intervening stay at home or elsewhere were considered "indirect" patient-sharing events. We assessed the frequency of readmissions to another OC hospital within various time points from discharge and examined interhospital sharing of patients with Clostridium difficile infection.In 2005, OC hospitals had 319,918 admissions. Twenty-nine percent of patients were admitted at least twice, with a median interval between discharge and readmission of 53 days. Of the patients with 2 or more admissions, 75% were admitted to more than 1 hospital. Ninety-four percent of interhospital patient sharing occurred indirectly. When we used 10 shared patients as a measure of potential interhospital exposure, 6 (19%) of 32 hospitals "exposed" more than 50% of all OC hospitals within 6 months, and 17 (53%) exposed more than 50% within 12 months. Hospitals shared 1 or more patient with a median of 28 other hospitals. When we evaluated patients with C. difficile infection, 25% were readmitted within 12 weeks; 41% were readmitted to different hospitals, and less than 30% of these readmissions were direct transfers.In a large metropolitan county, interhospital patient sharing was a potential avenue for transmission of infectious agents. Indirect sharing with an intervening stay at home or elsewhere composed the bulk of potential exposures and occurred unbeknownst to hospitals.

  View details for DOI 10.1086/656747

  View details for PubMedID 20874503

  View details for PubMedCentralID PMC3064463

• Association of serotype with risk of death due to pneumococcal pneumonia: a meta-analysis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Weinberger, D. M., Harboe, Z. B., Sanders, E. A., Ndiritu, M., Klugman, K. P., Rückinger, S., Dagan, R., Adegbola, R., Cutts, F., Johnson, H. L., O'Brien, K. L., Scott, J. A., Lipsitch, M. 2010; 51 (6): 692-9

  Abstract

  The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness, and disease incidence. There has been some debate, though, regarding whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regard to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death due to IPD is a stable serotype-associated property across studies and then compared the pooled effect estimates with epidemiologic and biological correlates.We performed a systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis. Study-specific estimates of risk of death (risk ratio [RR]) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared with RRs from adults with low comorbidity scores to evaluate potential confounding by host factors.Significant differences were found in the RR estimates among serotypes in patients with bacteremic pneumonia. Overall, serotypes 1, 7F, and 8 were associated with decreased RRs, and serotypes 3, 6A, 6B, 9N, and 19F were associated with increased RRs. Outcomes among meningitis patients did not differ significantly among serotypes. Serotypes with increased RRs had a high carriage prevalence, had low invasiveness, and were more heavily encapsulated in vitro.These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property.

  View details for DOI 10.1086/655828

  View details for PubMedID 20715907

  View details for PubMedCentralID PMC2927802

• Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPARα, PPARγ and LXRα PLOS ONE Goldwasser, J., Cohen, P. Y., Yang, E., Balaguer, P., Yarmush, M. L., Nahmias, Y. 2010; 5 (8): e12399

  Abstract

  Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARalpha, PPARgamma, and LXRalpha. We show it activates the ligand-binding domain of both PPARalpha and PPARgamma, while inhibiting LXRalpha in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRalpha, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARalpha co-activator, PGC1alpha. The flavonoid activates PPAR response element (PPRE) while suppressing LXRalpha response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRalpha-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRalpha inhibitor.

  View details for DOI 10.1371/journal.pone.0012399

  View details for Web of Science ID 000281234700023

  View details for PubMedID 20811644

  View details for PubMedCentralID PMC2928300

• Test and Treat DC: Forecasting the Impact of a Comprehensive HIV Strategy in Washington DC CLINICAL INFECTIOUS DISEASES Walensky, R. P., Paltiel, A., Losina, E., Morris, B. L., Scott, C. A., Rhode, E. R., Seage, G. R., Freedberg, K. A., CEPAC Investigators 2010; 51 (4): 392–400

  Abstract

  The United States and international agencies have signaled their commitment to containing the human immunodeficiency virus (HIV) epidemic via early case identification and linkage to antiretroviral therapy (ART) immediately at diagnosis. We forecast outcomes of this approach if implemented in Washington DC.Using a mathematical model of HIV case detection and treatment, we evaluated combinations of HIV screening and ART initiation strategies. We define current practice as no regular screening program and ART at CD4 counts < or = 350 cells/microL, and we define test and treat as annual screening and administration of ART at diagnosis. Outcomes include life expectancy of HIV-infected persons and changes in the population time with transmissible HIV RNA levels. Data, largely from Washington DC, include undiagnosed HIV prevalence of 0.6%, annual incidence of 0.13%, 31% rate of test offer, 60% rate of acceptance, and 50% linkage to care. Input parameters, including optimized ART efficacy, are varied in sensitivity analyses.Projected life expectancies, from an initial mean age of 41 years, are 23.9, 25.0, and 25.6 years for current practice, test and treat, and test and treat with optimized ART, respectively. Compared with current practice, test and treat leads to a 14.7% reduction in time spent with transmissible HIV RNA level in the next 5 years; test and treat with optimized ART results in a 27.3% reduction.An expanded HIV test and treat program in Washington DC will increase life expectancy of HIV-infected patients but will have a modest impact on HIV transmission over the next 5 years and is unlikely to halt the HIV epidemic.

  View details for DOI 10.1086/655130

  View details for Web of Science ID 000279998300009

  View details for PubMedID 20617921

  View details for PubMedCentralID PMC2906630

• Oseltamivir for treatment and prevention of pandemic influenza A/H1N1 virus infection in households, Milwaukee, 2009. BMC infectious diseases Goldstein, E., Cowling, B. J., O'Hagan, J. J., Danon, L., Fang, V. J., Hagy, A., Miller, J. C., Reshef, D., Robins, J., Biedrzycki, P., Lipsitch, M. 2010; 10: 211

  Abstract

  During an influenza pandemic, a substantial proportion of transmission is thought to occur in households. We used data on influenza progression in individuals and their contacts collected by the City of Milwaukee Health Department (MHD) to study the transmission of pandemic influenza A/H1N1 virus in 362 households in Milwaukee, WI, and the effects of oseltamivir treatment and chemoprophylaxis.135 households had chronological information on symptoms and oseltamivir usage for all household members. The effect of oseltamivir treatment and other factors on the household secondary attack rate was estimated using univariate and multivariate logistic regression with households as the unit of analysis. The effect of oseltamivir treatment and other factors on the individual secondary attack rate was estimated using univariate and multivariate logistic regression with individual household contacts as the unit of analysis, and a generalized estimating equations approach was used to fit the model to allow for clustering within households.Oseltamivir index treatment on onset day or the following day (early treatment) was associated with a 42% reduction (OR: 0.58, 95% CI: 0.19, 1.73) in the odds of one or more secondary infections in a household and a 50% reduction (OR: 0.5, 95% CI: 0.17, 1.46) in the odds of a secondary infection in individual contacts. The confidence bounds are wide due to a small sample of households with early oseltamivir index usage - in 29 such households, 5 had a secondary attack. Younger household contacts were at higher risk of infection (OR: 2.79, 95% CI: 1.50-5.20).Early oseltamivir treatment may be beneficial in preventing H1N1pdm influenza transmission; this may have relevance to future control measures for influenza pandemics. Larger randomized trials are needed to confirm this finding statistically.

  View details for DOI 10.1186/1471-2334-10-211

  View details for PubMedID 20642862

  View details for PubMedCentralID PMC2919545

• Re-emergence of the type 1 pilus among Streptococcus pneumoniae isolates in Massachusetts, USA VACCINE Regev-Yochay, G., Hanage, W. P., Trzcinski, K., Rifas-Shiman, S. L., Lee, G., Bessolo, A., Huang, S. S., Pelton, S. I., McAdam, A. J., Finkelstein, J. A., Lipsitch, M., Malley, R. 2010; 28 (30): 4842-4846

  Abstract

  Pneumococcal type 1 pilus proteins have been proposed as potential vaccine candidates. Following conjugate pneumococcal vaccination, the prevalence of the pneumococcal type 1 pilus declined dramatically, a decline associated with the elimination of vaccine-type (VT) strains. Here we show that between 2004 and 2007, there has been a significant increase in pilus prevalence, now exceeding rates from the pre-conjugate vaccine era. This increase is primarily due to non-VT strains. These emerging piliated non-VT strains are mostly novel clones, with some exceptions. The rise in pilus type 1 frequency across multiple distinct genetic backgrounds suggests that the pilus may confer an intrinsic advantage.

  View details for DOI 10.1016/j.vaccine.2010.04.042

  View details for Web of Science ID 000280345700023

  View details for PubMedID 20434550

  View details for PubMedCentralID PMC2897942

• Negative controls: a tool for detecting confounding and bias in observational studies. Epidemiology (Cambridge, Mass.) Lipsitch, M., Tchetgen Tchetgen, E., Cohen, T. 2010; 21 (3): 383-8

  Abstract

  Noncausal associations between exposures and outcomes are a threat to validity of causal inference in observational studies. Many techniques have been developed for study design and analysis to identify and eliminate such errors. Such problems are not expected to compromise experimental studies, where careful standardization of conditions (for laboratory work) and randomization (for population studies) should, if applied properly, eliminate most such noncausal associations. We argue, however, that a routine precaution taken in the design of biologic laboratory experiments--the use of "negative controls"--is designed to detect both suspected and unsuspected sources of spurious causal inference. In epidemiology, analogous negative controls help to identify and resolve confounding as well as other sources of error, including recall bias or analytic flaws. We distinguish 2 types of negative controls (exposure controls and outcome controls), describe examples of each type from the epidemiologic literature, and identify the conditions for the use of such negative controls to detect confounding. We conclude that negative controls should be more commonly employed in observational studies, and that additional work is needed to specify the conditions under which negative controls will be sensitive detectors of other sources of error in observational studies.

  View details for DOI 10.1097/EDE.0b013e3181d61eeb

  View details for PubMedID 20335814

  View details for PubMedCentralID PMC3053408

• Pre-dispensing of antivirals to high-risk individuals in an influenza pandemic. Influenza and other respiratory viruses Goldstein, E., Miller, J. C., O'Hagan, J. J., Lipsitch, M. 2010; 4 (2): 101-12

  Abstract

  We consider the net benefits of pre-dispensing antivirals to high-risk individuals during an influenza pandemic, where the measure of the benefit is the number of severe outcomes (such as deaths or hospitalizations) prevented by antivirals in the whole population. One potential benefit of pre-dispensing is that individuals to whom antivirals have been pre-dispensed may be able to initiate treatment earlier than if they had to wait to obtain and fill a prescription, reducing their risk of progression to severe disease. If this benefit exceeds the side effects of misuse for the category of individuals to whom antivirals were pre-dispensed, and if antiviral supply exceeds overall population demand (which appears relevant for several countries including US in the 2009 H1N1 pandemic), pre-dispensing a quantity of antivirals not exceeding the difference between supply and demand is always beneficial. In this study, we consider the net benefits of pre-dispensing antivirals under various scenarios, including demand exceeding supply, and derive mathematical conditions under which antiviral pre-dispensing is advantageous on balance. For individuals whose relative risk of severe outcome is high enough, such as immunosuppressed individuals (particularly children) and possibly individuals with neurological disorders, pre-dispensing is always beneficial at a given level of antiviral stockpile with modest assumptions on the relative benefit of early treatment by a pre-dispensed course, regardless of the overall population demand for antivirals during the course of an epidemic. Making additional assumptions on either the overall population demand for antivirals (which appear relevant for the 2009 H1N1 pandemic) or on the relative benefit of pre-dispensing would make pre-dispensing net beneficial with inclusion of a larger number of persons such as pregnant women and morbidly obese adults.

  View details for DOI 10.1111/j.1750-2659.2009.00128.x

  View details for PubMedID 20167050

  View details for PubMedCentralID PMC3075926

• Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States PLOS BIOLOGY Shaman, J., Pitzer, V. E., Viboud, C., Grenfell, B. T., Lipsitch, M. 2010; 8 (2): e1000316

  Abstract

  Much of the observed wintertime increase of mortality in temperate regions is attributed to seasonal influenza. A recent reanalysis of laboratory experiments indicates that absolute humidity strongly modulates the airborne survival and transmission of the influenza virus. Here, we extend these findings to the human population level, showing that the onset of increased wintertime influenza-related mortality in the United States is associated with anomalously low absolute humidity levels during the prior weeks. We then use an epidemiological model, in which observed absolute humidity conditions temper influenza transmission rates, to successfully simulate the seasonal cycle of observed influenza-related mortality. The model results indicate that direct modulation of influenza transmissibility by absolute humidity alone is sufficient to produce this observed seasonality. These findings provide epidemiological support for the hypothesis that absolute humidity drives seasonal variations of influenza transmission in temperate regions.

