Prasanna Jagannathan

All Publications

• Natural killer cell antibody-dependent cellular cytotoxicity to Plasmodium falciparum is impacted by cellular phenotypes, erythrocyte polymorphisms, parasite diversity and intensity of transmission. Clinical & translational immunology Tukwasibwe, S., Lewis, S. N., Taremwa, Y., van der Ploeg, K., Press, K. D., Ty, M., Namirimu Nankya, F., Musinguzi, K., Nansubuga, E., Bach, F., Chamai, M., Okitwi, M., Tumusiime, G., Nakimuli, A., Colucci, F., Kamya, M. R., Nankabirwa, J. I., Arinaitwe, E., Greenhouse, B., Dorsey, G., Rosenthal, P. J., Ssewanyana, I., Jagannathan, P. 2024; 13 (11): e70005

  Abstract

  Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, Plasmodium falciparum strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56dim and CD56neg populations. NK cell degranulation was enhanced in response to opsonised P. falciparum schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate P. falciparum schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.

  View details for DOI 10.1002/cti2.70005

  View details for PubMedID 39493859

  View details for PubMedCentralID PMC11528551

• Clinical immunity to malaria involves epigenetic reprogramming of innate immune cells. PNAS nexus Nideffer, J., Ty, M., Donato, M., John, R., Kajubi, R., Ji, X., Nankya, F., Musinguzi, K., Press, K. D., Yang, N., Camanag, K., Greenhouse, B., Kamya, M., Feeney, M. E., Dorsey, G., Utz, P. J., Pulendran, B., Khatri, P., Jagannathan, P. 2024; 3 (8): pgae325

  Abstract

  The regulation of inflammation is a critical aspect of disease tolerance and naturally acquired clinical immunity to malaria. Here, we demonstrate using RNA sequencing and epigenetic landscape profiling by cytometry by time-of-flight, that the regulation of inflammatory pathways during asymptomatic parasitemia occurs downstream of pathogen sensing-at the epigenetic level. The abundance of certain epigenetic markers (methylation of H3K27 and dimethylation of arginine residues) and decreased prevalence of histone variant H3.3 correlated with suppressed cytokine responses among monocytes of Ugandan children. Such an epigenetic signature was observed across diverse immune cell populations and not only characterized active asymptomatic parasitemia but also correlated with future long-term disease tolerance and clinical immunity when observed in uninfected children. Pseudotime analyses revealed a potential trajectory of epigenetic change that correlated with a child's age and recent parasite exposure and paralleled the acquisition of clinical immunity. Thus, our data support a model whereby exposure to Plasmodium falciparum induces epigenetic changes that regulate excessive inflammation and contribute to naturally acquire clinical immunity to malaria.

  View details for DOI 10.1093/pnasnexus/pgae325

  View details for PubMedID 39161730

  View details for PubMedCentralID PMC11331423

• The impact of Plasmodium-driven immunoregulatory networks on immunity to malaria. Nature reviews. Immunology Boyle, M. J., Engwerda, C. R., Jagannathan, P. 2024

  Abstract

  Malaria, caused by infection with Plasmodium parasites, drives multiple regulatory responses across the immune landscape. These regulatory responses help to protect against inflammatory disease but may in some situations hamper the acquisition of adaptive immune responses that clear parasites. In addition, the regulatory responses that occur during Plasmodium infection may negatively affect malaria vaccine efficacy in the most at-risk populations. Here, we discuss the specific cellular mechanisms of immunoregulatory networks that develop during malaria, with a focus on knowledge gained from human studies and studies that involve the main malaria parasite to affect humans, Plasmodium falciparum. Leveraging this knowledge may lead to the development of new therapeutic approaches to increase protective immunity to malaria during infection or after vaccination.

  View details for DOI 10.1038/s41577-024-01041-5

  View details for PubMedID 38862638

  View details for PubMedCentralID 8191919

• Malaria-specific Type 1 regulatory T cells are more abundant in first pregnancies and associated with placental malaria. EBioMedicine Kirosingh, A. S., Delmastro, A., Kakuru, A., van der Ploeg, K., Bhattacharya, S., Press, K. D., Ty, M., Parte, L., Kizza, J., Muhindo, M., Devachanne, S., Gamain, B., Nankya, F., Musinguzi, K., Rosenthal, P. J., Feeney, M. E., Kamya, M., Dorsey, G., Jagannathan, P. 2023; 95: 104772

  Abstract

  Malaria in pregnancy (MIP) causes higher morbidity in primigravid compared to multigravid women; however, the correlates and mechanisms underlying this gravidity-dependent protection remain incompletely understood. We aimed to compare the cellular immune response between primigravid and multigravid women living in a malaria-endemic region and assess for correlates of protection against MIP.We characterised the second trimester cellular immune response among 203 primigravid and multigravid pregnant women enrolled in two clinical trials of chemoprevention in eastern Uganda, utilizing RNA sequencing, flow cytometry, and functional assays. We compared responses across gravidity and determined associations with parasitaemia during pregnancy and placental malaria.Using whole blood RNA sequencing, no significant differentially expressed genes were identified between primigravid (n = 12) and multigravid (n = 11) women overall (log 2(FC) > 2, FDR < 0.1). However, primigravid (n = 49) women had higher percentages of malaria-specific, non-naïve CD4+ T cells that co-expressed IL-10 and IFNγ compared with multigravid (n = 85) women (p = 0.000023), and higher percentages of these CD4+ T cells were associated with greater risks of parasitaemia in pregnancy (Rs = 0.49, p = 0.001) and placental malaria (p = 0.0073). These IL-10 and IFNγ co-producing CD4+ T cells had a genomic signature of Tr1 cells, including expression of transcription factors cMAF and BATF and cell surface makers CTLA4 and LAG-3.Malaria-specific Tr1 cells were highly prevalent in primigravid Ugandan women, and their presence correlated with a higher risk of malaria in pregnancy. Understanding whether suppression of Tr1 cells plays a role in naturally acquired gravidity-dependent immunity may aid the development of new vaccines or treatments for MIP.This work was funded by NIH (PO1 HD059454, U01 AI141308, U19 AI089674, U01 AI155325, U01 AI150741), the March of Dimes (Basil O'Connor award), and the Bill and Melinda Gates Foundation (OPP 1113682).

  View details for DOI 10.1016/j.ebiom.2023.104772

  View details for PubMedID 37634385

• Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria. Science translational medicine Ty, M., Sun, S., Callaway, P. C., Rek, J., Press, K. D., van der Ploeg, K., Nideffer, J., Hu, Z., Klemm, S., Greenleaf, W., Donato, M., Tukwasibwe, S., Arinaitwe, E., Nankya, F., Musinguzi, K., Andrew, D., de la Parte, L., Mori, D. M., Lewis, S. N., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Blish, C., Utz, P. J., Khatri, P., Dorsey, G., Kamya, M., Boyle, M., Feeney, M., Ssewanyana, I., Jagannathan, P. 2023; 15 (680): eadd9012

  Abstract

  Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dim NK cells. Higher frequencies of CD56neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.

  View details for DOI 10.1126/scitranslmed.add9012

  View details for PubMedID 36696483

• Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study. eLife Hu, Z., van der Ploeg, K., Chakraborty, S., Arunachalam, P. S., Mori, D. A., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Hedlin, H., de la Parte, L., Press, K., Ty, M., Tan, G. S., Blish, C., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Butte, A. J., Singh, U., Pulendran, B., Wang, T. T., Jagannathan, P. 2022; 11

  Abstract

  The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

  View details for DOI 10.7554/eLife.77943

  View details for PubMedID 36239699

• TNF-alpha+ CD4+ Tcells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies. Cell reports. Medicine van der Ploeg, K., Kirosingh, A. S., Mori, D. A., Chakraborty, S., Hu, Z., Sievers, B. L., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Press, K. D., Ty, M. C., Ruiz-Betancourt, D. R., de la Parte, L., Tan, G. S., Blish, C. A., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Singh, U., Wang, T. T., Jagannathan, P. 2022: 100640

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4+ Tcells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4+ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4+ Tcells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+ response shifts from cells producing interferon gamma (IFNgamma) to tumor necrosis factor alpha (TNF-alpha) from 5days to 4months post-enrollment, with IFNgamma-IL-21-TNF-alpha+ CD4+ Tcells the predominant population detected at later time points. Greater percentages of IFNgamma-IL-21-TNF-alpha+ CD4+ Tcells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7months post-infection (⍴= 0.4, p= 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNgamma- and TNF-alpha-producing, spike-protein-specific CD4+ Tcells. These data suggest that SARS-CoV-2-specific, TNF-alpha-producing CD4+ Tcells may play an important role in antibody maintenance following COVID-19.

  View details for DOI 10.1016/j.xcrm.2022.100640

  View details for PubMedID 35588734

• Age-related Changes in Malaria Clinical Phenotypes During Infancy are Modified by Sickle Cell Trait. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Zehner, N., Adrama, H., Kakuru, A., Andra, T., Kajubi, R., Conrad, M., Nankya, F., Clark, T. D., Kamya, M., Rodriguez-Barraquer, I., Dorsey, G., Jagannathan, P. 2021

  Abstract

  BACKGROUND: Young infants are protected against Plasmodium falciparum malaria. Mechanisms driving this protection remain unclear due to a poor understanding of malaria clinical phenotypes during infancy.METHODS: We enrolled a birth cohort of 678 infants in Busia, Uganda, an area of high malaria transmission. We followed infants through 12 months of age, and quantified protection against parasitemia and clinical disease.RESULTS: Symptomatic malaria incidence increased from 1.2 to 2.6 episodes per person year between 0-<6 months and 6-12 months of age, while the monthly probability of asymptomatic parasitemia given infection decreased from 32% to 21%. Sickle cell trait (HbAS) was protective against symptomatic malaria (incidence rate ratio (IRR) = 0.57 comparing HbAS vs. HbAA, 95% CI 0.44-0.74, p<0.001), but age modified this relationship (Pint=<0.001), with non-linear protection that waned between 0-9 months of age before increasing. Increasing age was associated with higher parasite densities at the time of infection, and, in infants with HbAS, a reduced ability to tolerate high parasite densities without fever.CONCLUSIONS: Age-dependent changes in HbAS protective efficacy in infancy were accompanied by differential loss of anti-parasite and anti-disease protection among HbAS and HbAA infants. This provides a framework for investigating mechanisms underlying infant protection against malaria.

  View details for DOI 10.1093/cid/ciab245

  View details for PubMedID 33738485

• Patients with uncomplicated COVID-19 have long-term persistent symptoms and functional impairment similar to patients with severe COVID-19: a cautionary tale during a global pandemic. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Jacobson, K. B., Rao, M., Bonilla, H., Subramanian, A., Hack, I., Madrigal, M., Singh, U., Jagannathan, P., Grant, P. 2021

  Abstract

  To assess the prevalence of persistent functional impairment after COVID-19, we assessed 118 individuals 3-4 months after their initial COVID-19 diagnosis with a symptom survey, work productivity and activity index questionnaire, and 6-minute walk test. We found significant persistent symptoms and functional impairment, even in non-hospitalized patients with COVID-19.

  View details for DOI 10.1093/cid/ciab103

  View details for PubMedID 33624010

• Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nature communications Jagannathan, P. n., Andrews, J. R., Bonilla, H. n., Hedlin, H. n., Jacobson, K. B., Balasubramanian, V. n., Purington, N. n., Kamble, S. n., de Vries, C. R., Quintero, O. n., Feng, K. n., Ley, C. n., Winslow, D. n., Newberry, J. n., Edwards, K. n., Hislop, C. n., Choong, I. n., Maldonado, Y. n., Glenn, J. n., Bhatt, A. n., Blish, C. n., Wang, T. n., Khosla, C. n., Pinsky, B. A., Desai, M. n., Parsonnet, J. n., Singh, U. n. 2021; 12 (1): 1967

  Abstract

  Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.