  View details for DOI 10.1371/journal.pbio.1000316

  View details for Web of Science ID 000275257300005

  View details for PubMedID 20186267

  View details for PubMedCentralID PMC2826374

• Reconstructing influenza incidence by deconvolution of daily mortality time series. Proceedings of the National Academy of Sciences of the United States of America Goldstein, E., Dushoff, J., Ma, J., Plotkin, J. B., Earn, D. J., Lipsitch, M. 2009; 106 (51): 21825-9

  Abstract

  We propose a mathematically straightforward method to infer the incidence curve of an epidemic from a recorded daily death curve and time-to-death distribution; the method is based on the Richardson-Lucy deconvolution scheme from optics. We apply the method to reconstruct the incidence curves for the 1918 influenza epidemic in Philadelphia and New York State. The incidence curves are then used to estimate epidemiological quantities, such as daily reproductive numbers and infectivity ratios. We found that during a brief period before the official control measures were implemented in Philadelphia, the drop in the daily number of new infections due to an average infector was much larger than expected from the depletion of susceptibles during that period; this finding was subjected to extensive sensitivity analysis. Combining this with recorded evidence about public behavior, we conclude that public awareness and change in behavior is likely to have had a major role in the slowdown of the epidemic even in a city whose response to the 1918 influenza epidemic is considered to have been among the worst in the U.S.

  View details for DOI 10.1073/pnas.0902958106

  View details for PubMedID 20080801

  View details for PubMedCentralID PMC2796142

• Estimates of the prevalence of pandemic (H1N1) 2009, United States, April-July 2009. Emerging infectious diseases Reed, C., Angulo, F. J., Swerdlow, D. L., Lipsitch, M., Meltzer, M. I., Jernigan, D., Finelli, L. 2009; 15 (12): 2004-7

  Abstract

  Through July 2009, a total of 43,677 laboratory-confirmed cases of influenza A pandemic (H1N1) 2009 were reported in the United States, which is likely a substantial underestimate of the true number. Correcting for under-ascertainment using a multiplier model, we estimate that 1.8 million-5.7 million cases occurred, including 9,000-21,000 hospitalizations.

  View details for DOI 10.3201/eid1512.091413

  View details for PubMedID 19961687

  View details for PubMedCentralID PMC3375879

• The Severity of Pandemic H1N1 Influenza in the United States, from April to July 2009: A Bayesian Analysis PLOS MEDICINE Presanis, A. M., De Angelis, D., Hagy, A., Reed, C., Riley, S., Cooper, B. S., Finelli, L., Biedrzycki, P., Lipsitch, M., New York City Swine Flu Invest Tea 2009; 6 (12): e1000207

  Abstract

  Accurate measures of the severity of pandemic (H1N1) 2009 influenza (pH1N1) are needed to assess the likely impact of an anticipated resurgence in the autumn in the Northern Hemisphere. Severity has been difficult to measure because jurisdictions with large numbers of deaths and other severe outcomes have had too many cases to assess the total number with confidence. Also, detection of severe cases may be more likely, resulting in overestimation of the severity of an average case. We sought to estimate the probabilities that symptomatic infection would lead to hospitalization, ICU admission, and death by combining data from multiple sources.We used complementary data from two US cities: Milwaukee attempted to identify cases of medically attended infection whether or not they required hospitalization, while New York City focused on the identification of hospitalizations, intensive care admission or mechanical ventilation (hereafter, ICU), and deaths. New York data were used to estimate numerators for ICU and death, and two sources of data--medically attended cases in Milwaukee or self-reported influenza-like illness (ILI) in New York--were used to estimate ratios of symptomatic cases to hospitalizations. Combining these data with estimates of the fraction detected for each level of severity, we estimated the proportion of symptomatic patients who died (symptomatic case-fatality ratio, sCFR), required ICU (sCIR), and required hospitalization (sCHR), overall and by age category. Evidence, prior information, and associated uncertainty were analyzed in a Bayesian evidence synthesis framework. Using medically attended cases and estimates of the proportion of symptomatic cases medically attended, we estimated an sCFR of 0.048% (95% credible interval [CI] 0.026%-0.096%), sCIR of 0.239% (0.134%-0.458%), and sCHR of 1.44% (0.83%-2.64%). Using self-reported ILI, we obtained estimates approximately 7-9 x lower. sCFR and sCIR appear to be highest in persons aged 18 y and older, and lowest in children aged 5-17 y. sCHR appears to be lowest in persons aged 5-17; our data were too sparse to allow us to determine the group in which it was the highest.These estimates suggest that an autumn-winter pandemic wave of pH1N1 with comparable severity per case could lead to a number of deaths in the range from considerably below that associated with seasonal influenza to slightly higher, but with the greatest impact in children aged 0-4 and adults 18-64. These estimates of impact depend on assumptions about total incidence of infection and would be larger if incidence of symptomatic infection were higher or shifted toward adults, if viral virulence increased, or if suboptimal treatment resulted from stress on the health care system; numbers would decrease if the total proportion of the population symptomatically infected were lower than assumed.

  View details for DOI 10.1371/journal.pmed.1000207

  View details for Web of Science ID 000273060600018

  View details for PubMedID 19997612

  View details for PubMedCentralID PMC2784967

• H1N1 vaccination and adults with underlying health conditions in the US. PLoS currents Goldstein, E., Lipsitch, M. 2009; 1: RRN1132

  Abstract

  65% of fatalities from pH1N1 infections in a large US case series occur in adults with underlying health conditions other than pregnancy, but it appears that only relatively few high-risk adults will get vaccinated during the fall wave of pH1N1 transmission. There are several reasons for this problem; the most important is vaccine shortage. High risk adults (other than pregnant women) were not part of the initial, narrow priority cohort which included pregnant women and children ages 0.5-4; this is despite the fact that some of those high risk groups, such as adults with immunosuppressive conditions and possibly individuals with neurological disorders, have a relative risk for fatality (per capita) higher than pregnant women, and over 28-fold higher than healthy children under the age of 4. With more vaccine becoming available than needed in the initial priority cohort, a broader group which includes high risk adults and individuals under 24 becomes eligible for vaccine in many locations. Nonetheless, due to continuing high demand, high-risk adults face competition for vaccine from healthy individuals under 24; additionally, some locations specifically prioritize school students over high-risk adults. Finally, there is an issue of awareness and a shortage of specific channels that target high risk adults other than pregnant women and facilitate vaccine distribution among them in the US.

  View details for DOI 10.1371/currents.RRN1132

  View details for PubMedID 20029669

  View details for PubMedCentralID PMC2781303

• Antiviral usage for H1N1 treatment: pros, cons and an argument for broader prescribing guidelines in the United States. PLoS currents Goldstein, E., Lipsitch, M. 2009; 1: RRN1122

  Abstract

  Current CDC guidelines for antiviral treatment of people with influenza like illness (ILI) effectively discourage treatment of people with no underlying medical conditions unless they exhibit severe symptoms, such as evidence of lower respiratory tract infection or clinical deterioration. This guidance is unlike that provided by some other countries, which allow for treatment of most moderately symptomatic individuals. We examine evidence for benefits of antiviral usage for influenza treatment, including its relation to severe outcomes for the current pandemic H1N1 strain. We also discuss some of the potential cons of antiviral usage. In the current situation in the US, with an elevated and evidently growing burden of influenza hospitalizations and mortality, a high percentage of individuals infected with influenza (with almost all of those carrying the H1N1pdm strain) among those who exhibit ILI and get tested for influenza virus, very low levels of antiviral resistance and little time left for antiviral resistance to take off before large quantities of vaccine become available, we think it is worthwhile to consider a revision to the current antiviral usage recommendations, such that physicians would be encouraged to consider prescribing antivirals to individuals with moderate to severe symptoms who present for treatment.Note: Very recently CDC has adopted clarifications for its antiviral usage guidelines: http://www.cdc.gov/H1N1flu/antivirals/facts_clinicians.htm.

  View details for DOI 10.1371/currents.RRN1122

  View details for PubMedID 20029660

  View details for PubMedCentralID PMC2770576

• How to maintain surveillance for novel influenza A H1N1 when there are too many cases to count. Lancet (London, England) Lipsitch, M., Hayden, F. G., Cowling, B. J., Leung, G. M. 2009; 374 (9696): 1209-11

  View details for DOI 10.1016/S0140-6736(09)61377-5

  View details for PubMedID 19679345

• Cost-Effectiveness of Preventing Loss to Follow-up in HIV Treatment Programs: A Cote d'Ivoire Appraisal PLOS MEDICINE Losina, E., Toure, H., Uhler, L. M., Anglaret, X., Paltiel, A., Balestre, E., Walensky, R. P., Messou, E., Weinstein, M. C., Dabis, F., Freedberg, K. A., ART-LINC Collaboration Int Epidemi, CEPAC Int Investigators 2009; 6 (10): e1000173

  Abstract

  Data from HIV treatment programs in resource-limited settings show extensive rates of loss to follow-up (LTFU) ranging from 5% to 40% within 6 mo of antiretroviral therapy (ART) initiation. Our objective was to project the clinical impact and cost-effectiveness of interventions to prevent LTFU from HIV care in West Africa.We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model to project the clinical benefits and cost-effectiveness of LTFU-prevention programs from a payer perspective. These programs include components such as eliminating ART co-payments, eliminating charges to patients for opportunistic infection-related drugs, improving personnel training, and providing meals and reimbursing for transportation for participants. The efficacies and costs of these interventions were extensively varied in sensitivity analyses. We used World Health Organization criteria of <3x gross domestic product per capita (3x GDP per capita = US$2,823 for Côte d'Ivoire) as a plausible threshold for "cost-effectiveness." The main results are based on a reported 18% 1-y LTFU rate. With full retention in care, projected per-person discounted life expectancy starting from age 37 y was 144.7 mo (12.1 y). Survival losses from LTFU within 1 y of ART initiation ranged from 73.9 to 80.7 mo. The intervention costing US$22/person/year (e.g., eliminating ART co-payment) would be cost-effective with an efficacy of at least 12%. An intervention costing US$77/person/year (inclusive of all the components described above) would be cost-effective with an efficacy of at least 41%.Interventions that prevent LTFU in resource-limited settings would substantially improve survival and would be cost-effective by international criteria with efficacy of at least 12%-41%, depending on the cost of intervention, based on a reported 18% cumulative incidence of LTFU at 1 y after ART initiation. The commitment to start ART and treat HIV in these settings should include interventions to prevent LTFU.

  View details for DOI 10.1371/journal.pmed.1000173

  View details for Web of Science ID 000272032300016

  View details for PubMedID 19859538

  View details for PubMedCentralID PMC2762030

• The severity of pandemic H1N1 influenza in the United States, April - July 2009. PLoS currents Presanis, A. M., Lipsitch, M., , Hagy, A., Reed, C., Riley, S., Cooper, B., Biedrzycki, P., Finelli, L., B, J. 2009; 1: RRN1042

  Abstract

  BackgroundAccurate measures of the severity of pandemic influenza A/H1N1 (pH1N1) are needed to assess the likely impact of an anticipated resurgence in the autumn in the Northern Hemisphere. Severity has been difficult to measure because jurisdictions with large numbers of deaths and other severe outcomes have had too many cases to assess the total number with confidence. Also, detection of severe cases may be more likely. Methods and FindingsWe used complementary data from two US cities: Milwaukee attempted to identify cases of medically attended infection whether or not they required hospitalization, while New York City focused on the identification of hospitalizations, intensive care admission or mechanical ventilation (hereafter, ICU), and deaths. New York data were used to estimate numerators for ICU and death, and two sources of data: medically attended cases in Milwaukee or self-reported influenza-like illness in New York, were used to estimate ratios of symptomatic cases:hospitalizations. Combining these data with estimates of the fraction detected for each level of severity, we estimated the proportion of symptomatic cases that died (symptomatic case-fatality ratio, sCFR), required ICU (sCIR), and required hospitalization (sCHR), overall and by age category. Evidence, prior information and associated uncertainty were analyzed in a Bayesian evidence synthesis framework. Using medically attended cases and estimates of the proportion of symptomatic cases medically attended, we estimated sCFR of 0.048% (95% credible interval, CI 0.026%-0.096%), sCIR of 0.239% (0.134%-0.458%), and sCHR of 1.44% (0.83%-2.64%). Using self-reported ILI, we obtained estimates approximately 7-9x lower. sCFR and sCIR appear to be highest in persons 18 and older, and lowest in children 5-17. sCHR appears to be lowest in persons 5-17; our data were too sparse to allow us to determine the group in which it was the highest. ConclusionsThese estimates suggest that an autumn-winter pandemic wave of pH1N1 with comparable severity per case could lead to a number of deaths in the range from considerably below that associated with seasonal influenza to slightly higher, but with greatest impact in young children and non-elderly adults. These estimates of impact depend on assumptions about total incidence of infection and would be larger if incidence of symptomatic infection were higher or shifted toward adults, if viral virulence increased, or if suboptimal treatment resulted from stress on the health care system; numbers would decrease if the proportion infected or symptomatic were lower.

  View details for DOI 10.1371/currents.RRN1042

  View details for PubMedID 20029614

  View details for PubMedCentralID PMC2762775

• Exploring the relationship between incidence and the average age of infection during seasonal epidemics. Journal of theoretical biology Pitzer, V. E., Lipsitch, M. 2009; 260 (2): 175-85

  Abstract

  The inverse relationship between the incidence and the average age of first infection for immunizing agents has become a basic tenet in the theory underlying the mathematical modeling of infectious diseases. However, this relationship assumes that the infection has reached an endemic equilibrium. In reality, most infectious diseases exhibit seasonal and/or long-term oscillations in incidence. We use a seasonally forced age-structured SIR model to explore the relationship between the number of cases and the average age of first infection over a single epidemic cycle. Contrary to the relationship for the equilibrium dynamics, we find that the average age of first infection is greatest at or near the peak of the epidemic when mixing is homogeneous. We explore the sensitivity of our findings to assumptions about the natural history of infection, population mixing behavior, the mechanism of seasonality, and of the timing of case reporting in relation to the infectious period. We conclude that seasonal variation in the average age of first infection tends to be greatest for acute infections, and the relationship between the number of cases and the average age of first infection can vary depending on the nature of population mixing and the natural history of infection.

  View details for DOI 10.1016/j.jtbi.2009.06.008

  View details for PubMedID 19527734

  View details for PubMedCentralID PMC2745250

• Use of cumulative incidence of novel influenza A/H1N1 in foreign travelers to estimate lower bounds on cumulative incidence in Mexico. PloS one Lipsitch, M., Lajous, M., O'Hagan, J. J., Cohen, T., Miller, J. C., Goldstein, E., Danon, L., Wallinga, J., Riley, S., Dowell, S. F., Reed, C., McCarron, M. 2009; 4 (9): e6895

  Abstract

  An accurate estimate of the total number of cases and severity of illness of an emerging infectious disease is required both to define the burden of the epidemic and to determine the severity of disease. When a novel pathogen first appears, affected individuals with severe symptoms are more likely to be diagnosed. Accordingly, the total number of cases will be underestimated and disease severity overestimated. This problem is manifest in the current epidemic of novel influenza A/H1N1.We used a simple approach to leverage measures of incident influenza A/H1N1 among a relatively small and well observed group of US, UK, Spanish and Canadian travelers who had visited Mexico to estimate the incidence among a much larger and less well surveyed population of Mexican residents. We estimate that a minimum of 113,000 to 375,000 cases of novel influenza A/H1N1 have occurred in Mexicans during the month of April, 2009. Such an estimate serves as a lower bound because it does not account for underreporting of cases in travelers or for nonrandom mixing between Mexican residents and visitors, which together could increase the estimates by more than an order of magnitude.We find that the number of cases in Mexican residents may exceed the number of confirmed cases by two to three orders of magnitude. While the extent of disease spread is greater than previously appreciated, our estimate suggests that severe disease is uncommon since the total number of cases is likely to be much larger than those of confirmed cases.

  View details for DOI 10.1371/journal.pone.0006895

  View details for PubMedID 19742302

  View details for PubMedCentralID PMC2731883

• Predispensing of antivirals to high-risk individuals in an influenza pandemic. PLoS currents Goldstein, E., Miller, J. C., O'Hagan, J., Lipsitch, M. 2009; 1: RRN1007

  Abstract

  We consider the net benefits of predispensing antivirals to high-risk individuals during an influenza pandemic, where the measure of the benefit is the number of severe outcomes (such as deaths or hospitalizations) prevented by antivirals in the whole population. One potential benefit of predispensing is that individuals to whom antivirals have been predispensed may be able to initiate treatment earlier than if they had to wait to obtain and fill a prescription, reducing their risk of progression to severe disease. If this benefit exceeds the side effects of misuse for the category of individuals to whom antivirals were predispensed, and if antiviral supply exceeds overall population demand (which appears relevant for several countries including US in the current H1N1 pandemic), predispensing a quantity of antivirals not exceeding the difference between supply and demand is always beneficial. In this paper we consider the net benefits of predispensing antivirals under various scenarios, including demand exceeding supply, and derive mathematical conditions under which antiviral predispensing is advantageous on balance. For individuals whose relative risk of severe outcome is high enough, such as immunosuppressed individuals (particularly children) and possibly individuals with neurological disorders, predispensing is always beneficial at a given level of antiviral stockpile with modest assumptions on the relative benefit of early treatment by a predispensed course, regardless of the overall population demand for antivirals during the course of an epidemic. Making additional assumptions on either the overall population demand for antivirals (which appear relevant in the current situation) or on the relative benefit of predispensing would make predispensing net beneficial with inclusion of a larger number of persons such as pregnant women and morbidly obese adults.

  View details for DOI 10.1371/currents.RRN1007

  View details for PubMedID 20029604

  View details for PubMedCentralID PMC2762331

• Epidemiology and risk factors for Staphylococcus aureus colonization in children in the post-PCV7 era BMC INFECTIOUS DISEASES Lee, G. M., Huang, S. S., Rifas-Shiman, S. L., Hinrichsen, V. L., Pelton, S. I., Kleinman, K., Hanage, W. P., Lipsitch, M., McAdam, A. J., Finkelstein, J. A. 2009; 9

  Abstract

  The incidence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) has risen dramatically in the U.S., particularly among children. Although Streptococcus pneumoniae colonization has been inversely associated with S. aureus colonization in unvaccinated children, this and other risk factors for S. aureus carriage have not been assessed following widespread use of the heptavalent pneumococcal conjugate vaccine (PCV7). Our objectives were to (1) determine the prevalence of S. aureus and MRSA colonization in young children in the context of widespread use of PCV7; and (2) examine risk factors for S. aureus colonization in the post-PCV7 era, including the absence of vaccine-type S. pneumoniae colonization.Swabs of the anterior nares (S. aureus) were obtained from children enrolled in an ongoing study of nasopharyngeal pneumococcal colonization of healthy children in 8 Massachusetts communities. Children 3 months to <7 years of age seen for well child or sick visits in primary care offices from 11/03-4/04 and 10/06-4/07 were enrolled. S. aureus was identified and antibiotic susceptibility testing was performed. Epidemiologic risk factors for S. aureus colonization were collected from parent surveys and chart reviews, along with data on pneumococcal colonization. Multivariate mixed model analyses were performed to identify factors associated with S. aureus colonization.Among 1,968 children, the mean age (SD) was 2.7 (1.8) years, 32% received an antibiotic in the past 2 months, 2% were colonized with PCV7 strains and 24% were colonized with non-PCV7 strains. The prevalence of S. aureus colonization remained stable between 2003-04 and 2006-07 (14.6% vs. 14.1%), while MRSA colonization remained low (0.2% vs. 0.9%, p = 0.09). Although absence of pneumococcal colonization was not significantly associated with S. aureus colonization, age (6-11 mo vs. > or =5 yrs, OR 0.39 [95% CI 0.24-0.64]; 1-1.99 yrs vs. > or =5 yrs, OR 0.35 [0.23-0.54]; 2-2.99 yrs vs. > or =5 yrs, OR 0.45 [0.28-0.73]; 3-3.99 yrs vs. > or =5 yrs, OR 0.53 [0.33-0.86]) and recent antibiotic use were significant predictors in multivariate models.In Massachusetts, S. aureus and MRSA colonization remained stable from 2003-04 to 2006-07 among children <7 years despite widespread use of pneumococcal conjugate vaccine. S. aureus nasal colonization varies by age and is inversely correlated with recent antibiotic use.

  View details for DOI 10.1186/1471-2334-9-110

  View details for Web of Science ID 000268570600001

  View details for PubMedID 19594890

• Managing and reducing uncertainty in an emerging influenza pandemic. The New England journal of medicine Lipsitch, M., Riley, S., Cauchemez, S., Ghani, A. C., Ferguson, N. M. 2009; 361 (2): 112-5

  View details for DOI 10.1056/NEJMp0904380

  View details for PubMedID 19474417

  View details for PubMedCentralID PMC3066026

• Pneumococcal capsular polysaccharide structure predicts serotype prevalence. PLoS pathogens Weinberger, D. M., Trzciński, K., Lu, Y. J., Bogaert, D., Brandes, A., Galagan, J., Anderson, P. W., Malley, R., Lipsitch, M. 2009; 5 (6): e1000476

  Abstract

  There are 91 known capsular serotypes of Streptococcus pneumoniae. The nasopharyngeal carriage prevalence of particular serotypes is relatively stable worldwide, but the host and bacterial factors that maintain these patterns are poorly understood. Given the possibility of serotype replacement following vaccination against seven clinically important serotypes, it is increasingly important to understand these factors. We hypothesized that the biochemical structure of the capsular polysaccharides could influence the degree of encapsulation of different serotypes, their susceptibility to killing by neutrophils, and ultimately their success during nasopharyngeal carriage. We sought to measure biological differences among capsular serotypes that may account for epidemiological patterns. Using an in vitro assay with both isogenic capsule-switch variants and clinical carriage isolates, we found an association between increased carriage prevalence and resistance to non-opsonic neutrophil-mediated killing, and serotypes that were resistant to neutrophil-mediated killing tended to be more heavily encapsulated, as determined by FITC-dextran exclusion. Next, we identified a link between polysaccharide structure and carriage prevalence. Significantly, non-vaccine serotypes that have become common in vaccinated populations tend to be those with fewer carbons per repeat unit and low energy expended per repeat unit, suggesting a novel biological principle to explain patterns of serotype replacement. More prevalent serotypes are more heavily encapsulated and more resistant to neutrophil-mediated killing, and these phenotypes are associated with the structure of the capsular polysaccharide, suggesting a direct relationship between polysaccharide biochemistry and the success of a serotype during nasopharyngeal carriage and potentially providing a method for predicting serotype replacement.

  View details for DOI 10.1371/journal.ppat.1000476

  View details for PubMedID 19521509

  View details for PubMedCentralID PMC2689349

• The pneumococcal pilus predicts the absence of Staphylococcus aureus co-colonization in pneumococcal carriers. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Regev-Yochay, G., Lipsitch, M., Basset, A., Rubinstein, E., Dagan, R., Raz, M., Malley, R. 2009; 48 (6): 760-3

  Abstract

  The determinants of the negative association between Streptococcus pneumoniae and Stapylococcus aureus colonization are unknown. In this matched case-control study, the odds of co-colonization with S. aureus were significantly lower for individuals carrying a piliated versus a nonpiliated S. pneumoniae strain, suggesting the pilus may be a determinant of the negative association.