  View details for DOI 10.1038/s41467-021-22177-1

  View details for PubMedID 33785743

• Intermittent preventive treatment with dihydroartemisinin-piperaquine and risk of malaria following cessation in young Ugandan children: a double-blind, randomised, controlled trial. The Lancet. Infectious diseases Muhindo, M. K., Jagannathan, P., Kakuru, A., Opira, B., Olwoch, P., Okiring, J., Nalugo, N., Clark, T. D., Ruel, T., Charlebois, E., Feeney, M. E., Havlir, D. V., Dorsey, G., Kamya, M. R. 2019

  Abstract

  BACKGROUND: Intermittent preventive treatment (IPT) of malaria with dihydroartemisinin-piperaquine is a promising strategy for malaria prevention in young African children. However, the optimal dosing strategy is unclear and conflicting evidence exists regarding the risk of malaria after cessation of chemoprevention. We aimed to compare two dosing strategies of IPT with dihydroartemisinin-piperaquine in young Ugandan children, and to evaluate the risk of malaria after cessation of IPT.METHODS: In this double-blind, randomised controlled phase 2 trial, women and their unborn children were recruited at Tororo District Hospital (Tororo, Uganda). Eligible participants were HIV-negative women aged 16 years or older with a viable pregnancy (gestational age 12-20 weeks). Women and their unborn children were randomly assigned (1:1:1:1) to one of four treatment groups, all receiving dihydroartemisinin-piperaquine, on the basis of the IPT intervention received by the woman during pregnancy: women every 8 weeks, children every 4 weeks; women every 4 weeks, children every 4 weeks; women every 8 weeks, children every 12 weeks; and women every 4 weeks, children every 12 weeks. Block randomisation was done by an independent investigator using a computer-generated randomisation list (permuted block sizes of six and 12). We analysed children on the basis of their random assignment to receive dihydroartemisinin-piperaquine (20 mg/160 mg tablets) once daily for 3 consecutive days every 4 weeks or 12 weeks. Children received study drugs from age 8 weeks to 24 months and were followed-up to age 36 months. Participants and investigators were masked to treatment allocation. The primary outcome was the incidence of symptomatic malaria during the intervention and following cessation of the intervention, adjusted for potential confounders. The primary outcome and safety were assessed in the modified intention-to-treat population, which included all children who reached 8 weeks of age and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02163447.FINDINGS: Between Oct 21, 2014, and May 18, 2015, 191 children were born, of whom 183 reached 8 weeks of age and received at least one dose of study drug and thus were included in the primary analysis (96 children in the 4-week group and 87 in the 12-week group). During the intervention, the incidence of symptomatic malaria was significantly lower among children treated every 4 weeks than children treated every 12 weeks; three episodes occurred among children treated every 4 weeks (incidence 0·018 episodes per person-year) compared with 61 episodes among children treated every 12 weeks (incidence 0·39 episodes per person-year; adjusted incidence rate ratio [aIRR] 0·041, 95% CI 0·012-0·150, p<0·0001). After cessation of IPT, children who had previously received dihydroartemisinin-piperaquine every 4 weeks had a lower incidence of symptomatic malaria than children who were treated every 12 weeks; 62 episodes occurred among children previously treated every 4 weeks (incidence 0·73 episodes per person-year) compared with 83 episodes among children treated every 12 weeks (incidence 1·1 episodes per person-year; aIRR 0·62, 0·40-0·95, p=0·028). In the 4-week group, 94 (98%) of 96 children had adverse events versus 87 (100%) of 87 children in the 12-week group. The most commonly reported adverse event was cough in both treatment groups (94 [98%] in the 4-week group vs 87 [100%] in the 12-week group). 16 children had severe adverse events (seven [7%] children in the 4-week group vs nine [10%] children in the 12-week group). No severe adverse events were thought to be related to study drug administration. One death occurred during the intervention (age 8 weeks to 24 months), which was due to respiratory failure unrelated to malaria.INTERPRETATION: IPT with dihydroartemisinin-piperaquine given every 4 weeks was superior to treatment every 12 weeks for the prevention of malaria during childhood, and this protection was extended for up to 1 year after cessation of IPT.FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

  View details for DOI 10.1016/S1473-3099(19)30299-3

  View details for PubMedID 31307883

• Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial. PLoS medicine Jagannathan, P., Kakuru, A., Okiring, J., Muhindo, M. K., Natureeba, P., Nakalembe, M., Opira, B., Olwoch, P., Nankya, F., Ssewanyana, I., Tetteh, K., Drakeley, C., Beeson, J., Reiling, L., Clark, T. D., Rodriguez-Barraquer, I., Greenhouse, B., Wallender, E., Aweeka, F., Prahl, M., Charlebois, E. D., Feeney, M. E., Havlir, D. V., Kamya, M. R., Dorsey, G. 2018; 15 (7): e1002606

  Abstract

  BACKGROUND: Intermittent preventive treatment of malaria in pregnancy (IPTp) with dihydroartemisinin-piperaquine (IPTp-DP) has been shown to reduce the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (IPTp-SP). However, limited data exist on how IPTp regimens impact malaria risk during infancy. We conducted a double-blinded randomized controlled trial (RCT) to test the hypothesis that children born to mothers given IPTp-DP would have a lower incidence of malaria during infancy compared to children born to mothers who received IPTp-SP.METHODS AND FINDINGS: We compared malaria metrics among children in Tororo, Uganda, born to women randomized to IPTp-SP given every 8 weeks (SP8w, n = 100), IPTp-DP every 8 weeks (DP8w, n = 44), or IPTp-DP every 4 weeks (DP4w, n = 47). After birth, children were given chemoprevention with DP every 12 weeks from 8 weeks to 2 years of age. The primary outcome was incidence of malaria during the first 2 years of life. Secondary outcomes included time to malaria from birth and time to parasitemia following each dose of DP given during infancy. Results are reported after adjustment for clustering (twin gestation) and potential confounders (maternal age, gravidity, and maternal parasitemia status at enrolment).The study took place between June 2014 and May 2017. Compared to children whose mothers were randomized to IPTp-SP8w (0.24 episodes per person year [PPY]), the incidence of malaria was higher in children born to mothers who received IPTp-DP4w (0.42 episodes PPY, adjusted incidence rate ratio [aIRR] 1.92; 95% CI 1.00-3.65, p = 0.049) and nonsignificantly higher in children born to mothers who received IPT-DP8w (0.30 episodes PPY, aIRR 1.44; 95% CI 0.68-3.05, p = 0.34). However, these associations were modified by infant sex. Female children whose mothers were randomized to IPTp-DP4w had an apparently 4-fold higher incidence of malaria compared to female children whose mothers were randomized to IPTp-SP8w (0.65 versus 0.20 episodes PPY, aIRR 4.39, 95% CI 1.87-10.3, p = 0.001), but no significant association was observed in male children (0.20 versus 0.28 episodes PPY, aIRR 0.66, 95% CI 0.25-1.75, p = 0.42). Nonsignificant increases in malaria incidence were observed among female, but not male, children born to mothers who received DP8w versus SP8w. In exploratory analyses, levels of malaria-specific antibodies in cord blood were similar between IPTp groups and sex. However, female children whose mothers were randomized to IPTp-DP4w had lower mean piperaquine (PQ) levels during infancy compared to female children whose mothers received IPTp-SP8w (coef 0.81, 95% CI 0.65-1.00, p = 0.048) and male children whose mothers received IPTp-DP4w (coef 0.72, 95% CI 0.57-0.91, p = 0.006). There were no significant sex-specific differences in PQ levels among children whose mothers were randomized to IPTp-SP8w or IPTp-DP8w. The main limitations were small sample size and childhood provision of DP every 12 weeks in infancy.CONCLUSIONS: Contrary to our hypothesis, preventing malaria in pregnancy with IPTp-DP in the context of chemoprevention with DP during infancy does not lead to a reduced incidence of malaria in childhood; in this setting, it may be associated with an increased incidence of malaria in females. Future studies are needed to better understand the biological mechanisms of in utero drug exposure on drug metabolism and how this may affect the dosing of antimalarial drugs for treatment and prevention during infancy.TRIAL REGISTRATION: ClinicalTrials.gov number NCT02163447.

  View details for PubMedID 30016328

• Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy NEW ENGLAND JOURNAL OF MEDICINE Kakuru, A., Jagannathan, P., Muhindo, M. K., Natureeba, P., Awori, P., Nakalembe, M., Opira, B., Olwoch, P., Ategeka, J., Nayebare, P., Clark, T. D., Feeney, M. E., Charlebois, E. D., Rizzuto, G., Muehlenbachs, A., Havlir, D. V., Kamya, M. R., Dorsey, G. 2016; 374 (10): 928-939

  Abstract

  Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed.We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria.The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events.The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin-piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.).

  View details for DOI 10.1056/NEJMoa1509150

  View details for Web of Science ID 000371660000006

  View details for PubMedID 26962728

• Loss and dysfunction of Vd2? ?d T cells are associated with clinical tolerance to malaria. Science translational medicine Jagannathan, P., Kim, C. C., Greenhouse, B., Nankya, F., Bowen, K., Eccles-James, I., Muhindo, M. K., Arinaitwe, E., Tappero, J. W., Kamya, M. R., Dorsey, G., Feeney, M. E. 2014; 6 (251): 251ra117-?

  Abstract

  Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vδ2(+) subset of γδ T cells have intrinsic reactivity to malaria antigens, can mediate killing of Plasmodium falciparum merozoites, and expand markedly in vivo after malaria infection in previously naïve hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated γδ T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of Vδ2(+) γδ T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of proinflammatory Vδ2(+) γδ T cells were associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of Vδ2(+) γδ T cells that may facilitate immunological tolerance of the parasite.

  View details for DOI 10.1126/scitranslmed.3009793

  View details for PubMedID 25163477

  View details for PubMedCentralID PMC4198150

• IFN gamma/IL-10 Co-producing Cells Dominate the CD4 Response to Malaria in Highly Exposed Children PLOS PATHOGENS Jagannathan, P., Eccles-James, I., Bowen, K., Nankya, F., Auma, A., Wamala, S., Ebusu, C., Muhindo, M. K., Arinaitwe, E., Briggs, J., Greenhouse, B., Tappero, J. W., Kamya, M. R., Dorsey, G., Feeney, M. E. 2014; 10 (1)

  Abstract

  Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4(+) T cell responses were measurable in nearly all children, with the majority of children having CD4(+) T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4(+) T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001) and inversely correlated with duration since malaria (Rho = -0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003). While TNFα-producing CD4(+) T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4(+) T cells dominating this response among highly exposed children. These CD4(+) T cells may play important modulatory roles in the development of antimalarial immunity.

  View details for DOI 10.1371/journal.ppat.1003864

  View details for Web of Science ID 000332640900031

  View details for PubMedID 24415936

• Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution. Science translational medicine Hamlin, R. E., Pienkos, S. M., Chan, L., Stabile, M. A., Pinedo, K., Rao, M., Grant, P., Bonilla, H., Holubar, M., Singh, U., Jacobson, K. B., Jagannathan, P., Maldonado, Y., Holmes, S. P., Subramanian, A., Blish, C. A. 2024; 16 (773): eadr1032

  Abstract

  Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor-β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2-like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

  View details for DOI 10.1126/scitranslmed.adr1032

  View details for PubMedID 39536117

• Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens. PLoS pathogens Reyes, R. A., Turner, L., Ssewanyana, I., Jagannathan, P., Feeney, M. E., Lavstsen, T., Greenhouse, B., Bol, S., Bunnik, E. M. 2024; 20 (10): e1012661

  Abstract

  Plasmodium falciparum infections elicit strong humoral immune responses to two main groups of antigens expressed by blood-stage parasites: merozoite antigens that are involved in the erythrocyte invasion process and variant surface antigens that mediate endothelial sequestration of infected erythrocytes. Long-lived B cells against both antigen classes can be detected in the circulation for years after exposure, but have not been directly compared. Here, we studied the phenotype of long-lived memory and atypical B cells to merozoite antigens (MSP1 and AMA1) and variant surface antigens (the CIDRα1 domain of PfEMP1) in ten Ugandan adults before and after local reduction of P. falciparum transmission. After a median of 1.7 years without P. falciparum infections, the percentage of antigen-specific activated B cells declined, but long-lived antigen-specific B cells were still detectable in all individuals. The majority of MSP1/AMA1-specific B cells were CD95+CD11c+ memory B cells, which are primed for rapid differentiation into antibody-secreting cells, and FcRL5-T-bet- atypical B cells. On the other hand, most CIDRα1-specific B cells were CD95-CD11c- memory B cells. CIDRα1-specific B cells were also enriched among a subset of atypical B cells that seem poised for antigen presentation. These results point to differences in how these antigens are recognized or processed by the immune system and how P. falciparum-specific B cells will respond upon re-infection.