  View details for DOI 10.1086/597040

  View details for PubMedID 19207082

  View details for PubMedCentralID PMC2674784

• Influenza seasonality: lifting the fog. Proceedings of the National Academy of Sciences of the United States of America Lipsitch, M., Viboud, C. 2009; 106 (10): 3645-6

  View details for DOI 10.1073/pnas.0900933106

  View details for PubMedID 19276125

  View details for PubMedCentralID PMC2656132

• No coexistence for free: neutral null models for multistrain pathogens. Epidemics Lipsitch, M., Colijn, C., Cohen, T., Hanage, W. P., Fraser, C. 2009; 1 (1): 2-13

  Abstract

  In most pathogens, multiple strains are maintained within host populations. Quantifying the mechanisms underlying strain coexistence would aid public health planning and improve understanding of disease dynamics. We argue that mathematical models of strain coexistence, when applied to indistinguishable strains, should meet criteria for both ecological neutrality and population genetic neutrality. We show that closed clonal transmission models which can be written in an "ancestor-tracing" form that meets the former criterion will also satisfy the latter. Neutral models can be a parsimonious starting point for studying mechanisms of strain coexistence; implications for past and future studies are discussed.

  View details for DOI 10.1016/j.epidem.2008.07.001

  View details for PubMedID 21352747

  View details for PubMedCentralID PMC3099423

• Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS pathogens Lu, Y. J., Gross, J., Bogaert, D., Finn, A., Bagrade, L., Zhang, Q., Kolls, J. K., Srivastava, A., Lundgren, A., Forte, S., Thompson, C. M., Harney, K. F., Anderson, P. W., Lipsitch, M., Malley, R. 2008; 4 (9): e1000159

  Abstract

  Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell-dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1(-/-) mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-gamma or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines.

  View details for DOI 10.1371/journal.ppat.1000159

  View details for PubMedID 18802458

  View details for PubMedCentralID PMC2528945

• Antibiotic overuse: The influence of social norms JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Buchman, T. G., Dushoff, J., Effron, M. B., Ehrlich, P. R., FitzPatrick, S., Laxminarayan, R., Levin, B., Levin, S. A., Lipsitch, M., Malani, A., Nemeroff, C., Otto, S. P., Patel, V. L., Solomkin, J. S. 2008; 207 (2): 265-275

  View details for DOI 10.1016/j.jamcollsurg.2008.02.035

  View details for Web of Science ID 000258517600017

  View details for PubMedID 18656057

• Too little of a good thing: a paradox of moderate infection control. Epidemiology (Cambridge, Mass.) Cohen, T., Lipsitch, M. 2008; 19 (4): 588-9

  Abstract

  Epidemic theory dictates that a reduction in the force of infection by a pathogen is associated with an increase in the average age at which individuals are exposed. For those pathogens that cause more severe disease among hosts of an older age, interventions that limit transmission can paradoxically increase the burden of disease in a population.

  View details for DOI 10.1097/EDE.0b013e31817734ba

  View details for PubMedID 18552592

  View details for PubMedCentralID PMC2652751

• Epidemiologic evidence for serotype-specific acquired immunity to pneumococcal carriage. The Journal of infectious diseases Weinberger, D. M., Dagan, R., Givon-Lavi, N., Regev-Yochay, G., Malley, R., Lipsitch, M. 2008; 197 (11): 1511-8

  Abstract

  Nasopharyngeal carriage of Streptococcus pneumoniae is required for transmission of the bacteria and for invasive disease. There have been conflicting reports as to whether protection against carriage is serotype specific and which immune mechanisms drive carriage. Analyzing longitudinal carriage data from Israeli toddlers in day care, we found a lower risk of colonization with types 6A, 14, and 23F after previous exposure to the homologous type. Nonsignificant trends suggesting possible protection derived from prior exposure were found for types 19A and 23A. Furthermore, we found that, for types 14 and 23F, this specific protection correlated with increased serotype-specific antibody concentration. We found no evidence of specific protection for type 6B, group 15, or type 19F. Our findings imply that at least some serotypes generate anti-capsular antibodies that can reduce the risk of carriage in unimmunized toddlers.

  View details for DOI 10.1086/587941

  View details for PubMedID 18471062

• Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells. Infection and immunity Trzciński, K., Thompson, C. M., Srivastava, A., Basset, A., Malley, R., Lipsitch, M. 2008; 76 (6): 2678-84

  Abstract

  CD4(+) T-cell-dependent acquired immunity confers antibody-independent protection against pneumococcal colonization. Since this mechanism is poorly understood for extracellular bacteria, we assessed the antigen specificity of the induction and recall of this immune response by using BALB/c DO11.10Rag(-/-) mice, which lack mature B and T cells except for CD4(+) T cells specific for the OVA(323-339) peptide derived from ovalbumin. Serotype 6B Streptococcus pneumoniae strain 603S and unencapsulated strain Rx1Delta lytA were modified to express OVA(323-339) as a fusion protein with surface protein A (PspA) (strains 603OVA(1) and Rx1Delta lytAOVA(1)) or with PspA, neuraminidase A, and pneumolysin (Rx1Delta lytAOVA(3)). Whole-cell vaccines (WCV) were made of ethanol-killed cells of Rx1Delta lytA plus cholera toxin (CT) adjuvant, of Rx1Delta lytAOVA(1) + CT (WCV-OVA(1)), and of Rx1Delta lytAOVA(3) + CT (WCV-OVA(3)). Mice intranasally immunized with WCV-OVA(1), but not with WCV or CT alone, were protected against intranasal challenge with 603OVA(1). There was no protection against strain 603S in mice immunized with WCV-OVA(1). These results indicate antigen specificity of both immune induction and the recall response. Effector action was not restricted to antigen-bearing bacteria since colonization by 603S was reduced in animals immunized with vaccines made of OVA-expressing strains when ovalbumin or killed Rx1Delta lytAOVA(3) antigen was administered around the time of challenge. CD4(+) T-cell-mediated protection against pneumococcal colonization can be induced in an antigen-specific fashion and requires specific antigen for effective bacterial clearance, but this activity may extend beyond antigen-expressing bacteria. These results are consistent with the recruitment and/or activation of phagocytic or other nonspecific effectors by antigen-specific CD4(+) T cells.

  View details for DOI 10.1128/IAI.00141-08

  View details for PubMedID 18391006

  View details for PubMedCentralID PMC2423086

• Generation interval contraction and epidemic data analysis. Mathematical biosciences Kenah, E., Lipsitch, M., Robins, J. M. 2008; 213 (1): 71-9

  Abstract

  The generation interval is the time between the infection time of an infected person and the infection time of his or her infector. Probability density functions for generation intervals have been an important input for epidemic models and epidemic data analysis. In this paper, we specify a general stochastic SIR epidemic model and prove that the mean generation interval decreases when susceptible persons are at risk of infectious contact from multiple sources. The intuition behind this is that when a susceptible person has multiple potential infectors, there is a "race" to infect him or her in which only the first infectious contact leads to infection. In an epidemic, the mean generation interval contracts as the prevalence of infection increases. We call this global competition among potential infectors. When there is rapid transmission within clusters of contacts, generation interval contraction can be caused by a high local prevalence of infection even when the global prevalence is low. We call this local competition among potential infectors. Using simulations, we illustrate both types of competition. Finally, we show that hazards of infectious contact can be used instead of generation intervals to estimate the time course of the effective reproductive number in an epidemic. This approach leads naturally to partial likelihoods for epidemic data that are very similar to those that arise in survival analysis, opening a promising avenue of methodological research in infectious disease epidemiology.

  View details for DOI 10.1016/j.mbs.2008.02.007

  View details for PubMedID 18394654

  View details for PubMedCentralID PMC2365921

• In vitro bactericidal activity of Streptococcus pneumoniae and bactericidal susceptibility of Staphylococcus aureus strains isolated from cocolonized versus noncocolonized children. Journal of clinical microbiology Regev-Yochay, G., Malley, R., Rubinstein, E., Raz, M., Dagan, R., Lipsitch, M. 2008; 46 (2): 747-9

  Abstract

  Streptococcus pneumoniae is bactericidal to Staphylococcus aureus in vitro. To determine whether this in vitro effect accounts for the inverse relation between S. pneumoniae and S. aureus colonization reported in previous epidemiologic studies, we compared S. pneumoniae and S. aureus strains from cocolonized children to those from noncocolonized children. Cocolonizing pneumococci were less bactericidal and cocolonizing staphylococci less susceptible to this effect; however, the magnitude of the effect was small. Thus, in vitro killing is not the major determinant of the pattern of cocolonization.

  View details for DOI 10.1128/JCM.01781-07

  View details for PubMedID 18039795

  View details for PubMedCentralID PMC2238136

• Patterns of antigenic diversity and the mechanisms that maintain them. Journal of the Royal Society, Interface Lipsitch, M., O'Hagan, J. J. 2007; 4 (16): 787-802

  Abstract

  Many of the remaining challenges in infectious disease control involve pathogens that fail to elicit long-lasting immunity in their hosts. Antigenic variation is a common reason for this failure and a contributor to the complexity of vaccine design. Diversifying selection by the host immune system is commonly, and often correctly, invoked to explain antigenic variability in pathogens. However, there is a wide variety of patterns of antigenic variation across space and time, and within and between hosts, and we do not yet understand the determinants of these different patterns. This review describes five such patterns, taking as examples two bacteria (Streptococcus pneumoniae and Neisseria meningitidis), two viruses (influenza A and HIV-1), as well as the pathogens (taken as a group) for which antigenic variation is negligible. Pathogen-specific explanations for these patterns of diversity are critically evaluated, and the patterns are compared against predictions of theoretical models for antigenic diversity. Major remaining challenges are highlighted, including the identification of key protective antigens in bacteria, the design of vaccines to combat antigenic variability for viruses and the development of more systematic explanations for patterns of antigenic variation.

  View details for DOI 10.1098/rsif.2007.0229

  View details for PubMedID 17426010

  View details for PubMedCentralID PMC2394542

• Strain characteristics of Streptococcus pneumoniae carriage and invasive disease isolates during a cluster-randomized clinical trial of the 7-valent pneumococcal conjugate vaccine. The Journal of infectious diseases Lipsitch, M., O'Neill, K., Cordy, D., Bugalter, B., Trzcinski, K., Thompson, C. M., Goldstein, R., Pelton, S., Huot, H., Bouchet, V., Reid, R., Santosham, M., O'Brien, K. L. 2007; 196 (8): 1221-7

  Abstract

  Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has led to significant reductions in disease while changing pneumococcal population dynamics via herd immunity and serotype replacement. We performed multilocus sequence typing (MLST) on 590 pneumococcal isolates obtained during the American Indian clinical trial of PCV7, in which communities were randomized for eligible children to receive either PCV7 or a meningococcal conjugate vaccine (MCV). Sequence types (STs) were analyzed to determine the impact of the vaccine on pneumococcal population structure and to assess the possible impact of pneumococcal genetic background on vaccine effects. One hundred forty-three STs were obtained, the most frequent being ST199, the only one that included vaccine serotypes (VTs), non-vaccine-associated nonvaccine serotypes (NVA/NVTs), and vaccine-associated serotypes (VATs). Serotype replacement observed in the PCV communities was due to a diverse population of STs, most of which also existed in the MCV communities. Possible capsular switching to create novel ST associations with NVA/NVTs was detected only once. Reductions in VTs and changes in VATs in PCV communities did not show evidence of variation by ST, after accounting for lower vaccine effectiveness against serotype 19F. These observations suggest the hypothesis that the vaccine acts as a "serotype filter": its effect on a particular strain can be predicted on the basis of the serotype of the strain, with little effect of genetic background (as assessed by MLST) over and above capsule. If sustained, such patterns provide some cause for optimism that rapid evolution of PCV escape strains with drug resistance or high virulence is unlikely.

  View details for DOI 10.1086/521831

  View details for PubMedID 17955441

  View details for PubMedCentralID PMC3350793

• Serum antipneumococcal antibodies and pneumococcal colonization in adults with chronic obstructive pulmonary disease JOURNAL OF INFECTIOUS DISEASES Malley, R., Lipsitch, M., Bogaert, D., Thompson, C. M., Hermans, P., Watkins, A. C., Sethi, S., Murphy, T. F. 2007; 196 (6): 928-935

  Abstract

  Antibodies to pneumococcus are thought to represent the primary mechanism of naturally acquired resistance to colonization. Here, however, we show that, in patients with chronic obstructive pulmonary disease (COPD), resistance to pneumococcal colonization is not associated with higher concentrations of serum anti-capsular or -noncapsular antibodies. We compared preacquisition serum antibody concentrations to capsular antigens 6B, 7F, 14, 19F, and 23F from patients with COPD who did and did not acquire pneumococcal respiratory tree colonization over the course of 2 years. Colonized patients did not have lower anti-capsular antibody concentrations than control subjects who did not acquire pneumococcus. We found no difference in functional antibody concentrations between colonized patients and control subjects. Furthermore, colonized patients had significantly higher preacquisition concentration of antibody directed against the whole cell and pneumococcal surface protein A than control subjects. We thus conclude that, in adult patients with COPD, resistance to pneumococcal colonization is unlikely to be determined by higher serum antibody concentrations to pneumococcal antigens.

  View details for DOI 10.1086/520937

  View details for Web of Science ID 000249251800018

  View details for PubMedID 17703425

• SpxB is a suicide gene of Streptococcus pneumoniae and confers a selective advantage in an in vivo competitive colonization model. Journal of bacteriology Regev-Yochay, G., Trzcinski, K., Thompson, C. M., Lipsitch, M., Malley, R. 2007; 189 (18): 6532-9

  Abstract

  The human bacterial pathogen Streptococcus pneumoniae dies spontaneously upon reaching stationary phase. The extent of S. pneumoniae death at stationary phase is unusual in bacteria and has been conventionally attributed to autolysis by the LytA amidase. In this study, we show that spontaneous pneumococcal death is due to hydrogen peroxide (H(2)O(2)), not LytA, and that the gene responsible for H(2)O(2) production (spxB) also confers a survival advantage in colonization. Survival of S. pneumoniae in stationary phase was significantly prolonged by eliminating H(2)O(2) in any of three ways: chemically by supplementing the media with catalase, metabolically by growing the bacteria under anaerobic conditions, or genetically by constructing DeltaspxB mutants that do not produce H(2)O(2). Likewise, addition of H(2)O(2) to exponentially growing S. pneumoniae resulted in a death rate similar to that of cells in stationary phase. While DeltalytA mutants did not lyse at stationary phase, they died at a rate similar to that of the wild-type strain. Furthermore, we show that the death process induced by H(2)O(2) has features of apoptosis, as evidenced by increased annexin V staining, decreased DNA content, and appearance as assessed by transmission electron microscopy. Finally, in an in vivo rat model of competitive colonization, the presence of spxB conferred a selective advantage over the DeltaspxB mutant, suggesting an explanation for the persistence of this gene. We conclude that a suicide gene of pneumococcus is spxB, which induces an apoptosis-like death in pneumococci and confers a selective advantage in nasopharyngeal cocolonization.

  View details for DOI 10.1128/JB.00813-07

  View details for PubMedID 17631628

  View details for PubMedCentralID PMC2045178

• Estimating variability in the transmission of severe acute respiratory syndrome to household contacts in Hong Kong, China. American journal of epidemiology Pitzer, V. E., Leung, G. M., Lipsitch, M. 2007; 166 (3): 355-63

  Abstract

  The extensive data collection and contact tracing that occurred during the 2003 outbreak of severe acute respiratory syndrome (SARS) in Hong Kong, China, allowed the authors to examine how the probability of transmission varied from the date of symptom onset to the date of hospitalization for household contacts of SARS patients. Using a discrete-time likelihood model, the authors estimated the transmission probability per contact for each day following the onset of symptoms. The results suggested that there may be two peaks in the probability of SARS transmission, the first occurring around day 2 after symptom onset and the second occurring approximately 10 days after symptom onset. Index patients who were aged 60 years or older or whose lactate dehydrogenase level was elevated upon admission to the hospital (indicating higher viral loads) were more likely to transmit SARS to their contacts. There was little variation in the daily transmission probabilities before versus after the introduction of public health interventions on or around March 26, 2003. This study suggests that the probability of transmission of SARS is dependent upon characteristics of the index patients and does not simply reflect temporal variability in the viral load of SARS cases.

  View details for DOI 10.1093/aje/kwm082

  View details for PubMedID 17493952

  View details for PubMedCentralID PMC7110150

• Little evidence for genetic susceptibility to influenza A (H5N1) from family clustering data. Emerging infectious diseases Pitzer, V. E., Olsen, S. J., Bergstrom, C. T., Dowell, S. F., Lipsitch, M. 2007; 13 (7): 1074-6

  Abstract

  The apparent clustering of human cases of influenza A (H5N1) among blood relatives has been considered as evidence of genetic variation in susceptibility. We show that, by chance alone, a high proportion of clusters are expected to be limited to blood relatives when infection is a rare event.

  View details for DOI 10.3201/eid1307.061538

  View details for PubMedID 18214184

  View details for PubMedCentralID PMC2878232

• The effect of antiretroviral therapy on secondary transmission of HIV among men who have sex with men. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America McCormick, A. W., Walensky, R. P., Lipsitch, M., Losina, E., Hsu, H., Weinstein, M. C., Paltiel, A. D., Freedberg, K. A., Seage, G. R. 2007; 44 (8): 1115-22

  Abstract

  Antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) RNA load and the probability of transmitting HIV to an HIV-uninfected partner. However, the potential reduction in secondary transmission associated with ART may be offset by the longer duration of infectiousness.To estimate the effects of ART on the secondary transmission of HIV among men who have sex with men, we used a previously published state-transition model of HIV disease to simulate the clinical and virologic course of HIV infection among 2 cohorts of men who have sex with men: (1) a cohort of individuals who were not receiving ART and (2) a cohort of individuals treated with US guideline-concordant ART. The model tracked the number of acts of unprotected insertive anal intercourse, transmission risk per act as determined by HIV RNA level, and the number of secondary cases generated in each cohort.The estimated mean number of secondary transmissions from an HIV-infected individual after 10, 20, and 30 years of infection were 1.9, 2.5, and 2.5, respectively, in the untreated cohort, compared with 1.4, 1.8, and 2.3, respectively, in the treated cohort. The total number of transmissions for the treated cohort began to exceed the total number of transmissions for the untreated cohort 33 years after infection; over the entire course of infection, treatment with ART led to a 23% increase in secondary infections. All estimates of the impact of ART on secondary transmission were sensitive to changes in risk behaviors.These results suggest that ART must be accompanied by effective HIV-related risk reduction interventions. Programs that target prevention to decrease further HIV transmission are crucial to epidemic control.

  View details for DOI 10.1086/512816

  View details for PubMedID 17366461

  View details for PubMedCentralID PMC2365722

• Antiviral resistance and the control of pandemic influenza. PLoS medicine Lipsitch, M., Cohen, T., Murray, M., Levin, B. R. 2007; 4 (1): e15

  Abstract

  The response to the next influenza pandemic will likely include extensive use of antiviral drugs (mainly oseltamivir), combined with other transmission-reducing measures. Animal and in vitro studies suggest that some strains of influenza may become resistant to oseltamivir while maintaining infectiousness (fitness). Use of antiviral agents on the scale anticipated for the control of pandemic influenza will create an unprecedented selective pressure for the emergence and spread of these strains. Nonetheless, antiviral resistance has received little attention when evaluating these plans.We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic. The model predicts that even if antiviral treatment or prophylaxis leads to the emergence of a transmissible resistant strain in as few as 1 in 50,000 treated persons and 1 in 500,000 prophylaxed persons, widespread use of antivirals may strongly promote the spread of resistant strains at the population level, leading to a prevalence of tens of percent by the end of a pandemic. On the other hand, even in circumstances in which a resistant strain spreads widely, the use of antivirals may significantly delay and/or reduce the total size of the pandemic. If resistant strains carry some fitness cost, then, despite widespread emergence of resistance, antivirals could slow pandemic spread by months or more, and buy time for vaccine development; this delay would be prolonged by nondrug control measures (e.g., social distancing) that reduce transmission, or use of a stockpiled suboptimal vaccine. Surprisingly, the model suggests that such nondrug control measures would increase the proportion of the epidemic caused by resistant strains.The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Therefore, the risk of resistance should be considered in pandemic planning and monitored closely during a pandemic.

  View details for DOI 10.1371/journal.pmed.0040015

  View details for PubMedID 17253900

  View details for PubMedCentralID PMC1779817

• Interference between Streptococcus pneumoniae and Staphylococcus aureus: In vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae. Journal of bacteriology Regev-Yochay, G., Trzcinski, K., Thompson, C. M., Malley, R., Lipsitch, M. 2006; 188 (13): 4996-5001

  Abstract

  The bactericidal activity of Streptococcus pneumoniae toward Staphylococcus aureus is mediated by hydrogen peroxide. Catalase eliminated this activity. Pneumococci grown anaerobically or genetically lacking pyruvate oxidase (SpxB) were not bactericidal, nor were nonpneumococcal streptococci. These results provide a possible mechanistic explanation for the interspecies interference observed in epidemiologic studies.

  View details for DOI 10.1128/JB.00317-06

  View details for PubMedID 16788209

  View details for PubMedCentralID PMC1482988

• Upgrading antibiotic use within a class: tradeoff between resistance and treatment success. Proceedings of the National Academy of Sciences of the United States of America Wang, Y. C., Lipsitch, M. 2006; 103 (25): 9655-60

  Abstract

  Increasing resistance to antibiotics creates the need for prudent antibiotic use. When resistance to various antibiotics within a class is driven by stepwise accumulation of mutations, a dilemma may exist in regard to replacing an antibiotic that is losing effectiveness due to resistance with a new drug within the same class. Such replacement may enhance treatment success in the short term but promote the spread of highly resistant strains. We used mathematical models to quantify the tradeoff between minimizing treatment failures (by switching early) and minimizing the proliferation of the highly resistant strain (by delaying the switch). Numerical simulations were applied to investigate the cumulative prevalence of the highly resistant strain (Resistance) and the cumulative number of treatment failures (Failure) that resulted from following different antibiotic use policies. Whereas never switching to the new drug always minimizes Resistance and maximizes Failure, immediate switching usually maximizes Resistance and minimizes Failure. Thus, in most circumstances, there is a strict tradeoff in which early use of the new drug enhances treatment effectiveness while hastening the rise of high-level resistance. This tradeoff is most acute when acquired resistance is rare and the highly resistant strain is readily transmissible. However, exceptions occur when use of the new drug frequently leads to acquired resistance and when the highly resistant strain has substantial "fitness cost"; these circumstances tend to favor an immediate switch. We discuss the implications of these considerations in regard to antibiotic choices for Streptococcus pneumoniae.

  View details for DOI 10.1073/pnas.0600636103

  View details for PubMedID 16772381

  View details for PubMedCentralID PMC1480462

• Pandemic influenza: risk of multiple introductions and the need to prepare for them. PLoS medicine Mills, C. E., Robins, J. M., Bergstrom, C. T., Lipsitch, M. 2006; 3 (6): e135

  Abstract

  Containing an emerging influenza H5N1 pandemic in its earliest stages may be feasible, but containing multiple introductions of a pandemic-capable strain would be more difficult. Mills and colleagues argue that multiple introductions are likely, especially if risk of a pandemic is high.

  View details for DOI 10.1371/journal.pmed.0030135

  View details for PubMedID 17214503

  View details for PubMedCentralID PMC1370924

• Beneficial and perverse effects of isoniazid preventive therapy for latent tuberculosis infection in HIV-tuberculosis coinfected populations. Proceedings of the National Academy of Sciences of the United States of America Cohen, T., Lipsitch, M., Walensky, R. P., Murray, M. 2006; 103 (18): 7042-7

  Abstract

  In sub-Saharan Africa, where the emergence of HIV has caused dramatic increases in tuberculosis (TB) case notifications, new strategies for TB control are necessary. Isoniazid preventive therapy (IPT) for HIV-TB coinfected individuals reduces the reactivation of latent Mycobacterium tuberculosis infections and is being evaluated as a potential community-wide strategy for improving TB control. We developed a mathematical model of TB/HIV coepidemics to examine the impact of community-wide implementation of IPT for TB-HIV coinfected individuals on the dynamics of drug-sensitive and -resistant TB epidemics. We found that community-wide IPT will reduce the incidence of TB in the short-term but may also speed the emergence of drug-resistant TB. We conclude that community-wide IPT in areas of emerging HIV and drug-resistant TB should be coupled with diagnostic and treatment policies designed to identify and effectively treat the increasing proportion of patients with drug-resistant TB.