  View details for DOI 10.1371/journal.ppat.1012661

  View details for PubMedID 39466842

• Intermittent preventive treatment for malaria in pregnancy and infant growth: a mediation analysis of a randomised trial. EBioMedicine Tong, Y., Ratnasiri, K., Hanif, S., Nguyen, A. T., Roh, M. E., Dorsey, G., Kakuru, A., Jagannathan, P., Benjamin-Chung, J. 2024; 109: 105397

  Abstract

  Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses.We analysed data from 633 infants born to mothers enrolled in a randomised trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs. sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0 to 12 months of age. Using generalised linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anaemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrolment, maternal age, maternal parasitaemia at enrolment, education, and wealth.SP increased mean LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased mean WLZ by 0.11-0.28 Z from 2 to 8 months compared to SP among infants of multigravidae; at these ages, confidence intervals for mean differences excluded 0. We did not observe differences among primigravida. Mediators of SP included birth weight, birth length, maternal stem cell factor, and DNER. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery.In high malaria transmission settings, this exploratory study suggests different IPTp regimens may influence infant growth among multigravidae, potentially through distinct pathways, in the exclusive breastfeeding period, when few other interventions are available.Stanford Center for Innovation in Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/j.ebiom.2024.105397

  View details for PubMedID 39418986

• The statistical design and analysis of pandemic platform trials: Implications for the future. Journal of clinical and translational science Lindsell, C. J., Shotwell, M., Anstrom, K. J., Berry, S., Brittain, E., Harrell, F. E., Geller, N., Grund, B., Hughes, M. D., Jagannathan, P., Leifer, E., Moser, C. B., Price, K. L., Proschan, M., Stewart, T., Thomas, S., Touloumi, G., LaVange, L. 2024; 8 (1): e155

  Abstract

  The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Cross-Trial Statistics Group gathered lessons learned from statisticians responsible for the design and analysis of the 11 ACTIV therapeutic master protocols to inform contemporary trial design as well as preparation for a future pandemic. The ACTIV master protocols were designed to rapidly assess what treatments might save lives, keep people out of the hospital, and help them feel better faster. Study teams initially worked without knowledge of the natural history of disease and thus without key information for design decisions. Moreover, the science of platform trial design was in its infancy. Here, we discuss the statistical design choices made and the adaptations forced by the changing pandemic context. Lessons around critical aspects of trial design are summarized, and recommendations are made for the organization of master protocols in the future.

  View details for DOI 10.1017/cts.2024.514

  View details for PubMedID 39540110

  View details for PubMedCentralID PMC11557281

• ACTIV trials: Lessons learned in trial design in the setting of an emergent pandemic. Journal of clinical and translational science Keshtkar-Jahromi, M., Anstrom, K. J., Barkauskas, C., Brown, S. M., Daar, E. S., Fischer, W., Gibbs, K. W., Higgs, E. S., Hughes, M. D., Jagannathan, P., LaVange, L., Lindsell, C. J., Nayak, S. U., Paredes, R., Parmar, M., Peltan, I. D., Proschan, M., Shotwell, M. S., Vock, D. M., Yokum, T., Adam, S. J. 2024; 8 (1): e151

  Abstract

  Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.

  View details for DOI 10.1017/cts.2024.1

  View details for PubMedID 39478775

  View details for PubMedCentralID PMC11523015

• ACTIV trials: Lessons learned in trial design in the setting of an emergent pandemic JOURNAL OF CLINICAL AND TRANSLATIONAL SCIENCE Keshtkar-Jahromi, M., Anstrom, K. J., Barkauskas, C., Brown, S. M., Daar, E. S., Fischer, W., Gibbs, K. W., Higgs, E. S., Hughes, M. D., Jagannathan, P., LaVange, L., Lindsell, C. J., Nayak, S. U., Paredes, R., Parmar, M., Peltan, I. D., Proschan, M., Shotwell, M. S., Vock, D. M., Yokum, T., Adam, S. J. 2024; 8 (1)

  View details for DOI 10.1017/cts.2024.1

  View details for Web of Science ID 001331194600001

• ACTIV trials: cross-trial lessons learned for master protocol implementation JOURNAL OF CLINICAL AND TRANSLATIONAL SCIENCE Keshtkar-Jahromi, M., Adam, S. J., Brar, I., Chung, L. K., Currier, J. S., Daar, E. S., Davey, V. J., Denning, E. T., Gelijns, A. C., Higgs, E. S., Jagannathan, P., Javan, A., Jensen, T. O., Jilg, N., Kalomenidis, I., Kim, P., Nayak, S. U., Newell, M., Taiwo, B. O., Yokum, T., Delph, Y. 2024; 8 (1)

  View details for DOI 10.1017/cts.2024.507

  View details for Web of Science ID 001334555800001

• The statistical design and analysis of pandemic platform trials: Implications for the future JOURNAL OF CLINICAL AND TRANSLATIONAL SCIENCE Lindsell, C. J., Shotwell, M., Anstrom, K. J., Berry, S., Brittain, E., Harrell, F. E., Geller, N., Grund, B., Hughes, M. D., Jagannathan, P., Leifer, E., Moser, C. B., Price, K. L., Proschan, M., Stewart, T., Thomas, S., Touloumi, G., Lavange, L. 2024; 8 (1)

  View details for DOI 10.1017/cts.2024.514

  View details for Web of Science ID 001334555700001

• ACTIV trials: cross-trial lessons learned for master protocol implementation. Journal of clinical and translational science Keshtkar-Jahromi, M., Adam, S. J., Brar, I., Chung, L. K., Currier, J. S., Daar, E. S., Davey, V. J., Denning, E. T., Gelijns, A. C., Higgs, E. S., Jagannathan, P., Javan, A. C., Jensen, T. O., Jilg, N., Kalomenidis, I., Kim, P., Nayak, S. U., Newell, M., Taiwo, B. O., Yokum, T., Delph, Y. 2024; 8 (1): e152

  Abstract

  The United States Government (USG) public-private partnership "Accelerating COVID-19 Treatment Interventions and Vaccines" (ACTIV) was launched to identify safe, effective therapeutics to treat patients with Coronavirus Disease 2019 (COVID-19) and prevent hospitalization, progression of disease, and death. Eleven original master protocols were developed by ACTIV, and thirty-seven therapeutic agents entered evaluation for treatment benefit. Challenges encountered during trial implementation led to innovations enabling initiation and enrollment of over 26,000 participants in the trials. While only two ACTIV trials continue to enroll, the recommendations here reflect information from all the trials as of May 2023. We review clinical trial implementation challenges and corresponding lessons learned to inform future therapeutic clinical trials implemented in response to a public health emergency and the conduct of complex clinical trials during "peacetime," as well.

  View details for DOI 10.1017/cts.2024.507

  View details for PubMedID 39540114

  View details for PubMedCentralID PMC11557279

• Time to Sustained Recovery Among Outpatients With COVID-19 Receiving Montelukast vs Placebo: The ACTIV-6 Randomized Clinical Trial. JAMA network open Rothman, R. L., Stewart, T. G., Mourad, A., Boulware, D. R., McCarthy, M. W., Thicklin, F., Garcia Del Sol, I. T., Garcia, J. L., Bramante, C. T., Shah, N. S., Singh, U., Williamson, J. C., Rebolledo, P. A., Jagannathan, P., Schwasinger-Schmidt, T., Ginde, A. A., Castro, M., Jayaweera, D., Sulkowski, M., Gentile, N., McTigue, K., Felker, G. M., DeLong, A., Wilder, R., Collins, S., Dunsmore, S. E., Adam, S. J., Hanna, G. J., Shenkman, E., Hernandez, A. F., Naggie, S., Lindsell, C. J., Accelerating COVID-19 Therapeutic Interventions and Vaccines-6 Study Group and Investigators, Hanna, G., Fraser, R., Ward, M., Gamboa Jackson, J., McAdams, M. P., Vail, J., Korzekwinski, K., Oyelakin, M., Chopp, J., Randle, D., Dockery, S., Adkins, R., Crow, M., Nowell, E., Wells, K., Herbert, A., Stone, A., Heavlin, H., Brown, L., Harding, T., Harrington, A., Beauchaine, M., Lindblom, K., Burns, A., Aamodt, D., Collins, J., Dixon, S., Gao, Y., Graves, J., Grindstaff, J., Harrell, F., Lai, J., Liao, V., Lopez, I., Manis, E., Mankowski, K., Marlin, J., Merkel, A., Nwosu, S., Obregon, S., Orozco, D., Prato, N., Rhode, M., Shirey-Rice, J., Vermillion, K., Smith, J., Tan, H., Vance, M., Weir, M., Bianchi, R., Premas, J., Gupta, M., Karawan, G., Lima, S., Ziomek, C., Arena, J., DeAlmeida, S., Malik, A., Bryce, J., Swint, S., Ramin, S., Nataraj, J., Deider, J., Cruz, R., Ramirez, A. M., Henault, L., Marcus, J., Southwell, A., Jacques, G., Sexton, C., Tiffany, B., Tanner, C., Sahelian, A., George-Adebayo, C., Adebayo, A., Zapatero, J., Clement, J., Ronan, T., Woods, A., Gallegos, C., Flys, T., Sloan, O., Olofintuyi, A., Samraj, J., Vasbinder, A., Averett, A., Slandzicki, A., Wallen, J., Vogel, C., Munoz, S., Kavtaradze, D., Watson, C., Singleton, D., Sevier, M., Rivon, M., Del Pilar, A., Spangler, A., Rao, S., Cantu, L., Krishna, A., Daugherty, H., Kerr, B., Evans, K., Spees, R., Marta, M., Dolor, R., Vergara, L., Jordan, J., Burruss, V., Hurst, T., Ofotokun, I., Zhang, C., Traenkner, J., Atha, M. M., Prabhu, R., Klicka, K., Lightfeather, A., James, V., Rogers, M., Oragwu, C., Oguego, N., Pillai, R., Gabriel, A., Ghaly, E., Michal, M., Vasquez, M., Mamon, A., Sheets, M., Hassanien, G., Ismail, S., Samir, Y., Meltzer, A., Shahamatdar, S., Heidish, R. S., Loganathan, A., Brehaut, S., Roche, A., Mehta, M., Koppinger, N., Baez, J., Pagan, I., Abdelsayed, D., Aziz, M., Robinson, P., Lozinski, G., Nguyen, J., Griffin, A., Morris, M., Love, N., Mattox, B., Martin, R., Pardue, V., Rowland, T., Ruiz-Unger, J., Reyes, L., Zamora, Y., Bacallao, N., Cienki, J., Cohen, J., Yuan, Y., Li, J., Szeto, J., Stelmash, L., Mekhael, S., Morales Castillo, L., Gutierrez, A., Prieto, S., Amon, A., Barbera, A., Bugajski, A., Willis, W., Jacklin, K., Lamb, D., Harper, A., Stout, E., Griffin, M., Pyram-Bernard, N., Quintero, A., Clark, N., Barsanti-Sekhar, M., Carbrera-Mendez, C., Evans, M. R., Adhami, E., Carillo, G., Maria, J., Paudel, D., Raymond, O., Summers, J., Turner, T., Lenert, L., Panaccione, E., Szwast, E., Reynolds, A., Abdulghani, A., Vasoya, P., Miller, C., Wiley, H., Chan, A., Khizer, S., Adeyemi, O., Chi, W. N., Chen, J., Morton-Jost, M., Castex, J., Quirch, A., Belani, H., Machicado, R., Bjornsson, B., Olivo, J., Maldonado, M., Vecchiarelli, A., Gaytan-Alvarez, D., Cherukuri, V., Alicic, R., Lambert, A. A., Urbat, C., Baxter, J., Cooper, A., Linn, D., Fisher, L., Patel, V., Talati, R., Patel, P., Ellison, L., Roman, A., Harrison, J., Moy, J., Naquiallah, D., Shah, B., Quintero, O., Scott, J., Jazayeri, Y., O'Donnell, A., Pathak, D., Gupta, A., Chandrasekar, N., Curtis, C., White, B., Dockery, M., Fortt, T., Fortt, A., Jones-Ince, I., McKee, A., Wilson, J., Marcelin, J., Farlow, B., Grady, C., Richwine, R., Pazier, P., Michelson, E., Watts, S., Kariyawasam, D., Rodriguez, L., Manresa, I., Achong, A. A., Garcia, M. C., Khetpal, S., Posey, F., Mahadevan, A., Gnoni, M., Van de Weerd, C., Lowenkron, J., Sappington, E., Roberts, M., Wang, J., Adams, M., Ding, X., Co, M., D'Andrea, M., Lim, S., Swink, W., Bozant, E., Young, M., Wilson, M., Eastin, C., Cheathem, A., Nadeem, A., Walters, C., Powers-Fletcher, M., Brown, D., Miller, D., Mukunzi, S., Manning, B., Terry-White, M., Crizaldo, M. C., Isache, C., Bowman, J., Callaghan-Brown, A., Martin, D., Ast, A., Duran, B., Cornejo, A., Archer, A., Almanzar, M., Motel, V., Pullen, M., Anderson, B., Bhat, N., Parra, D., Campora, P., Robinson, M., Seithel, M., Kendrick, L., Helming, D., Pollock, K., Sekikawa, A., Klawson, E., Arnold, J., Weiland, N., Ostrosky-Zeichner, L., Patel, B., Umana, V., Nielsen, L., Grimes, C. Z., Patterson, T. F., Tragus, R., Soileau, B. T., Heath, T., Hinjosa, E., Gutierrez, C., Jackson, P. E., Hallowell, C., Haughey, H. M., Vaidya-Tank, B., Gould, C., Goyal, P., Sommers, S., Pangburn, H., Jones, C., Michalowski, L., Wortham, B., Abbott, R., Umana, U., Alleyne, C., Witting, B., Armas, E., Perez Landaburo, R. O., De La Cruz, M., Ballmajo, M., Alvarez, J. 2024; 7 (10): e2439332