  View details for DOI 10.1073/pnas.0600349103

  View details for PubMedID 16632605

  View details for PubMedCentralID PMC1459015

• Incremental increase in fitness cost with increased beta -lactam resistance in pneumococci evaluated by competition in an infant rat nasal colonization model. The Journal of infectious diseases Trzcinski, K., Thompson, C. M., Gilbey, A. M., Dowson, C. G., Lipsitch, M. 2006; 193 (9): 1296-303

  Abstract

  We evaluated the impact of resistant penicillin-binding protein (PBP) allele acquisition on the ability of penicillin-resistant (PEN-R) pneumococcal strains to compete with penicillin-susceptible (PEN-S) ancestors for upper-respiratory-tract (URT) colonization.PEN-S serotype 2, 6B, and 9V strains were transformed into derivatives expressing an increasing number of PEN-R PBP forms (2X, 2X-1A, and 2X-1A-2B for serotype 2 and 2X, 2X-2B, and 2X-2B-1A for 6B and 9V). Infant rats were inoculated intranasally with a mix of a PEN-R and PEN-S strains. For consecutive days, samples were collected for assessment of the ratio of PEN-S to PEN-R cells colonizing the URT. The selective index (SI), defined as the change in the natural logarithm of the ratio of PEN-S to PEN-R strains from the inoculum to the nasal-wash samples, quantified differences in fitness.SIs significantly > 0 (indicating a cost of resistant allele acquisition) were observed 4-5 days after colonization in all but serotype 6B pbp2x transfomants. Additional replacements with low-affinity forms of pbp2b and pbp1a genes reduced further ability to compete in all strains.The cost of penicillin-resistance acquisition for the Streptococcus pneumoniae strain competing with its susceptible ancestor to colonize the URT increases with the number of resistant pbp alleles acquired.

  View details for DOI 10.1086/501367

  View details for PubMedID 16586368

• The influence of hitchhiking and deleterious mutation upon asexual mutation rates. Genetics Palmer, M. E., Lipsitch, M. 2006; 173 (1): 461-72

  Abstract

  The question of how natural selection affects asexual mutation rates has been considered since the 1930s, yet our understanding continues to deepen. The distribution of mutation rates observed in natural bacteria remains unexplained. It is well known that environmental constancy can favor minimal mutation rates. In contrast, environmental fluctuation (e.g., at period T) can create indirect selective pressure for stronger mutators: genes modifying mutation rate may "hitchhike" to greater frequency along with environmentally favored mutations they produce. This article extends a well-known model of Leigh to consider fitness genes with multiple mutable sites (call the number of such sites alpha). The phenotypic effect of such a gene is enabled if all sites are in a certain state and disabled otherwise. The effects of multiple deleterious loci are also included (call the number of such loci gamma). The analysis calculates the indirect selective effects experienced by a gene inducing various mutation rates for given values of alpha, gamma, and T. Finite-population simulations validate these results and let us examine the interaction of drift with hitchhiking selection. We close by commenting on the importance of other factors, such as spatiotemporal variation, and on the origin of variation in mutation rates.

  View details for DOI 10.1534/genetics.105.049445

  View details for PubMedID 16489233

  View details for PubMedCentralID PMC1461451

• Inefficient cytotoxic T lymphocyte-mediated killing of HIV-1-infected cells in vivo. PLoS biology Asquith, B., Edwards, C. T., Lipsitch, M., McLean, A. R. 2006; 4 (4): e90

  Abstract

  Understanding the role of cytotoxic T lymphocytes (CTLs) in controlling HIV-1 infection is vital for vaccine design. However, it is difficult to assess the importance of CTLs in natural infection. Different human leukocyte antigen (HLA) class I alleles are associated with different rates of progression to AIDS, indicating that CTLs play a protective role. Yet virus clearance rates following antiretroviral therapy are not impaired in individuals with advanced HIV disease, suggesting that weakening of the CTL response is not the major underlying cause of disease progression and that CTLs do not have an important protective role. Here we reconcile these apparently conflicting studies. We estimate the selection pressure exerted by CTL responses that drive the emergence of immune escape variants, thereby directly quantifying the efficiency of HIV-1-specific CTLs in vivo. We estimate that only 2% of productively infected CD4+ cell death is attributable to CTLs recognising a single epitope. We suggest that CTLs kill a large number of infected cells (about 10(7)) per day but are not responsible for the majority of infected cell death.

  View details for DOI 10.1371/journal.pbio.0040090

  View details for PubMedID 16515366

  View details for PubMedCentralID PMC1395353

• Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide INFECTION AND IMMUNITY Malley, R., Srivastava, A., Lipsitch, M., Thompson, C. M., Watkins, C., Tzianabos, A., ANDERSON, P. W. 2006; 74 (4): 2187-2195

  Abstract

  Serotype-specific immunity to Streptococcus pneumoniae is conferred by antibodies to the capsular polysaccharides, which define the 90 known serotypes. Whether antibody to the species-common cell wall polysaccharide (C-Ps) is protective has been a matter of controversy. Here we show that C-Ps given intranasally with mucosal adjuvant increased the resistance of mice to experimental nasopharyngeal colonization by capsulated S. pneumoniae of serotype 6B. This immunity could be induced in mice congenitally lacking immunoglobulin but was dependent upon CD4+ T cells. Elimination of the charged amino group on the polymer backbone by N acetylation of C-Ps reduced the immunity, as did treatment of the mice with antibody to the cytokine interleukin-17A at the time of challenge, both consistent with the hypothesis of T-cell activation due to the zwitterionic motif of the polymer. C-Ps also protected in a model of fatal aspiration pneumonia by heavily capsulated serotype 3. These findings suggest a novel immunization strategy against S. pneumoniae.

  View details for DOI 10.1128/IAI.74.4.2187-2195.2006

  View details for Web of Science ID 000236477000022

  View details for PubMedID 16552049

  View details for PubMedCentralID PMC1418935

• Antibodies to conserved pneumococcal antigens correlate with, but are not required for, protection against pneumococcal colonization induced by prior exposure in a mouse model. Infection and immunity Trzcinski, K., Thompson, C., Malley, R., Lipsitch, M. 2005; 73 (10): 7043-6

  Abstract

  In mice following intranasal exposure to Streptococcus pneumoniae, protection against pneumococcal colonization was independent of antibody but dependent on CD4(+) T cells. Nonetheless, concentrations of antibodies to three conserved pneumococcal antigens correlated with protection against colonization. Concentrations of antibodies to conserved pneumococcal antigens may be correlates of protection without being effectors of protection.

  View details for DOI 10.1128/IAI.73.10.7043-7046.2005

  View details for PubMedID 16177389

  View details for PubMedCentralID PMC1230924

• Modeling community- and individual-level effects of child-care center attendance on pneumococcal carriage. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Huang, S. S., Finkelstein, J. A., Lipsitch, M. 2005; 40 (9): 1215-22

  Abstract

  The prevalence of pneumococcal carriage varies widely across communities. This variation is not fully explained by risk factors at the individual level but may be explained by factors producing effects at both the individual and community levels, such as child-care center (CCC) attendance.We developed a transmission model to evaluate whether the combined risks of attending CCCs and associating with playmates who attend CCCs account for a large proportion of the variability in the prevalence of pneumococcal carriage across communities. We based parameters for the model on data from a multicommunity study.According to our model, differences in the proportion of children who attend CCCs can account for a range of 4%-56% in the prevalence of pneumococcal carriage across communities. Our model, which was based on data collected from 16 Massachusetts communities, predicts that the odds of carriage associated with CCC attendance are 2-3 times the odds associated with no CCC attendance (individual-level effect). The model also predicts that the odds of carriage for nonattendees in a community with CCCs are up to 6 times the odds for children in a community without CCCs (community-level effect). In addition, the mean number of hours spent at CCCs by a single attendee appears to exert effects on pneumococcal carriage that are independent of either the proportion of CCC attendance in the community or the mean number of hours these attendees spend in child care.We used data from multiple communities to develop a transmission model that explains marked differences in pneumococcal carriage across communities by variations in CCC attendance. This model only accounts for CCC attendance among young children and does not include other known risk factors for pneumococcal carriage.

  View details for DOI 10.1086/428580

  View details for PubMedID 15825020

• Capsule homology does not increase the frequency of transformation of linked penicillin binding proteins PBP 1a and PBP 2x in Streptococcus pneumoniae. Antimicrobial agents and chemotherapy Trzciński, K., MacNeil, A., Klugman, K. P., Lipsitch, M. 2005; 49 (4): 1591-2

  Abstract

  Penicillin resistance is mainly confined to a limited number of Streptococcus pneumoniae serotypes. Given linkage between the capsular biosynthesis locus and two penicillin binding proteins, we tested whether capsule homology increases transformation rates of penicillin resistance. Transformation rates in homologous donor-recipient pairs were no higher than expected, falsifying this hypothesis.

  View details for DOI 10.1128/AAC.49.4.1591-1592.2005

  View details for PubMedID 15793147

  View details for PubMedCentralID PMC1068637

• CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proceedings of the National Academy of Sciences of the United States of America Malley, R., Trzcinski, K., Srivastava, A., Thompson, C. M., Anderson, P. W., Lipsitch, M. 2005; 102 (13): 4848-53

  Abstract

  Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on the presence of anticapsular antibodies. We found, however, that colonization with live pneumococci of serotypes 6B, 7F, or 14 protected mice against recolonization by any of the serotypes and that protection from acquisition of a heterologous or homologous strain did not depend on anticapsular antibody. Further, intranasal immunization by live pneumococcal colonization or by a killed, nonencapsulated whole-cell vaccine protected antibody-deficient mice against colonization, suggesting independence of antibodies to any pneumococcal antigens. Protection by intranasal immunization with whole-cell vaccine was completely abrogated in T cell-deficient mice, and in mice that were congenitally deficient in CD4(+) T cells or depleted of these cells at the time of challenge. In contrast, mice congenitally deficient in, or depleted of, CD8(+) T cells were fully protected. Protection in this model was observed beyond 2 months after immunization, arguing against innate or nonspecific immune mechanisms. Thus, we find that immunity to pneumococcal colonization can be induced in the absence of antibody, independent of the capsular type, and this protection requires the presence of CD4(+) T cells at the time of challenge.

  View details for DOI 10.1073/pnas.0501254102

  View details for PubMedID 15781870

  View details for PubMedCentralID PMC555733

• Are anticapsular antibodies the primary mechanism of protection against invasive pneumococcal disease? PLoS medicine Lipsitch, M., Whitney, C. G., Zell, E., Kaijalainen, T., Dagan, R., Malley, R. 2005; 2 (1): e15

  Abstract

  Antibody to capsular polysaccharide has been the basis of several vaccines that offer protection against invasive disease from Streptococcus pneumoniae. The success of such vaccines has led to the inference that natural protection against invasive pneumococcal disease is largely conferred by anticapsular antibody. If this is so, one would expect that the decline in disease from different serotypes would vary significantly, and that the appearance of substantial concentrations of anticapsular antibodies would coincide temporally with the decline in age-specific incidence.Using incidence data from the United States, we show that, on the contrary, the decline in incidence with age is quite similar for the seven most important serogroups, despite large differences in exposure in the population. Moreover, only modest increases in antibody concentration occur over the second and third years of life, a period in which serotype-specific incidence declines to less than 25% of its peak. We also present detailed data on the distribution of antibody concentrations in Israeli toddlers, which are consistent with the United States findings. The same conclusion is supported by new data on age-specific incidence in Finland, which is compared with published data on antibody acquisition in Finnish toddlers.We suggest some additional studies of the mechanisms of protection that could distinguish among potential alternative mechanisms, including acquired immunity to noncapsular antigens, maturation of nonspecific immune responses, or changes in anatomy or exposure.