  Abstract

  Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain.Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19.Design, Setting, and Participants: This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites.Interventions: Participants were randomized 1:1 to receive montelukast, 10 mg once daily, or matched placebo for 14 days.Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis.Results: Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P=.63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P=.48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group).Conclusions and Relevance: In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19.Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

  View details for DOI 10.1001/jamanetworkopen.2024.39332

  View details for PubMedID 39422912

• Measurement of circulating viral antigens post-SARS-CoV-2 infection in a multicohort study. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases Swank, Z., Borberg, E., Chen, Y., Senussi, Y., Chalise, S., Manickas-Hill, Z., Yu, X. G., Li, J. Z., Alter, G., Henrich, T. J., Kelly, J. D., Hoh, R., Goldberg, S. A., Deeks, S. G., Martin, J. N., Peluso, M. J., Talla, A., Li, X., Skene, P., Bumol, T. F., Torgerson, T. R., Czartoski, J. L., McElrath, M. J., Karlson, E. W., Walt, D. R., RECOVER consortium authors, Abraham, R., Ager, A., Aguilar, F. A., Ahmadi-Izad, G., Ahmed, D. R., Alvarez, A., Anderson, B., Asencios, W. D., Atha, M., Beaty, C. L., Bedi, B., Berry, J. A., Boone, D., Bower, M., Bremner, J. D., Brent, C., Brown-Smith, K., Bull, R., Bush, P. A., Capo, G., Carl-Igwe, K., Chitadze, C., Chukwumerije, N., Clyburn, E., Collins, S., Costello, J., Couture, G., Craft, A., Cribbs, S. K., Cui, X., Dandy, A., Rio, C. D., Jasarevic, R., Detelich, J. F., Dixon, C., Dow, J., Doyle, D., Elchommali, J., Ibeawuchi, C., Elsey, I., Fineman, R., Francis, A. G., Franks, N., Gallini, J., Gander, J. C., Gray, N., Grimes, A., Gutter, E., Han, J. E., Hang, T. P., Harding, J., Hernandez, L., Hewitt, L. N., Holloway, C., Hudgins, A. F., Huerta, C., Ibeawuchi, C., Ifejika, C., Ingram, K. D., Javia, V. N., Jeter, M., Johnson, B., Joseph, Y., Juarez, M., Kajan, D., Khalil, L., Kirkpatrick, C. M., Kleinhenz, D., Kolailat, I., Koumanelis, A., Koumanelis, A., Kozoman, R., Krishnan, S., Lainez, J., Lawrence, B., Lee, M. A., Leon, J. D., Lew, V., Lewis, K. C., Litvack, M., Maroney, M., Maier, C. L., Makkaoui, N., Marconi, V. C., Martin, C. F., Martinez, M., Mbogo, L., McCaslin, A., McIntyre, J., Moanna, A., Montoya, M., Morales, E., Moran, C. A., Morgan-Billingslea, J., Murray, C., Nelson, R., Neuman, R. B., Nguyen, T., Ofotokun, I., Ojemakinde, E. I., Ojoawo, B., Osinski, E., Oviedo, S., Panganiban, B., Paredes-Gaitan, Y., Patzer, R. E., Pemu, P., Prude, M., Rahman, K., Ramakrishnan, G., Rebolledo, P. A., Roberts, M., Robinson, K., Rogers, C., Rouphael, N. G., Searles, C., Shah, A., Segall, M., Shaw, R. M., Silva, R., Simpson, C., Simpson-Derrell, K., Sirajud-Deen, T., Smith, V. E., Stringer, A., Stroud, J., Suthar, M. S., Sylber, C., Sylvera, A., Tanner, T., Teunis, L. J., Tolbert, M., Thomas, K. M., Thompson, S. G., Titanji, K., Toy, C., Traenkner, J., Truong, A., Unterberger, K., Vaccarino, V., Varney, K., Vyas, K., Vyas, K., Walker, T. A., Walkow, M., Wang, D., Wesley, T., Wiley, Z., Wimberly, E., Winston, J. R., Winter, T. J., Wongtrakool, C., Aikawa, M., Alba, G. A., Aung, T. N., Baden, L., Baslet, G., Bassett, I. V., Bennett, L., Bhattacharyya, S., Blazey-Martin, D., Buring, J., Cagnina, R. E., Chen, L. Q., Clark, C. 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H., Copeland, D., Blakley, F. D., Hall, Y., Kevin Kondo, Lerma, L., Lindsay, J., Marti, H., Maughan, C., Minor, T., Taylor, B., Vincent, H., Zissis, M., Anderson, B., Bardhan, S., Castro-Baucom, L., Chisolm, D., Corchado, C., Damian, A. J., Daniel, C., DasGupta, S., Dehority, W., Feldman, C., Fessel, J., Rosas, L. G., Horowitz, C., John, J., Khullar, D., Lopez, K., Lutrick, K., Marquez, C., McDonald Pinkett, S., Myaskovsky, L., Regino, L., Rhoads, K., St John Thomas, G., Stewart de Ramirez, S., Tsevat, J., Valencia, C., Vangeepuram, N., Walden, A., Wiley, Z., Williams, N., Yin, S., Blachman, N., Boutin, N., Burton, P., Catallozzi, M., Clark, C., Dworetzky, B., Edwards, B., Ferrer, R. L., Huang, B., Judd, S., Laury, S., Musick, H., Pathak, D., Pogreba-Brown, K., Raissy, H., Richardson, L., Rothman, R., Wagner, L., Wallace, A., Adams, S. R., Akintonwa, T., Aragon, L., Bander, B., Bishof, K., Blancero, F., Brooks, G., Carignan, E., Carmilani, M., Castro-Baucom, L., Cerda, M., Coombs, K., Copeland, D., Corchado, C., Davis, H., Blakley, F. D., Diggs, M., Edwards, B., Brown, H. E., Favors, U., Fields, W., Fisher, L., Fitzgerald, M., Gaffney, A., Witvliet, M. G., Garcia, R., Gustafson, T., Guthe, N., Hall, Y., Holmes, V., Hornig, M., Hornig, M., Jefferson, W., Kim, C., Kochis, N., Kondo, K., Lam, J., Lawrence, F., Lerma, L., Letts, R., Lewis, J., Lindsay, J., Lopez, S., Marti, H., Martinez, T., Maughan, C., McCorkell, L., McGrath, R., Minor, T. T., Moore, C., Nguyen, K., Nichols, L., O'Brien, L., Olson, H., Peddie, A., Perlowski, A., Lorenzo, E. P., Prentiss, L., Raytselis, N., Regino, L., Roberts, M., Rochez, N., Rockwell, M., Rutter, J., Rochez, N., Seibert, E., Sekar, A., Smith, C., Stiles, L., Taylor, B., Taylor, E., Thompson, J., Trapp, S., Valdiva, S., Vincent, H., Wallace, A., Wilensky, R., Williams, M., Williams, N., Dawson, K. W., Wylam, A., Zissis, M. 2024

  Abstract

  OBJECTIVES: To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms.METHODS: Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records.RESULTS: Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18-24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18-22%) between 4 and 7months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis ≥1month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40-45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4-2.2).DISCUSSION: The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.

  View details for DOI 10.1016/j.cmi.2024.09.001

  View details for PubMedID 39389851

• Gestational SARS-CoV-2 Infection in a Ugandan Birth Cohort: High Incidence, Mild Maternal Disease, and Evidence of Association with Transient Infant Stunting. The American journal of tropical medicine and hygiene Jacobson, K. B., Roltgen, K., Lam, B., Nayebare, P., Kakuru, A., Kizza, J., Aguti, M., Nankya, F., Briggs, J., Takahashi, S., Greenhouse, B., Rodriguez-Barraquer, I., van der Ploeg, K., Wohlstadter, J. N., Sigal, G. B., Roh, M. E., Nankabirwa, J. I., Cuu, G., Gaw, S. L., Rosenthal, P. J., Kamya, M. R., Ssewanyana, I., Dorsey, G., Boyd, S. D., Jagannathan, P. 2024

  Abstract

  Many questions remain about the prevalence and effects of SARS-CoV-2 infection in malaria-endemic African countries like Uganda, particularly in vulnerable groups such as pregnant women. We describe SARS-CoV-2 immunoglobulin (Ig)G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria chemoprevention trials in Uganda. From December 2020-February 2022, among 400 unvaccinated pregnant women enrolled at 12-20 weeks gestation and followed through delivery, 128 (32%) were seronegative for anti-SARS-CoV-2 IgG and IgM at enrollment and delivery, 80 (20%) were infected prior to or early in pregnancy, and 192 (48%) were infected or re-infected with SARS-CoV-2 during pregnancy. We observed preferential binding of plasma IgG to Wuhan-Hu-1-like antigens in individuals seroconverting up to early 2021, and to Delta variant antigens in a subset of individuals in mid-2021. Breadth of IgG binding to all variants improved over time, consistent with affinity maturation of the antibody response in the cohort. No women experienced severe respiratory illness during the study. SARS-CoV-2 infection in early pregnancy was associated with lower median length-for-age Z-score at age 3 months compared with no infection or late pregnancy infect (-1.54 versus -0.37 and -0.51, P = 0.009). These findings suggest that pregnant Ugandan women experienced high levels of SARS-CoV-2 infection without severe respiratory illness. Variant-specific serology testing demonstrated evidence of antibody affinity maturation at the population level. Early gestational SARS-CoV-2 infection was associated with transient shorter stature in early infancy. Further research should explore the significance of this finding and define targeted measures to prevent infection in pregnancy.

  View details for DOI 10.4269/ajtmh.23-0801

  View details for PubMedID 39288758

• The expanding universe of type I regulatory T cell biology: a new role in cancer immunotherapy. Immunology and cell biology Nideffer, J. F., Jagannathan, P. 2024

  Abstract

  In this article, we discuss new findings which suggest that type I regulatory T (Tr1) cells can interfere with cancer vaccine efficacy in mice by exerting strong regulatory control over antitumor immune responses.

  View details for DOI 10.1111/imcb.12822

  View details for PubMedID 39261289

• Dramatic resurgence of malaria after 7 years of intensive vector control interventions in Eastern Uganda. PLOS global public health Kamya, M. R., Nankabirwa, J. I., Arinaitwe, E., Rek, J., Zedi, M., Maiteki-Sebuguzi, C., Opigo, J., Staedke, S. G., Oruni, A., Donnelly, M. J., Greenhouse, B., Briggs, J., Krezanoski, P. J., Bousema, T., Rosenthal, P. J., Olwoch, P., Jagannathan, P., Rodriguez-Barraquer, I., Dorsey, G. 2024; 4 (8): e0003254

  Abstract

  Tororo District, Uganda experienced a dramatic decrease in malaria burden from 2015-19 during 5 years of indoor residual spraying (IRS) with carbamate (Bendiocarb) and then organophosphate (Actellic) insecticides. However, a marked resurgence occurred in 2020, which coincided with a change to a clothianidin-based IRS formulations (Fludora Fusion/SumiShield). To quantify the magnitude of the resurgence, investigate causes, and evaluate the impact of a shift back to IRS with Actellic in 2023, we assessed changes in malaria metrics in regions within and near Tororo District. Malaria surveillance data from Nagongera Health Center, Tororo District was included from 2011-2023. In addition, a cohort of 667 residents from 84 houses was followed from August 2020 through September 2023 from an area bordering Tororo and neighboring Busia District, where IRS has never been implemented. Cohort participants underwent passive surveillance for clinical malaria and active surveillance for parasitemia every 28 days. Mosquitoes were collected in cohort households every 2 weeks using CDC light traps. Female Anopheles were speciated and tested for sporozoites and phenotypic insecticide resistance. Temporal comparisons of malaria metrics were stratified by geographic regions. At Nagongera Health Center average monthly malaria cases varied from 419 prior to implementation of IRS; to 56 after 5 years of IRS with Bendiocarb and Actellic; to 1591 after the change in IRS to Fludora Fusion/SumiShield; to 155 after a change back to Actellic. Among cohort participants living away from the border in Tororo, malaria incidence increased over 8-fold (0.36 vs. 2.97 episodes per person year, p<0.0001) and parasite prevalence increased over 4-fold (17% vs. 70%, p<0.0001) from 2021 to 2022 when Fludora Fusion/SumiShield was used. Incidence decreased almost 5-fold (2.97 vs. 0.70, p<0.0001) and prevalence decreased by 39% (70% vs. 43%, p<0.0001) after shifting back to Actellic. There was a similar pattern among those living near the border in Tororo, with increased incidence between 2021 and 2022 (0.93 vs. 2.40, p<0.0001) followed by a decrease after the change to Actellic (2.40 vs. 1.33, p<0.001). Among residents of Busia, malaria incidence did not change significantly over the 3 years of observation. Malaria resurgence in Tororo was temporally correlated with the replacement of An. gambiae s.s. by An. funestus as the primary vector, with a marked decrease in the density of An. funestus following the shift back to IRS with Actellic. In Busia, An. gambiae s.s. remained the primary vector throughout the observation period. Sporozoite rates were approximately 50% higher among An. funestus compared to the other common malaria vectors. Insecticide resistance phenotyping of An. funestus revealed high tolerance to clothianidin, but full susceptibility to Actellic. A dramatic resurgence of malaria in Tororo was temporally associated with a change to clothianidin-based IRS formulations and emergence of An. funestus as the predominant vector. Malaria decreased after a shift back to IRS with Actellic. This study highlights the ability of malaria vectors to rapidly circumvent control efforts and the importance of high-quality surveillance systems to assess the impact of malaria control interventions and generate timely, actionable data.

  View details for DOI 10.1371/journal.pgph.0003254

  View details for PubMedID 39208072

  View details for PubMedCentralID PMC11361418

• CD4+ T cells display a spectrum of recall dynamics during re-infection with malaria parasites. Nature communications Lee, H. J., Moreira, M. L., Li, S., Asatsuma, T., Williams, C. G., Skinner, O. P., Asad, S., Bramhall, M., Jiang, Z., Liu, Z., Kerr, A. S., Engel, J. A., Soon, M. S., Straube, J., Barrera, I., Murray, E., Chen, F., Nideffer, J., Jagannathan, P., Haque, A. 2024; 15 (1): 5497

  Abstract

  Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4+ T cell subsets remain unresolved. Here, we examine antigen-experienced CD4+ T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic TEM cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with TCM/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4+ T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4+ T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection.

  View details for DOI 10.1038/s41467-024-49879-6

  View details for PubMedID 38944658

  View details for PubMedCentralID PMC11214622

• Sex differences and immune correlates of Long COVID development, persistence, and resolution. bioRxiv : the preprint server for biology Hamlin, R. E., Pienkos, S. M., Chan, L., Stabile, M. A., Pinedo, K., Rao, M., Grant, P., Bonilla, H., Holubar, M., Singh, U., Jacobson, K. B., Jagannathan, P., Maldonado, Y., Holmes, S. P., Subramanian, A., Blish, C. A. 2024

  Abstract

  Sex differences have been observed in acute COVID-19 and Long COVID (LC) outcomes, with greater disease severity and mortality during acute infection in males and a greater proportion of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to the pathogenesis of LC. To investigate the immunologic underpinnings of LC development and persistence, we used single-cell transcriptomics, single-cell proteomics, and plasma proteomics on blood samples obtained during acute SARS-CoV-2 infection and at 3 and 12 months post-infection in a cohort of 45 patients who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Specifically, males who would develop LC at 3 months had widespread increases in TGF-β signaling during acute infection in proliferating NK cells. Females who would develop LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, and increased IL1 signaling in monocytes at 12 months post infection. Several immune features of LC were also conserved across sexes. Both males and females with LC had reduced co-stimulatory signaling from monocytes and broad upregulation of NF-κB transcription factors. In both sexes, those with persistent LC demonstrated increased LAG3, a marker of T cell exhaustion, reduced ETS1 transcription factor expression across lymphocyte subsets, and elevated intracellular IL-4 levels in T cell subsets, suggesting that ETS1 alterations may drive an aberrantly elevated Th2-like response in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

  View details for DOI 10.1101/2024.06.18.599612

  View details for PubMedID 38948732

  View details for PubMedCentralID PMC11212991

• Pathways through which intermittent preventive treatment for malaria in pregnancy influences child growth faltering: a mediation analysis. medRxiv : the preprint server for health sciences Tong, Y., Ratnasiri, K., Hanif, S., Nguyen, A. T., Roh, M. E., Dorsey, G., Kakuru, A., Jagannathan, P., Benjamin-Chung, J. 2024

  Abstract

  Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses.We analyzed data from 633 infants born to mothers enrolled in a randomized trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0-12 months of age. Using generalized linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrollment, maternal age, maternal parasitemia at enrollment, education, and wealth.SP increased LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased WLZ by 0.11-0.28 Z from 2-8 months compared to SP among infants of multigravidae. We did not observe these differences among primigravida. Mediators of SP included increased birth weight and length and maternal stem cell factor at delivery. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery.In high malaria transmission settings, different IPTp regimens influenced infant growth among multigravidae through distinct pathways in the period of exclusive breastfeeding, when few other interventions are available.Stanford Center for Innovation and Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation.

  View details for DOI 10.1101/2024.06.09.24308656

  View details for PubMedID 38947035

  View details for PubMedCentralID PMC11213035

• Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial. JAMA internal medicine Geng, L. N., Bonilla, H., Hedlin, H., Jacobson, K. B., Tian, L., Jagannathan, P., Yang, P. C., Subramanian, A. K., Liang, J. W., Shen, S., Deng, Y., Shaw, B. J., Botzheim, B., Desai, M., Pathak, D., Jazayeri, Y., Thai, D., O'Donnell, A., Mohaptra, S., Leang, Z., Reynolds, G. Z., Brooks, E. F., Bhatt, A. S., Shafer, R. W., Miglis, M. G., Quach, T., Tiwari, A., Banerjee, A., Lopez, R. N., De Jesus, M., Charnas, L. R., Utz, P. J., Singh, U. 2024

  Abstract

  There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC).To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms.This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration.Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days.Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline.Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade.The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC.ClinicalTrials.gov Identifier: NCT05576662.

  View details for DOI 10.1001/jamainternmed.2024.2007

  View details for PubMedID 38848477

• Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens. bioRxiv : the preprint server for biology Reyes, R. A., Turner, L., Ssewanyana, I., Jagannathan, P., Feeney, M. E., Lavstsen, T., Greenhouse, B., Bol, S., Bunnik, E. M. 2024

  Abstract

  Plasmodium falciparum infections elicit strong humoral immune responses to two main groups of antigens expressed by blood-stage parasites: merozoite antigens that are involved in the erythrocyte invasion process and variant surface antigens that mediate endothelial sequestration of infected erythrocytes. Long-lived B cells against both antigen classes can be detected in the circulation for years after exposure, but have not been directly compared. Here, we studied the phenotype of long-lived memory and atypical B cells to merozoite antigens (MSP1 and AMA1) and variant surface antigens (the CIDRα1 domain of PfEMP1) in Ugandan adults before and after local reduction of P. falciparum transmission. After a median of 1.7 years without P. falciparum infections, the percentage of antigen-specific activated B cells declined, but long-lived antigen-specific B cells were still detectable in all individuals. The majority of MSP1/AMA1-specific B cells were CD95+CD11c+ memory B cells, which are primed for rapid differentiation into antibody-secreting cells, and FcRL5-T-bet- atypical B cells. On the other hand, most CIDRα1-specific B cells were CD95-CD11c- memory B cells. CIDRα1-specific B cells were also enriched among a subset of atypical B cells that seem poised for antigen presentation. These results point to differences in how these antigens are recognized or processed by the immune system and how P. falciparum-specific B cells will respond upon re-infection.

  View details for DOI 10.1101/2024.06.01.596978

  View details for PubMedID 38895251

  View details for PubMedCentralID PMC11185507

• Monthly Sulfadoxine-Pyrimethamine During Pregnancy Prevents Febrile Respiratory Illnesses: A Secondary Analysis of a Malaria Chemoprevention Trial in Uganda. Open forum infectious diseases Lee, J. J., Kakuru, A., Jacobson, K. B., Kamya, M. R., Kajubi, R., Ranjit, A., Gaw, S. L., Parsonnet, J., Benjamin-Chung, J., Dorsey, G., Jagannathan, P., Roh, M. E. 2024; 11 (4): ofae143

  Abstract

  Trials evaluating antimalarials for intermittent preventive treatment in pregnancy (IPTp) have shown that dihydroartemisinin-piperaquine (DP) is a more efficacious antimalarial than sulfadoxine-pyrimethamine (SP); however, SP is associated with higher birthweight, suggesting that SP demonstrates "nonmalarial" effects. Chemoprevention of nonmalarial febrile illnesses (NMFIs) was explored as a possible mechanism.In this secondary analysis, we leveraged data from 654 pregnant Ugandan women without HIV infection who participated in a randomized controlled trial comparing monthly IPTp-SP with IPTp-DP. Women were enrolled between 12 and 20 gestational weeks and followed through delivery. NMFIs were measured by active and passive surveillance and defined by the absence of malaria parasitemia. We quantified associations among IPTp regimens, incident NMFIs, antibiotic prescriptions, and birthweight.Mean "birthweight for gestational age" Z scores were 0.189 points (95% CI, .045-.333) higher in women randomized to IPTp-SP vs IPTp-DP. Women randomized to IPTp-SP had fewer incident NMFIs (incidence rate ratio, 0.74; 95% CI, .58-.95), mainly respiratory NMFIs (incidence rate ratio, 0.69; 95% CI, .48-1.00), vs IPTp-DP. Counterintuitively, respiratory NMFI incidence was positively correlated with birthweight in multigravidae. In total 75% of respiratory NMFIs were treated with antibiotics. Although overall antibiotic prescriptions were similar between arms, for each antibiotic prescribed, "birthweight for gestational age" Z scores increased by 0.038 points (95% CI, .001-.074).Monthly IPTp-SP was associated with reduced respiratory NMFI incidence, revealing a potential nonmalarial mechanism of SP and supporting current World Health Organization recommendations for IPTp-SP, even in areas with high-grade SP resistance. While maternal respiratory NMFIs are known risk factors of lower birthweight, most women in our study were presumptively treated with antibiotics, masking the potential benefit of SP on birthweight mediated through preventing respiratory NMFIs.

  View details for DOI 10.1093/ofid/ofae143

  View details for PubMedID 38585183

  View details for PubMedCentralID PMC10995957

• Dramatic resurgence of malaria after 7 years of intensive vector control interventions in Eastern Uganda. medRxiv : the preprint server for health sciences Kamya, M. R., Nankabirwa, J. I., Arinaitwe, E., Rek, J., Zedi, M., Maiteki-Sebuguzi, C., Opigo, J., Staedke, S. G., Oruni, A., Donnelly, M. J., Greenhouse, B., Briggs, J., Krezanoski, P. J., Bousema, T., Rosenthal, P. J., Olwoch, P., Jagannathan, P., Rodriguez-Barraquer, I., Dorsey, G. 2024

  Abstract

  Tororo District, Uganda experienced a dramatic decrease in malaria burden from 2015-19 following 5 years of indoor residual spraying (IRS) with carbamate (Bendiocarb) and then organophosphate (Actellic) insecticides. However, a marked resurgence occurred in 2020, which coincided with a change to a clothianidin-based IRS formulations (Fludora Fusion/SumiShield). To quantify the magnitude of the resurgence, investigate causes, and evaluate the impact of a shift back to IRS with Actellic in 2023, we assessed changes in malaria metrics in regions within and near Tororo District.Malaria surveillance data from Nagongera Health Center, Tororo District was included from 2011-2023. In addition, a cohort of 667 residents from 84 houses was followed from August 2020 through September 2023 from an area bordering Tororo and neighboring Busia District, where IRS has never been implemented. Cohort participants underwent passive surveillance for clinical malaria and active surveillance for parasitemia every 28 days. Mosquitoes were collected in cohort households every 2 weeks using CDC light traps. Female Anopheles were speciated and tested for sporozoites and phenotypic insecticide resistance. Temporal comparisons of malaria metrics were stratified by geographic regions.At Nagongera Health Center average monthly malaria cases varied from 419 prior to implementation of IRS; to 56 after 5 years of IRS with Bendiocarb and Actellic; to 1591 after the change in IRS to Fludora Fusion/SumiShield; to 155 after a change back to Actellic. Among cohort participants living away from the border in Tororo, malaria incidence increased over 8-fold (0.36 vs. 2.97 episodes per person year, p<0.0001) and parasite prevalence increased over 4-fold (17% vs. 70%, p<0.0001) from 2021 to 2022 when Fludora Fusion/SumiShield was used. Incidence decreased almost 5-fold (2.97 vs. 0.70, p<0.0001) and prevalence decreased by 39% (70% vs. 43%, p<0.0001) after shifting back to Actellic. There was a similar pattern among those living near the border in Tororo, with increased incidence between 2021 and 2022 (0.93 vs. 2.40, p<0.0001) followed by a decrease after the change to Actellic (2.40 vs. 1.33, p<0.001). Among residents of Busia, malaria incidence did not change significantly over the 3 years of observation. Malaria resurgence in Tororo was temporally correlated with the replacement of An. gambiae s.s. by An. funestus as the primary vector, with a marked decrease in the density of An. funestus following the shift back to IRS with Actellic. In Busia, An. gambiae s.s. remained the primary vector throughout the observation period. Sporozoite rates were approximately 50% higher among An. funestus compared to the other common malaria vectors. Insecticide resistance phenotyping of An. funestus revealed high tolerance to clothianidin, but full susceptibility to Actellic.A dramatic resurgence of malaria in Tororo was temporally associated with a change to clothianidin-based IRS formulations and emergence of An. funestus as the predominant vector. Malaria decreased after a shift back to IRS with Actellic. This study highlights the ability of malaria vectors to rapidly circumvent control efforts and the importance of high-quality surveillance systems to assess the impact of malaria control interventions and generate timely, actionable data.