  View details for DOI 10.1371/journal.pmed.0020015

  View details for PubMedID 15696204

  View details for PubMedCentralID PMC545206

• Transmissibility of 1918 pandemic influenza. Nature Mills, C. E., Robins, J. M., Lipsitch, M. 2004; 432 (7019): 904-6

  Abstract

  The 1918 influenza pandemic killed 20-40 million people worldwide, and is seen as a worst-case scenario for pandemic planning. Like other pandemic influenza strains, the 1918 A/H1N1 strain spread extremely rapidly. A measure of transmissibility and of the stringency of control measures required to stop an epidemic is the reproductive number, which is the number of secondary cases produced by each primary case. Here we obtained an estimate of the reproductive number for 1918 influenza by fitting a deterministic SEIR (susceptible-exposed-infectious-recovered) model to pneumonia and influenza death epidemic curves from 45 US cities: the median value is less than three. The estimated proportion of the population with A/H1N1 immunity before September 1918 implies a median basic reproductive number of less than four. These results strongly suggest that the reproductive number for 1918 pandemic influenza is not large relative to many other infectious diseases. In theory, a similar novel influenza subtype could be controlled. But because influenza is frequently transmitted before a specific diagnosis is possible and there is a dearth of global antiviral and vaccine stores, aggressive transmission reducing measures will probably be required.

  View details for DOI 10.1038/nature03063

  View details for PubMedID 15602562

  View details for PubMedCentralID PMC7095078

• Weather-based prediction of Plasmodium falciparum malaria in epidemic-prone regions of Ethiopia II. Weather-based prediction systems perform comparably to early detection systems in identifying times for interventions. Malaria journal Teklehaimanot, H. D., Schwartz, J., Teklehaimanot, A., Lipsitch, M. 2004; 3: 44

  Abstract

  Timely and accurate information about the onset of malaria epidemics is essential for effective control activities in epidemic-prone regions. Early warning methods that provide earlier alerts (usually by the use of weather variables) may permit control measures to interrupt transmission earlier in the epidemic, perhaps at the expense of some level of accuracy.Expected case numbers were modeled using a Poisson regression with lagged weather factors in a 4th-degree polynomial distributed lag model. For each week, the numbers of malaria cases were predicted using coefficients obtained using all years except that for which the prediction was being made. The effectiveness of alerts generated by the prediction system was compared against that of alerts based on observed cases. The usefulness of the prediction system was evaluated in cold and hot districts.The system predicts the overall pattern of cases well, yet underestimates the height of the largest peaks. Relative to alerts triggered by observed cases, the alerts triggered by the predicted number of cases performed slightly worse, within 5% of the detection system. The prediction-based alerts were able to prevent 10-25% more cases at a given sensitivity in cold districts than in hot ones.The prediction of malaria cases using lagged weather performed well in identifying periods of increased malaria cases. Weather-derived predictions identified epidemics with reasonable accuracy and better timeliness than early detection systems; therefore, the prediction of malarial epidemics using weather is a plausible alternative to early detection systems.

  View details for DOI 10.1186/1475-2875-3-44

  View details for PubMedID 15555061

  View details for PubMedCentralID PMC535541

• Weather-based prediction of Plasmodium falciparum malaria in epidemic-prone regions of Ethiopia I. Patterns of lagged weather effects reflect biological mechanisms. Malaria journal Teklehaimanot, H. D., Lipsitch, M., Teklehaimanot, A., Schwartz, J. 2004; 3: 41

  Abstract

  Malaria epidemics due to Plasmodium falciparum are reported frequently in the East African highlands with high case fatality rates. There have been formal attempts to predict epidemics by the use of climatic variables that are predictors of transmission potential. However, little consensus has emerged about the relative importance and predictive value of different factors. Understanding the reasons for variation is crucial to determining specific and important indicators for epidemic prediction. The impact of temperature on the duration of a mosquito's life cycle and the sporogonic phase of the parasite could explain the inconsistent findings.Daily average number of cases was modeled using a robust Poisson regression with rainfall, minimum temperature and maximum temperatures as explanatory variables in a polynomial distributed lag model in 10 districts of Ethiopia. To improve reliability and generalizability within similar climatic conditions, we grouped the districts into two climatic zones, hot and cold.In cold districts, rainfall was associated with a delayed increase in malaria cases, while the association in the hot districts occurred at relatively shorter lags. In cold districts, minimum temperature was associated with malaria cases with a delayed effect. In hot districts, the effect of minimum temperature was non-significant at most lags, and much of its contribution was relatively immediate.The interaction between climatic factors and their biological influence on mosquito and parasite life cycle is a key factor in the association between weather and malaria. These factors should be considered in the development of malaria early warning system.

  View details for DOI 10.1186/1475-2875-3-41

  View details for PubMedID 15541174

  View details for PubMedCentralID PMC535540

• Invited commentary: real-time tracking of control measures for emerging infections. American journal of epidemiology Lipsitch, M., Bergstrom, C. T. 2004; 160 (6): 517-9; discussion 520

  View details for DOI 10.1093/aje/kwh256

  View details for PubMedID 15353410

• Alert threshold algorithms and malaria epidemic detection. Emerging infectious diseases Teklehaimanot, H. D., Schwatrz, J., Teklehaimanot, A., Lipsitch, M. 2004; 10 (7): 1220-6

  Abstract

  We describe a method for comparing the ability of different alert threshold algorithms to detect malaria epidemics and use it with a dataset consisting of weekly malaria cases collected from health facilities in 10 districts of Ethiopia from 1990 to 2000. Four types of alert threshold algorithms are compared: weekly percentile, weekly mean with standard deviation (simple, moving average, and log-transformed case numbers), slide positivity proportion, and slope of weekly cases on log scale. To compare dissimilar alert types on a single scale, a curve was plotted for each type of alert, which showed potentially prevented cases versus number of alerts triggered over 10 years. Simple weekly percentile cutoffs appear to be as good as more complex algorithms for detecting malaria epidemics in Ethiopia. The comparative method developed here may be useful for testing other proposed alert thresholds and for application in other populations.

  View details for DOI 10.3201/eid1007.030722

  View details for PubMedID 15324541

  View details for PubMedCentralID PMC3323320

• Age-specific immunoglobulin g (IgG) and IgA to pneumococcal protein antigens in a population in coastal kenya. Infection and immunity Laine, C., Mwangi, T., Thompson, C. M., Obiero, J., Lipsitch, M., Scott, J. A. 2004; 72 (6): 3331-5

  Abstract

  Streptococcus pneumoniae is the primary etiological agent of community-acquired pneumonia and a major cause of meningitis and bacteremia. Three conserved pneumococcal proteins-pneumolysin, pneumococcal surface adhesin A (PsaA), and pneumococcal surface protein A (PspA)-are currently being investigated as vaccine candidates. Such protein-based vaccines, if proven effective, could provide a cheaper alternative to conjugate vaccine formulae. Few data from sub-Saharan Africa exist concerning the development of natural antibody to these antigens, however. To investigate the age-specific development of antiprotein immunoglobulin G (IgG) and IgA antibody responses, the sera of 220 persons 2 weeks to 84 years of age from coastal Kenya were assayed using enzyme-linked immunosorbent assays. IgG and IgA antibody responses to each antigen were observed in all age groups. Serum concentrations of IgG and IgA antibody responses to PspA and PdB (a recombinant toxoid derivative of pneumolysin), but not to PsaA, increased significantly with age (P < 0.001). No decline was observed in the sera of the elderly. Anti-protein IgG concentrations were only weakly correlated (0.30 < r < 0.56; P < 0.0001), as were IgA concentrations (0.24 < r < 0.54; P < 0.0001).

  View details for DOI 10.1128/IAI.72.6.3331-3335.2004

  View details for PubMedID 15155637

  View details for PubMedCentralID PMC415695

• Single-step capsular transformation and acquisition of penicillin resistance in Streptococcus pneumoniae. Journal of bacteriology Trzciński, K., Thompson, C. M., Lipsitch, M. 2004; 186 (11): 3447-52

  Abstract

  The capsule (cps) locus of Streptococcus pneumoniae is flanked by the pbp2x and pbp1a genes, coding for penicillin-binding proteins, enzymes involved in cell wall synthesis that are targets for beta-lactams. This linkage suggested to us that selection for beta-lactam resistance might coselect for capsular transformants. The recombination event would then involve PBP genes, as well as the cps operon, and would change both the serotype and the resistance profile of the strain. We transformed beta-lactam-susceptible strain TIGR4 by using whole genomic DNA extracted from multidrug-resistant strain GA71, a serotype 19F variant of pneumococcal clone Spain(23F)-1, and selected beta-lactam-resistant transformants. Smooth colonies appearing on selective plates were subcultured, serotyped by the Quellung reaction, and genotyped to confirm the presence of the GA71 pbp2x-cps19-pbp1a locus in the TIGR4 genetic background by restriction fragment length polymorphism analysis of the whole locus and its flanking regions. The results showed that a new serotype, combined with resistance to beta-lactams, could emerge in a susceptible strain via a single transformation event. Quantitative analysis showed that transfer of the cps locus had occurred at an elevated rate in beta-lactam-selected transformants. This suggests that in natural settings selection by host immunity and selection by antibiotics may be interrelated because of "hitchhiking" effects due to linkage of resistance determinants and the capsule locus.

  View details for DOI 10.1128/JB.186.11.3447-3452.2004

  View details for PubMedID 15150231

  View details for PubMedCentralID PMC415782

• The analysis of hospital infection data using hidden Markov models. Biostatistics (Oxford, England) Cooper, B., Lipsitch, M. 2004; 5 (2): 223-37

  Abstract

  Surveillance data for communicable nosocomial pathogens usually consist of short time series of low-numbered counts of infected patients. These often show overdispersion and autocorrelation. To date, almost all analyses of such data have ignored the communicable nature of the organisms and have used methods appropriate only for independent outcomes. Inferences that depend on such analyses cannot be considered reliable when patient-to-patient transmission is important. We propose a new method for analysing these data based on a mechanistic model of the epidemic process. Since important nosocomial pathogens are often carried asymptomatically with overt infection developing in only a proportion of patients, the epidemic process is usually only partially observed by routine surveillance data. We therefore develop a 'structured' hidden Markov model where the underlying Markov chain is generated by a simple transmission model. We apply both structured and standard (unstructured) hidden Markov models to time series for three important pathogens. We find that both methods can offer marked improvements over currently used approaches when nosocomial spread is important. Compared to the standard hidden Markov model, the new approach is more parsimonious, is more biologically plausible, and allows key epidemiological parameters to be estimated.

  View details for DOI 10.1093/biostatistics/5.2.223

  View details for PubMedID 15054027

• Construction of otherwise isogenic serotype 6B, 7F, 14, and 19F capsular variants of Streptococcus pneumoniae strain TIGR4. Applied and environmental microbiology Trzcinski, K., Thompson, C. M., Lipsitch, M. 2003; 69 (12): 7364-70

  Abstract

  The polysaccharide capsule is the primary virulence factor in Streptococcus pneumoniae. There are at least 90 serotypes of S. pneumoniae, identified based on the immunogenicity of different capsular sugars. The aim of this study was to construct pneumococcal strains that are isogenic except for capsular type. Serotype 4 strain TIGR4 was rendered unencapsulated by recombinational replacement of the capsular polysaccharide synthesis (cps) locus with the bicistronic Janus cassette (C. K. Sung, J. P. Claverys, and D. A. Morrison, Appl. Environ. Microbiol. 67:5190-5196, 2001). In subsequent transformation with chromosomal DNA, the cassette was replaced by the cps locus derived from a strain of a different serotype, either 6B, 7F, 14, or 19F. To minimize the risk of uncontrolled recombinational replacements in loci other than cps, the TIGRcps::Janus strain was "backcross" transformed three times with chromosomal DNA of subsequently constructed capsular type transformants. Capsular serotypes were confirmed in all new capsule variants by the Quellung reaction. Restriction fragment length polymorphism (RFLP) analysis of the cps locus confirmed the integrity of the cps region transformed into the TIGR strain, and RFLP of the flanking regions confirmed their identities with the corresponding regions of the recipient. Transformants had in vitro growth rates greater than or equal to that of TIGR4. All four strains were able to colonize C57BL/6 mice (female, 6 weeks old) for at least 7 days when mice were intranasally inoculated with 6 x 10(6) to 8 x 10(6) CFU. The constructed capsular variants of TIGR4 are suitable for use in studies on the role of S. pneumoniae capsular polysaccharide in immunity, colonization, and pathogenesis.