  View details for DOI 10.1101/2024.03.15.24304352

  View details for PubMedID 38559091

  View details for PubMedCentralID PMC10980127

• Editorial: Immune tolerance and human malaria. Frontiers in immunology Dobbs, K. R., Jagannathan, P., Dechavanne, C. 2024; 15: 1450480

  View details for DOI 10.3389/fimmu.2024.1450480

  View details for PubMedID 39026667

• Atypical B cells consist of subsets with distinct functional profiles. iScience Reyes, R. A., Batugedara, G., Dutta, P., Reers, A. B., Garza, R., Ssewanyana, I., Jagannathan, P., Feeney, M. E., Greenhouse, B., Bol, S., Ay, F., Bunnik, E. M. 2023; 26 (12): 108496

  Abstract

  Atypical B cells are a population of activated B cells that are commonly enriched in individuals with chronic immune activation but are also part of a normal immune response to infection or vaccination. To better define the role of atypical B cells in the human adaptive immune response, we performed single-cell sequencing of transcriptomes, cell surface markers, and B cell receptors in individuals with chronic exposure to the malaria parasite Plasmodium falciparum, a condition known to lead to accumulation of circulating atypical B cells. We identified three previously uncharacterized populations of atypical B cells with distinct transcriptional and functional profiles and observed marked differences among these three subsets in their ability to produce immunoglobulin G upon T-cell-dependent activation. Our findings help explain the conflicting observations in prior studies regarding the function of atypical B cells and highlight their different roles in the adaptive immune response in chronic inflammatory conditions.

  View details for DOI 10.1016/j.isci.2023.108496

  View details for PubMedID 38098745

• Safety and efficacy of inhaled interferon-β1a (SNG001) in adults with mild-to-moderate COVID-19: a randomized, controlled, phase II trial. EClinicalMedicine Jagannathan, P., Chew, K. W., Giganti, M. J., Hughes, M. D., Moser, C., Main, M. J., Monk, P. D., Javan, A. C., Li, J. Z., Fletcher, C. V., McCarthy, C., Wohl, D. A., Daar, E. S., Eron, J. J., Currier, J. S., Singh, U., Smith, D. M., Fischer, W. 2023; 65: 102250

  Abstract

  With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need.Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.govNCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021.The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm.In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia.The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  View details for DOI 10.1016/j.eclinm.2023.102250

  View details for PubMedID 37855026

  View details for PubMedCentralID PMC10579289

• Sex-Linked Differences in Malaria Risk Across the Lifespan. Current topics in microbiology and immunology Briggs, J., Murray, M., Nideffer, J., Jagannathan, P. 2023; 441: 185-208

  Abstract

  Despite the high burden of malaria worldwide, there is surprisingly scarce research on sex-based differences in malaria outside of pregnancy. A more thorough understanding of sexual dimorphism in malaria, and what underlies these sex-based differences, could elucidate the underlying mechanisms driving malaria pathogenesis and has the potential to inform malaria control efforts, including new vaccines. This review summarizes our current understanding of sex-based differences in the epidemiology of malaria across the lifespan, potential sex- or gender-based mechanisms driving these differences, and the knowledge gaps that need to be addressed.

  View details for DOI 10.1007/978-3-031-35139-6_7

  View details for PubMedID 37695429

  View details for PubMedCentralID 4157516

• The Tomato Brown Rugose Fruit Virus Movement Protein Gene Is a Novel Microbial Source Tracking Marker. Applied and environmental microbiology Natarajan, A., Fremin, B. J., Schmidtke, D. T., Wolfe, M. K., Zlitni, S., Graham, K. E., Brooks, E. F., Severyn, C. J., Sakamoto, K. M., Lacayo, N. J., Kuersten, S., Koble, J., Caves, G., Kaplan, I., Singh, U., Jagannathan, P., Rezvani, A. R., Bhatt, A. S., Boehm, A. B. 2023: e0058323

  Abstract

  Microbial source tracking (MST) identifies sources of fecal contamination in the environment using host-associated fecal markers. While there are numerous bacterial MST markers that can be used herein, there are few such viral markers. Here, we designed and tested novel viral MST markers based on tomato brown rugose fruit virus (ToBRFV) genomes. We assembled eight nearly complete genomes of ToBRFV from wastewater and stool samples from the San Francisco Bay Area in the United States. Next, we developed two novel probe-based reverse transcription-PCR (RT-PCR) assays based on conserved regions of the ToBRFV genome and tested the markers' sensitivities and specificities using human and non-human animal stool as well as wastewater. The ToBRFV markers are sensitive and specific; in human stool and wastewater, they are more prevalent and abundant than a commonly used viral marker, the pepper mild mottle virus (PMMoV) coat protein (CP) gene. We used the assays to detect fecal contamination in urban stormwater samples and found that the ToBRFV markers matched cross-assembly phage (crAssphage), an established viral MST marker, in prevalence across samples. Taken together, these results indicate that ToBRFV is a promising viral human-associated MST marker. IMPORTANCE Human exposure to fecal contamination in the environment can cause transmission of infectious diseases. Microbial source tracking (MST) can identify sources of fecal contamination so that contamination can be remediated and human exposures can be reduced. MST requires the use of host-associated MST markers. Here, we designed and tested novel MST markers from genomes of tomato brown rugose fruit virus (ToBRFV). The markers are sensitive and specific to human stool and highly abundant in human stool and wastewater samples.

  View details for DOI 10.1128/aem.00583-23

  View details for PubMedID 37404180

• Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design. PloS one Horwitz, L. I., Thaweethai, T., Brosnahan, S. B., Cicek, M. S., Fitzgerald, M. L., Goldman, J. D., Hess, R., Hodder, S. L., Jacoby, V. L., Jordan, M. R., Krishnan, J. A., Laiyemo, A. O., Metz, T. D., Nichols, L., Patzer, R. E., Sekar, A., Singer, N. G., Stiles, L. E., Taylor, B. S., Ahmed, S., Algren, H. A., Anglin, K., Aponte-Soto, L., Ashktorab, H., Bassett, I. V., Bedi, B., Bhadelia, N., Bime, C., Bind, M. C., Black, L. J., Blomkalns, A. L., Brim, H., Castro, M., Chan, J., Charney, A. W., Chen, B. K., Chen, L. Q., Chen, P., Chestek, D., Chibnik, L. B., Chow, D. C., Chu, H. Y., Clifton, R. G., Collins, S., Costantine, M. M., Cribbs, S. K., Deeks, S. G., Dickinson, J. D., Donohue, S. E., Durstenfeld, M. S., Emery, I. F., Erlandson, K. M., Facelli, J. C., Farah-Abraham, R., Finn, A. V., Fischer, M. S., Flaherman, V. J., Fleurimont, J., Fonseca, V., Gallagher, E. J., Gander, J. C., Gennaro, M. L., Gibson, K. S., Go, M., Goodman, S. N., Granger, J. P., Greenway, F. L., Hafner, J. W., Han, J. E., Harkins, M. S., Hauser, K. S., Heath, J. R., Hernandez, C. R., Ho, O., Hoffman, M. K., Hoover, S. E., Horowitz, C. R., Hsu, H., Hsue, P. Y., Hughes, B. L., Jagannathan, P., James, J. A., John, J., Jolley, S., Judd, S. E., Juskowich, J. J., Kanjilal, D. G., Karlson, E. W., Katz, S. D., Kelly, J. D., Kelly, S. W., Kim, A. Y., Kirwan, J. P., Knox, K. S., Kumar, A., Lamendola-Essel, M. F., Lanca, M., Lee-Lannotti, J. K., Lefebvre, R. C., Levy, B. D., Lin, J. Y., Logarbo, B. P., Logue, J. K., Longo, M. T., Luciano, C. A., Lutrick, K., Malakooti, S. K., Mallett, G., Maranga, G., Marathe, J. G., Marconi, V. C., Marshall, G. D., Martin, C. F., Martin, J. N., May, H. T., McComsey, G. A., McDonald, D., Mendez-Figueroa, H., Miele, L., Mittleman, M. A., Mohandas, S., Mouchati, C., Mullington, J. M., Nadkarni, G. N., Nahin, E. R., Neuman, R. B., Newman, L. T., Nguyen, A., Nikolich, J. Z., Ofotokun, I., Ogbogu, P. U., Palatnik, A., Palomares, K. T., Parimon, T., Parry, S., Parthasarathy, S., Patterson, T. F., Pearman, A., Peluso, M. J., Pemu, P., Pettker, C. M., Plunkett, B. A., Pogreba-Brown, K., Poppas, A., Porterfield, J. Z., Quigley, J. G., Quinn, D. K., Raissy, H., Rebello, C. J., Reddy, U. M., Reece, R., Reeder, H. T., Rischard, F. P., Rosas, J. M., Rosen, C. J., Rouphael, N. G., Rouse, D. J., Ruff, A. M., Saint Jean, C., Sandoval, G. J., Santana, J. L., Schlater, S. M., Sciurba, F. C., Selvaggi, C., Seshadri, S., Sesso, H. D., Shah, D. P., Shemesh, E., Sherif, Z. A., Shinnick, D. J., Simhan, H. N., Singh, U., Sowles, A., Subbian, V., Sun, J., Suthar, M. S., Teunis, L. J., Thorp, J. M., Ticotsky, A., Tita, A. T., Tragus, R., Tuttle, K. R., Urdaneta, A. E., Utz, P. J., VanWagoner, T. M., Vasey, A., Vernon, S. D., Vidal, C., Walker, T., Ward, H. D., Warren, D. E., Weeks, R. M., Weiner, S. J., Weyer, J. C., Wheeler, J. L., Whiteheart, S. W., Wiley, Z., Williams, N. J., Wisnivesky, J. P., Wood, J. C., Yee, L. M., Young, N. M., Zisis, S. N., Foulkes, A. S. 2023; 18 (6): e0286297

  Abstract

  SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.NCT05172024.

  View details for DOI 10.1371/journal.pone.0286297

  View details for PubMedID 37352211

  View details for PubMedCentralID PMC10289397

• Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC). eLife Mohandas, S., Jagannathan, P., Henrich, T. J., Sherif, Z. A., Bime, C., Quinlan, E., Portman, M. A., Gennaro, M., Rehman, J., RECOVER Mechanistic Pathways Task Force, Bradfute, S. B., Chen, B. K., Connors, T. J., Coombs, K., Gomez, C. R., Julg, B. D., Kim, C., Brian Reeves, W. 2023; 12

  Abstract

  With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.

  View details for DOI 10.7554/eLife.86014

  View details for PubMedID 37233729

• Regulation of fetal tolerance by KIR<SUP>+</SUP> regulatory CD8<SUP>+</SUP> T cells in human pregnancy Li, J., Li, L., Prunicki, M., Narasimhan, P., Mallajosyula, V., Kirosingh, A., Jagannathan, P., Winn, V., Nadeau, K., Gaw, S., Davis, M. M. AMER ASSOC IMMUNOLOGISTS. 2023

  View details for Web of Science ID 001106506502388

• Impact of high human genetic diversity in Africa on immunogenicity and efficacy of RTS,S/AS01 vaccine. Immunogenetics Tukwasibwe, S., Mboowa, G., Sserwadda, I., Nankabirwa, J. I., Arinaitwe, E., Ssewanyana, I., Taremwa, Y., Tumusiime, G., Kamya, M. R., Jagannathan, P., Nakimuli, A. 2023

  Abstract

  In modern medicine, vaccination is one of the most effective public health strategies to prevent infectious diseases. Indisputably, vaccines have saved millions of lives by reducing the burden of many serious infections such as polio, tuberculosis, measles, pneumonia, and tetanus. Despite the recent recommendation by the World Health Organization (WHO) to roll out RTS,S/AS01, this malaria vaccine still faces major challenges of variability in its efficacy partly due to high genetic variation in humans and malaria parasites. Immune responses to malaria vary between individuals and populations. Human genetic variation in immune system genes is the probable cause for this heterogeneity. In this review, we will focus on human genetic factors that determine variable responses to vaccination and how variation in immune system genes affect the immunogenicity and efficacy of the RTS,S/AS01 vaccine.

  View details for DOI 10.1007/s00251-023-01306-8

  View details for PubMedID 37084013

  View details for PubMedCentralID 7966294

• Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection. Immunity Gao, F., Mallajoysula, V., Arunachalam, P. S., van der Ploeg, K., Manohar, M., Röltgen, K., Yang, F., Wirz, O., Hoh, R., Haraguchi, E., Lee, J. Y., Willis, R., Ramachandiran, V., Li, J., Kathuria, K. R., Li, C., Lee, A. S., Shah, M. M., Sindher, S. B., Gonzalez, J., Altman, J. D., Wang, T. T., Boyd, S. D., Pulendran, B., Jagannathan, P., Nadeau, K. C., Davis, M. M. 2023

  Abstract

  T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring 1 week post the second vaccination (boost), whereas CD8+ T cells peaked 2 weeks later. These peripheral T cell responses were elevated compared with COVID-19 patients. We also found that previous SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that previous infection can influence the T cell response to vaccination.

  View details for DOI 10.1016/j.immuni.2023.03.005

  View details for PubMedID 36996809

  View details for PubMedCentralID PMC10017386

• Can we reduce malaria in pregnancy and improve birth outcomes? Lancet (London, England) Kakuru, A., Jagannathan, P. 2023

  View details for DOI 10.1016/S0140-6736(23)00101-0

  View details for PubMedID 36913960

• Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230. Immunity Ivanochko, D., Fabra-García, A., Teelen, K., van de Vegte-Bolmer, M., van Gemert, G. J., Newton, J., Semesi, A., de Bruijni, M., Bolscher, J., Ramjith, J., Szabat, M., Vogt, S., Kraft, L., Duncan, S., Lee, S. M., Kamya, M. R., Feeney, M. E., Jagannathan, P., Greenhouse, B., Sauerwein, R. W., Richter King, C., MacGill, R. S., Bousema, T., Jore, M. M., Julien, J. P. 2023; 56 (2): 420-432.e7

  Abstract

  Pfs230 is essential for Plasmodium falciparum transmission to mosquitoes and is the protein targeted by the most advanced malaria-transmission-blocking vaccine candidate. Prior understanding of functional epitopes on Pfs230 is based on two monoclonal antibodies (mAbs) with moderate transmission-reducing activity (TRA), elicited from subunit immunization. Here, we screened the B cell repertoire of two naturally exposed individuals possessing serum TRA and identified five potent mAbs from sixteen Pfs230 domain-1-specific mAbs. Structures of three potent and three low-activity antibodies bound to Pfs230 domain 1 revealed four distinct epitopes. Highly potent mAbs from natural infection recognized a common conformational epitope that is highly conserved across P. falciparum field isolates, while antibodies with negligible TRA derived from natural infection or immunization recognized three distinct sites. Our study provides molecular blueprints describing P. falciparum TRA, informed by contrasting potent and non-functional epitopes elicited by natural exposure and vaccination.

  View details for DOI 10.1016/j.immuni.2023.01.013

  View details for PubMedID 36792575

• Highly potent, naturally acquired human monoclonal antibodies against Pfs48/45 block Plasmodium falciparum transmission to mosquitoes. Immunity Fabra-García, A., Hailemariam, S., de Jong, R. M., Janssen, K., Teelen, K., van de Vegte-Bolmer, M., van Gemert, G. J., Ivanochko, D., Semesi, A., McLeod, B., Vos, M. W., de Bruijni, M. H., Bolscher, J. M., Szabat, M., Vogt, S., Kraft, L., Duncan, S., Kamya, M. R., Feeney, M. E., Jagannathan, P., Greenhouse, B., Dechering, K. J., Sauerwein, R. W., King, C. R., MacGill, R. S., Bousema, T., Julien, J. P., Jore, M. M. 2023; 56 (2): 406-419.e7

  Abstract

  Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite development in the mosquito, thereby blocking onward transmission, and provide a much-needed tool for malaria control and elimination. The parasite surface protein Pfs48/45 is a leading TBV candidate. Here, we isolated and characterized a panel of 81 human Pfs48/45-specific monoclonal antibodies (mAbs) from donors naturally exposed to Plasmodium parasites. Genetically diverse mAbs against each of the three domains (D1-D3) of Pfs48/45 were identified. The most potent mAbs targeted D1 and D3 and achieved >80% transmission-reducing activity in standard membrane-feeding assays, at 10 and 2 μg/mL, respectively. Co-crystal structures of D3 in complex with four different mAbs delineated two conserved protective epitopes. Altogether, these Pfs48/45-specific human mAbs provide important insight into protective and non-protective epitopes that can further our understanding of transmission and inform the design of refined malaria transmission-blocking vaccine candidates.

  View details for DOI 10.1016/j.immuni.2023.01.009

  View details for PubMedID 36792574

• Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference. Open forum infectious diseases Walter, K. S., Kim, E., Verma, R., Altamirano, J., Leary, S., Carrington, Y. J., Jagannathan, P., Singh, U., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Andrews, J. R. 2023; 10 (2): ofad001

  Abstract

  The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference.We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage.Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0-40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17-208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02-1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28-.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23-1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants.Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.

  View details for DOI 10.1093/ofid/ofad001

  View details for PubMedID 36751652

  View details for PubMedCentralID PMC9898879

• Seroprevalence of Antibodies to SARS-CoV-2 in Rural Households in Eastern Uganda, 2020-2022. JAMA network open Briggs, J., Takahashi, S., Nayebare, P., Cuu, G., Rek, J., Zedi, M., Kizza, T., Arinaitwe, E., Nankabirwa, J. I., Kamya, M., Jagannathan, P., Jacobson, K., Rosenthal, P. J., Dorsey, G., Greenhouse, B., Ssewanyana, I., Rodriguez-Barraquer, I. 2023; 6 (2): e2255978

  Abstract

  Importance: Estimating the true burden of SARS-CoV-2 infection has been difficult in sub-Saharan Africa owing to asymptomatic infections and inadequate testing capacity. Antibody responses from serologic surveys can provide an estimate of SARS-CoV-2 exposure at the population level.Objective: To estimate SARS-CoV-2 seroprevalence, attack rates, and reinfection in eastern Uganda using serologic surveillance from 2020 to early 2022.Design, Setting, and Participants: This cohort study was conducted in the Tororo and Busia districts of eastern Uganda. Plasma samples from participants in the Program for Resistance, Immunology, Surveillance, and Modeling of Malaria in Uganda Border Cohort were obtained at 4 sampling intervals: October to November 2020, March to April 2021, August to September 2021, and February to March 2022. Each participant contributed up to 4 time points for SARS-CoV-2 serology, with almost half of all participants contributing at all 4 time points, and almost 90% contributing at 3 or 4 time points. Information on SARS-CoV-2 vaccination status was collected from participants, with the earliest reported vaccinations in the cohort occurring in May 2021.Main Outcomes and Measures: The main outcomes of this study were antibody responses to the SARS-CoV-2 spike protein as measured with a bead-based serologic assay. Individual-level outcomes were aggregated to population-level SARS-CoV-2 seroprevalence, attack rates, and boosting rates. Estimates were weighted by the local age distribution according to census data.Results: A total of 1483 samples from 441 participants living in 76 households were tested. Of the 441 participants, 245 (55.6%) were female, and their mean (SD) age was 16.04 (16.04) years. By the end of the Delta wave and before widespread vaccination, adjusted SARS-CoV-2 seroprevalence was 67.7% (95% credible interval [CrI], 62.5%-72.6%) in the study population. During the subsequent Omicron wave, 84.8% (95% CrI, 67.9%-93.7%) of unvaccinated, previously seronegative individuals were infected for the first time, and 50.8% (95% CrI, 40.6%-59.7%) of unvaccinated, already seropositive individuals were likely reinfected, leading to an overall seropositivity of 96.0% (95% CrI, 93.4%-97.9%) in this population. These results suggest a lower probability of reinfection in individuals with higher preexisting antibody levels. There was evidence of household clustering of SARS-CoV-2 seroconversion. No significant associations were found between SARS-CoV-2 seroconversion and gender, household size, or recent Plasmodium falciparum malaria exposure.Conclusions and Relevance: In this cohort study in a rural population in eastern Uganda, there was evidence of very high SARS-CoV-2 infection rates throughout the pandemic inconsistent with national level case data and high reinfection rates during the Omicron wave.

  View details for DOI 10.1001/jamanetworkopen.2022.55978

  View details for PubMedID 36790811

• Tomato brown rugose fruit virus Mo gene is a novel microbial source tracking marker. bioRxiv : the preprint server for biology Natarajan, A., Fremin, B. J., Schmidtke, D. T., Wolfe, M. K., Zlitni, S., Graham, K. E., Brooks, E. F., Severyn, C. J., Sakamoto, K. M., Lacayo, N. J., Kuersten, S., Koble, J., Caves, G., Kaplan, I., Singh, U., Jagannathan, P., Rezvani, A. R., Bhatt, A. S., Boehm, A. B. 2023

  Abstract

  Microbial source tracking (MST) identifies sources of fecal contamination in the environment using fecal host-associated markers. While there are numerous bacterial MST markers, there are few viral markers. Here we design and test novel viral MST markers based on tomato brown rugose fruit virus (ToBRFV) genomes. We assembled eight nearly complete genomes of ToBRFV from wastewater and stool samples from the San Francisco Bay Area in the United States of America. Next, we developed two novel probe-based RT-PCR assays based on conserved regions of the ToBRFV genome, and tested the markers’ sensitivities and specificities using human and non-human animal stool as well as wastewater. TheToBRFV markers are sensitive and specific; in human stool and wastewater, they are more prevalent and abundant than a currently used marker, the pepper mild mottle virus (PMMoV) coat protein (CP) gene. We applied the assays to detect fecal contamination in urban stormwater samples and found that the ToBRFV markers matched cross-assembly phage (crAssphage), an established viral MST marker, in prevalence across samples. Taken together, ToBRFV is a promising viral human-associated MST marker.Human exposure to fecal contamination in the environment can cause transmission of infectious diseases. Microbial source tracking (MST) can identify sources of fecal contamination so that contamination can be remediated and human exposures can be reduced. MST requires the use of fecal host-associated MST markers. Here we design and test novel MST markers from genomes of tomato brown rugose fruit virus (ToBRFV). The markers are sensitive and specific to human stool, and highly abundant in human stool and wastewater samples.

  View details for DOI 10.1101/2023.01.09.523366

  View details for PubMedID 36712100

  View details for PubMedCentralID PMC9882089

• Type I regulatory T cells in malaria: of mice and men Jason Nideffer, Prasanna Jagannathan JOURNAL OF CLINICAL INVESTIGATION Nideffer, J., Jagannathan, P. 2023; 133 (1)

  Abstract

  Type I regulatory T (Tr1) cells are a population of regulatory CD4+ T cells implicated in the suppression of pathological immune responses across multiple diseases, but a unifying transcriptional signature of Tr1 identity across disease contexts has not been characterized. In this issue of the JCI, Edward, Ng, and colleagues identified a conserved transcriptional signature that distinguished Tr1 (IL-10+IFN-γ+) from Th1 (IL-10-IFN-γ+) cells in human and mouse malaria. This signature implicated genes encoding inhibitory receptors - including CTLA-4 and LAG-3 - and transcription factors - including cMAF. The authors identified coinhibitory receptor expression that distinguished Tr1 cells from other CD4+ T cell subsets. Furthermore, cMAF - and, to a lesser extent, BLIMP-1 - promoted IL-10 production in human CD4+ T cells. BLIMP-1 also played a role in supporting the expression of inhibitory receptors. These findings describe a few key features that seem to be conserved by Tr1 cells across multiple species, disease contexts, and marker definitions.