  View details for DOI 10.1128/AEM.69.12.7364-7370.2003

  View details for PubMedID 14660386

  View details for PubMedCentralID PMC309976

• Transmission dynamics and control of severe acute respiratory syndrome. Science (New York, N.Y.) Lipsitch, M., Cohen, T., Cooper, B., Robins, J. M., Ma, S., James, L., Gopalakrishna, G., Chew, S. K., Tan, C. C., Samore, M. H., Fisman, D., Murray, M. 2003; 300 (5627): 1966-70

  Abstract

  Severe acute respiratory syndrome (SARS) is a recently described illness of humans that has spread widely over the past 6 months. With the use of detailed epidemiologic data from Singapore and epidemic curves from other settings, we estimated the reproductive number for SARS in the absence of interventions and in the presence of control efforts. We estimate that a single infectious case of SARS will infect about three secondary cases in a population that has not yet instituted control measures. Public-health efforts to reduce transmission are expected to have a substantial impact on reducing the size of the epidemic.

  View details for DOI 10.1126/science.1086616

  View details for PubMedID 12766207

  View details for PubMedCentralID PMC2760158

• Geographic diversity and temporal trends of antimicrobial resistance in Streptococcus pneumoniae in the United States. Nature medicine McCormick, A. W., Whitney, C. G., Farley, M. M., Lynfield, R., Harrison, L. H., Bennett, N. M., Schaffner, W., Reingold, A., Hadler, J., Cieslak, P., Samore, M. H., Lipsitch, M. 2003; 9 (4): 424-30

  Abstract

  Resistance of Streptococcus pneumoniae to antibiotics is increasing throughout the United States, with substantial variation among geographic regions. We show that patterns of geographic variation are best explained by the intensity of selection for resistance, which is reflected by differences between the proportions of resistance within individual serotypes, rather than by differences between the frequencies of particular serotypes. Using a mathematical transmission model, we analyzed temporal trends in the proportions of singly and dually resistant organisms and found that pneumococcal strains resistant to both penicillin and erythromycin are increasing faster than strains singly resistant to either. Using the model, we predict that by 1 July 2004, in the absence of a vaccine, 41% of pneumococci at the Centers for Disease Control and Prevention (CDC)'s Active Bacterial Core surveillance (ABCs) sites, taken together, will be dually resistant, with 5% resistant to penicillin only and 5% to erythromycin only.

  View details for DOI 10.1038/nm839

  View details for PubMedID 12627227

• Multiple equilibria: tuberculosis transmission require unrealistic assumptions. Theoretical population biology Lipsitch, M., Murray, M. B. 2003; 63 (2): 169-70

  View details for DOI 10.1016/s0040-5809(02)00037-0

  View details for PubMedID 12615499

• Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proceedings of the National Academy of Sciences of the United States of America Malley, R., Henneke, P., Morse, S. C., Cieslewicz, M. J., Lipsitch, M., Thompson, C. M., Kurt-Jones, E., Paton, J. C., Wessels, M. R., Golenbock, D. T. 2003; 100 (4): 1966-71

  Abstract

  Streptococcus pneumoniae is one of the leading causes of invasive bacterial disease worldwide. Fragments of the cell wall and the cytolytic toxin pneumolysin have been shown to contribute substantially to inflammatory damage, although the interactions between pneumococcal components and host-cell structures have not been elucidated completely. Results of a previous study indicated that cell-wall components of pneumococci are recognized by Toll-like receptor (TLR)2 but suggested that pneumolysin induces inflammatory events independently of this receptor. In this study we tested the hypothesis that pneumolysin interacts with surface proteins of the TLR family other than TLR2. We found that pneumolysin stimulates tumor necrosis factor-alpha and IL-6 release in wild-type macrophages but not in macrophages from mice with a targeted deletion of the cytoplasmic TLR-adapter molecule myeloid differentiation factor 88, suggesting the involvement of the TLRs in pneumolysin recognition. Purified pneumolysin synergistically activated macrophage responses together with preparations of pneumococcal cell walls or staphylococcal peptidoglycan, which are known to activate TLR2. Furthermore, when compared with wild-type macrophages, macrophages from mice that carry a spontaneous mutation in TLR4 (P712H) were hyporesponsive to both pneumolysin alone and the combination of pneumolysin with pneumococcal cell walls. Finally, these TLR4-mutant mice were significantly more susceptible to lethal infection after intranasal colonization with pneumolysin-positive pneumococci than were control mice. We conclude that the interaction of pneumolysin with TLR4 is critically involved in the innate immune response to pneumococcus.

  View details for DOI 10.1073/pnas.0435928100

  View details for PubMedID 12569171

  View details for PubMedCentralID PMC149942

• Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures. BMC medical genetics Lipsitch, M., Bergstrom, C. T., Antia, R. 2003; 4: 2

  Abstract

  Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans.An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population.We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote.To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary.

  View details for DOI 10.1186/1471-2350-4-2

  View details for PubMedID 12542841

  View details for PubMedCentralID PMC149356

• Historical intensity of natural selection for resistance to tuberculosis. Genetics Lipsitch, M., Sousa, A. O. 2002; 161 (4): 1599-607

  Abstract

  Infections have long been thought to exert natural selection on humans. Infectious disease resistance is frequently invoked as a mechanism shaping human genetic diversity, but such hypotheses have rarely been quantitatively evaluated with direct measures of disease-related mortality. Enhancement of genetically determined resistance to tuberculosis by natural selection has been proposed as a factor explaining the decline of tuberculosis in Europe and North America in the period 1830-1950 (before the advent of antimicrobial chemotherapy) and the apparently reduced susceptibility of Europeans and their descendants to tuberculosis infection and/or disease. We used Swedish vital statistics from 1891 to 1900 to estimate that individuals who escaped mortality from pulmonary tuberculosis (PTB) during the European tuberculosis epidemic would have enjoyed a fitness advantage of 7-15% per generation compared to individuals who were susceptible to PTB mortality; individuals with 50% protection would have had a selection coefficient of 4-7%/generation. Selection during the peak of the European TB epidemic could have substantially reduced the frequency of already rare alleles conferring increased susceptibility to PTB mortality, but only if the phenotypic effects of these alleles were very large. However, if resistant alleles were rare at the beginning of this period, 300 years would not have been long enough for such selection to increase their frequency to epidemiologically significant levels. Reductions in the frequency of rare susceptibility alleles could have played at most a small part in the decline of the epidemic in the century preceding 1950. Natural selection by PTB deaths during the European TB epidemic alone cannot account for the presently low level of TB disease observed among Europeans and their descendants just prior to the appearance of antibiotic treatment.

  View details for DOI 10.1093/genetics/161.4.1599

  View details for PubMedID 12196403

  View details for PubMedCentralID PMC1462208

• Potential benefits of a serodiagnostic test for herpes simplex virus type 1 (HSV-1) to prevent neonatal HSV-1 infection. Sexually transmitted diseases Lipsitch, M., Davis, G., Corey, L. 2002; 29 (7): 399-405

  Abstract

  Changes in sexual practices have led to an increase in the incidence of genital herpes simplex virus type 1 (HSV-1) infections. Such infections affect an estimated 400 newborns each year, with serious consequences.To evaluate the use of a serodiagnostic test for HSV-1 to be used by pregnant women, and possibly their sexual partners, in preventing neonatal HSV-1 infections by identifying seronegative (at-risk) women.The number of cases of neonatal HSV-1 prevented by a test of a given sensitivity and specificity is estimated using two simple models parameterized with data from published sources.Used by women only, a 90%-specific test for HSV-1 could avert 71%-90% of the expected cases of infection among women using the test, requiring about 14,000 tests per case averted. This result depends linearly on the specificity of the test and does not depend on the sensitivity. Use by women and their partners results in more tests for the same benefit (about 24,000 tests per case averted if the test is 90% sensitive and 90% specific), because the only additional information provided by testing the partner of an at-risk woman is to determine that her partner may not be HSV-1 positive.The key feature of such a diagnostic test is its specificity; its use to identify at-risk women could provide public health benefits if the specificity exceeds 70%, but these benefits would increase dramatically for higher specificities. Use of such a test for couples is likely to be more costly and less effective than testing women only.

  View details for DOI 10.1097/00007435-200207000-00007

  View details for PubMedID 12170129

• Antibiotics in agriculture: when is it time to close the barn door? Proceedings of the National Academy of Sciences of the United States of America Lipsitch, M., Singer, R. S., Levin, B. R. 2002; 99 (9): 5752-4

  View details for DOI 10.1073/pnas.092142499

  View details for PubMedID 11983874

  View details for PubMedCentralID PMC122845

• Antimicrobial use and antimicrobial resistance: a population perspective. Emerging infectious diseases Lipsitch, M., Samore, M. H. 2002; 8 (4): 347-54

  Abstract

  The need to stem the growing problem of antimicrobial resistance has prompted multiple, sometimes conflicting, calls for changes in the use of antimicrobial agents. One source of disagreement concerns the major mechanisms by which antibiotics select resistant strains. For infections like tuberculosis, in which resistance can emerge in treated hosts through mutation, prevention of antimicrobial resistance in individual hosts is a primary method of preventing the spread of resistant organisms in the community. By contrast, for many other important resistant pathogens, such as penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium resistance is mediated by the acquisition of genes or gene fragments by horizontal transfer; resistance in the treated host is a relatively rare event. For these organisms, indirect, population-level mechanisms of selection account for the increase in the prevalence of resistance. These mechanisms can operate even when treatment has a modest, or even negative, effect on an individual host's colonization with resistant organisms.

  View details for DOI 10.3201/eid0804.010312

  View details for PubMedID 11971765

  View details for PubMedCentralID PMC2730242

• TRANSMISSION RATES AND HIV VIRULENCE: COMMENTS TO MASSAD. Evolution; international journal of organic evolution Lipsitch, M. 1997; 51 (1): 319-320

  View details for DOI 10.1111/j.1558-5646.1997.tb02416.x

  View details for PubMedID 28568797

• THE EVOLUTION OF VIRULENCE IN PATHOGENS WITH VERTICAL AND HORIZONTAL TRANSMISSION. Evolution; international journal of organic evolution Lipsitch, M., Siller, S., Nowak, M. A. 1996; 50 (5): 1729-1741

  Abstract

  The idea that vertical transmission of parasites selects for lower virulence is widely accepted. However, little theoretical work has considered the evolution of virulence for parasites with mixed horizontal plus vertical transmission. Many human, animal, and plant parasites are transmitted both vertically and horizontally, and some horizontal transmission is generally necessary to maintain parasites at all. We present a population-dynamical model for the evolution of virulence when both vertical and horizontal transmission are present. In the simplest such model, up to two infectious strains can coexist within one host population. Virulent, vertically transmitted pathogens can persist in a population when they provide protection against more virulent, horizontally transmitted strains. When virulence is maintained by a correlation with horizontal transmission rates, increased levels of vertical transmission always lower the evolutionarily stable (ESS) level of virulence. Contrary to existing theory, however, increases in opportunities for horizontal transmission also lower the ESS level of virulence. We explain these findings in light of earlier work and confirm them in simulations including imperfect vertical transmission. We describe further simulations, in which both vertical and horizontal transmission rates are allowed to evolve. The outcome of these simulations depends on whether high levels of vertical transmission are possible with low virulence. Finally, we argue against the notion of a virulence-avirulence continuum between horizontal and vertical transmission, and discuss our results in relation to empirical studies of transmission and virulence.

  View details for DOI 10.1111/j.1558-5646.1996.tb03560.x

  View details for PubMedID 28565576

• HOST POPULATION STRUCTURE AND THE EVOLUTION OF VIRULENCE: A "LAW OF DIMINISHING RETURNS". Evolution; international journal of organic evolution Lipsitch, M., Herre, E. A., Nowak, M. A. 1995; 49 (4): 743-748

  Abstract

  Structure in a population of host individuals, whether spatial or temporal, can have important effects on the transmission and evolutionary dynamics of its pathogens. One of these is to limit dispersal of pathogens and thus increase the amount of contact between a given pair or within a small group of host individuals. We introduce a "law of diminishing returns" that predicts an evolutionary decline of pathogen virulence whenever there are on average more possibilities of pathogen transmission between the same pair of hosts. Thus, the effect of repeated contact between hosts will be to shift the balance of any trade-off between virulence and transmissibility toward lower virulence.

  View details for DOI 10.1111/j.1558-5646.1995.tb02310.x

  View details for PubMedID 28565133