  View details for DOI 10.1172/JCI166019

  View details for Web of Science ID 000992543100002

  View details for PubMedID 36594472

  View details for PubMedCentralID PMC9797330

• Metagenomic next-generation sequencing to characterize potential etiologies of non-malarial fever in a cohort living in a high malaria burden area of Uganda. PLOS global public health Mwakibete, L., Takahashi, S., Ahyong, V., Black, A., Rek, J., Ssewanyana, I., Kamya, M., Dorsey, G., Jagannathan, P., Rodriguez-Barraquer, I., Tato, C. M., Greenhouse, B. 2023; 3 (5): e0001675

  Abstract

  Causes of non-malarial fevers in sub-Saharan Africa remain understudied. We hypothesized that metagenomic next-generation sequencing (mNGS), which allows for broad genomic-level detection of infectious agents in a biological sample, can systematically identify potential causes of non-malarial fevers. The 212 participants in this study were of all ages and were enrolled in a longitudinal malaria cohort in eastern Uganda. Between December 2020 and August 2021, respiratory swabs and plasma samples were collected at 313 study visits where participants presented with fever and were negative for malaria by microscopy. Samples were analyzed using CZ ID, a web-based platform for microbial detection in mNGS data. Overall, viral pathogens were detected at 123 of 313 visits (39%). SARS-CoV-2 was detected at 11 visits, from which full viral genomes were recovered from nine. Other prevalent viruses included Influenza A (14 visits), RSV (12 visits), and three of the four strains of seasonal coronaviruses (6 visits). Notably, 11 influenza cases occurred between May and July 2021, coinciding with when the Delta variant of SARS-CoV-2 was circulating in this population. The primary limitation of this study is that we were unable to estimate the contribution of bacterial microbes to non-malarial fevers, due to the difficulty of distinguishing bacterial microbes that were pathogenic from those that were commensal or contaminants. These results revealed the co-circulation of multiple viral pathogens likely associated with fever in the cohort during this time period. This study illustrates the utility of mNGS in elucidating the multiple potential causes of non-malarial febrile illness. A better understanding of the pathogen landscape in different settings and age groups could aid in informing diagnostics, case management, and public health surveillance systems.

  View details for DOI 10.1371/journal.pgph.0001675

  View details for PubMedID 37134083

• Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA Thaweethai, T., Jolley, S. E., Karlson, E. W., Levitan, E. B., Levy, B., McComsey, G. A., McCorkell, L., Nadkarni, G. N., Parthasarathy, S., Singh, U., Walker, T. A., Selvaggi, C. A., Shinnick, D. J., Schulte, C. C., Atchley-Challenner, R., Horwitz, L. I., Foulkes, A. S., RECOVER Consortium, Alba, G. A., Alicic, R., Altman, N., Anglin, K., Argueta, U., Ashktorab, H., Baslet, G., Bassett, I. V., Bateman, L., Bedi, B., Bhattacharyya, S., Bind, M., Blomkalns, A. L., Bonilla, H., Bush, P. A., Castro, M., Chan, J., Charney, A. W., Chen, P., Chibnik, L. B., Chu, H. Y., Clifton, R. G., Costantine, M. M., Cribbs, S. K., Davila Nieves, S. I., Deeks, S. G., Duven, A., Emery, I. F., Erdmann, N., Erlandson, K. M., Ernst, K. C., Farah-Abraham, R., Farner, C. E., Feuerriegel, E. M., Fleurimont, J., Fonseca, V., Franko, N., Gainer, V., Gander, J. C., Gardner, E. M., Geng, L. N., Gibson, K. S., Go, M., Goldman, J. D., Grebe, H., Greenway, F. L., Habli, M., Hafner, J., Han, J. E., Hanson, K. A., Heath, J., Hernandez, C., Hess, R., Hodder, S. L., Hoffman, M. K., Hoover, S. E., Huang, B., Hughes, B. L., Jagannathan, P., John, J., Jordan, M. R., Katz, S. D., Kaufman, E. S., Kelly, J. D., Kelly, S. W., Kemp, M. M., Kirwan, J. P., Klein, J. D., Knox, K. S., Krishnan, J. A., Kumar, A., Laiyemo, A. O., Lambert, A. A., Lanca, M., Lee-Iannotti, J. K., Logarbo, B. P., Longo, M. T., Luciano, C. A., Lutrick, K., Maley, J. H., Marathe, J. G., Marconi, V., Marshall, G. D., Martin, C. F., Matusov, Y., Mehari, A., Mendez-Figueroa, H., Mermelstein, R., Metz, T. D., Morse, R., Mosier, J., Mouchati, C., Mullington, J., Murphy, S. N., Neuman, R. B., Nikolich, J. Z., Ofotokun, I., Ojemakinde, E., Palatnik, A., Palomares, K., Parimon, T., Parry, S., Patterson, J. E., Patterson, T. F., Patzer, R. E., Peluso, M. J., Pemu, P., Pettker, C. M., Plunkett, B. A., Pogreba-Brown, K., Poppas, A., Quigley, J. G., Reddy, U., Reece, R., Reeder, H., Reeves, W. B., Reiman, E. M., Rischard, F., Rosand, J., Rouse, D. J., Ruff, A., Saade, G., Sandoval, G. J., Schlater, S. M., Shepherd, F., Sherif, Z. A., Simhan, H., Singer, N. G., Skupski, D. W., Sowles, A., Sparks, J. A., Sukhera, F. I., Taylor, B. S., Teunis, L., Thomas, R. J., Thorp, J. M., Thuluvath, P., Ticotsky, A., Tita, A. T., Tuttle, K. R., Urdaneta, A. E., Valdivieso, D., VanWagoner, T. M., Vasey, A., Verduzco-Gutierrez, M., Wallace, Z. S., Ward, H. D., Warren, D. E., Weiner, S. J., Welch, S., Whiteheart, S. W., Wiley, Z., Wisnivesky, J. P., Yee, L. M., Zisis, S. 2023

  Abstract

  Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.Exposure: SARS-CoV-2 infection.Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds).Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

  View details for DOI 10.1001/jama.2023.8823

  View details for PubMedID 37278994

• Predictors of SARS-CoV-2 RNA From Nasopharyngeal Swabs and Concordance With Other Compartments in Nonhospitalized Adults With Mild to Moderate COVID-19. Open forum infectious diseases Moser, C., Li, J. Z., Eron, J. J., Aga, E., Daar, E. S., Wohl, D. A., Coombs, R. W., Javan, A. C., Bender Ignacio, R. A., Jagannathan, P., Ritz, J., Sieg, S. F., Parikh, U. M., Hughes, M. D., Currier, J. S., Smith, D. M., Chew, K. W. 2022; 9 (11): ofac618

  Abstract

  Identifying characteristics associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding may be useful to understand viral compartmentalization, disease pathogenesis, and risks for viral transmission.Participants were enrolled August 2020 to February 2021 in ACTIV-2/A5401, a placebo-controlled platform trial evaluating investigational therapies for mild-to-moderate coronavirus disease 2019 (COVID-19), and underwent quantitative SARS-CoV-2 RNA testing on nasopharyngeal and anterior nasal swabs, oral wash/saliva, and plasma at entry (day 0, pretreatment) and days 3, 7, 14, and 28. Concordance of RNA levels (copies/mL) across compartments and predictors of nasopharyngeal RNA levels were assessed at entry (n = 537). Predictors of changes over time were evaluated among placebo recipients (n = 265) with censored linear regression models.Nasopharyngeal and anterior nasal RNA levels at study entry were highly correlated (r = 0.84); higher levels of both were associated with greater detection of RNA in plasma and oral wash/saliva. Older age, White non-Hispanic race/ethnicity, lower body mass index (BMI), SARS-CoV-2 immunoglobulin G seronegativity, and shorter prior symptom duration were associated with higher nasopharyngeal RNA at entry. In adjusted models, body mass index and race/ethnicity associations were attenuated, but the association with age remained (for every 10 years older, mean nasopharyngeal RNA was 0.27 log10 copies/mL higher; P < .001). Examining longitudinal viral RNA levels among placebo recipients, women had faster declines in nasopharyngeal RNA than men (mean change, -2.0 vs -1.3 log10 copies/mL, entry to day 3; P < .001).SARS-CoV-2 RNA shedding was concordant across compartments. Age was strongly associated with viral shedding, and men had slower viral clearance than women, which could explain sex differences in acute COVID-19 outcomes.

  View details for DOI 10.1093/ofid/ofac618

  View details for PubMedID 36467293

  View details for PubMedCentralID PMC9709705

• Age-dependent changes in circulating Tfh cells influence development of functional malaria antibodies in children. Nature communications Chan, J., Loughland, J. R., de la Parte, L., Okano, S., Ssewanyana, I., Nalubega, M., Nankya, F., Musinguzi, K., Rek, J., Arinaitwe, E., Tipping, P., Bourke, P., Andrew, D., Dooley, N., SheelaNair, A., Wines, B. D., Hogarth, P. M., Beeson, J. G., Greenhouse, B., Dorsey, G., Kamya, M., Hartel, G., Minigo, G., Feeney, M., Jagannathan, P., Boyle, M. J. 2022; 13 (1): 4159

  Abstract

  T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies are boosted in children with current infection, and are higher in females. The children with the very highest antibody levels have increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.

  View details for DOI 10.1038/s41467-022-31880-6

  View details for PubMedID 35851033

• Malaria in 2022: Increasing challenges, cautious optimism. Nature communications Jagannathan, P., Kakuru, A. 2022; 13 (1): 2678

  View details for DOI 10.1038/s41467-022-30133-w

  View details for PubMedID 35562368

• Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Holubar, M., Subramanian, A., Purington, N., Hedlin, H., Bunning, B., Walter, K. S., Bonilla, H., Boumis, A., Chen, M., Clinton, K., Dewhurst, L., Epstein, C., Jagannathan, P., Kaszynski, R. H., Panu, L., Parsonnet, J., Ponder, E. L., Quintero, O., Sefton, E., Singh, U., Soberanis, L., Truong, H., Andrews, J. R., Desai, M., Khosla, C., Maldonado, Y. 2022

  Abstract

  Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries.We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1: 1 to receive placebo or favipiravir (1800mg BID Day 1, 800 mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis.From July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48-1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54-1.29; sustained: HR 0.87, 95% CI 0.52-1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment.Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

  View details for DOI 10.1093/cid/ciac312

  View details for PubMedID 35446944

• Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med (New York, N.Y.) Natarajan, A., Zlitni, S., Brooks, E. F., Vance, S. E., Dahlen, A., Hedlin, H., Park, R. M., Han, A., Schmidtke, D. T., Verma, R., Jacobson, K. B., Parsonnet, J., Bonilla, H. F., Singh, U., Pinsky, B. A., Andrews, J. R., Jagannathan, P., Bhatt, A. S. 2022

  Abstract

  COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1,2 SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.3-5 Although much is known about early fecal RNA shedding, little is known about the long term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.6.We analyze the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlate shedding with disease symptoms.Fecal SARS-CoV-2 RNA is detected in 49.2% [95% Confidence interval = 38.2%-60.3%] of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at and after 4 months, 12.7% [8.5%-18.4%] of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% [2.0%-7.3%] shed at 7 months. Finally, we find that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA.The extended presence of viral RNA in feces, but not respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract, and that this infection can be prolonged in a subset of individuals with COVID-19.

  View details for DOI 10.1016/j.medj.2022.04.001

  View details for PubMedID 35434682

  View details for PubMedCentralID PMC9005383

• Targeted newborn metabolomics: prediction of gestational age from cord blood. Journal of perinatology : official journal of the California Perinatal Association Jasper, E. A., Oltman, S. P., Rogers, E. E., Dagle, J. M., Murray, J. C., Kamya, M., Kakuru, A., Kajubi, R., Ochieng, T., Adrama, H., Okitwi, M., Olwoch, P., Jagannathan, P., Clark, T. D., Dorsey, G., Ruel, T., Jelliffe-Pawlowski, L. L., Ryckman, K. K. 1800

  Abstract

  OBJECTIVE: Our study sought to determine whether metabolites from a retrospective collection of banked cord blood specimens could accurately estimate gestational age and to validate these findings in cord blood samples from Busia, Uganda.STUDY DESIGN: Forty-seven metabolites were measured by tandem mass spectrometry or enzymatic assays from 942 banked cord blood samples. Multiple linear regression was performed, and the best model was used to predict gestational age, in weeks, for 150 newborns from Busia, Uganda.RESULTS: The model including metabolites and birthweight, predicted the gestational ages within 2 weeks for 76.7% of the Ugandan cohort. Importantly, this model estimated the prevalence of preterm birth <34 weeks closer to the actual prevalence (4.67% and 4.00%, respectively) than a model with only birthweight which overestimates the prevalence by 283%.CONCLUSION: Models that include cord blood metabolites and birth weight appear to offer improvement in gestational age estimation over birth weight alone.

  View details for DOI 10.1038/s41372-021-01253-w

  View details for PubMedID 35067676

• Gender difference in the incidence of malaria diagnosed at public health facilities in Uganda. Malaria journal Okiring, J., Epstein, A., Namuganga, J. F., Kamya, E. V., Nabende, I., Nassali, M., Sserwanga, A., Gonahasa, S., Muwema, M., Kiwuwa, S. M., Staedke, S. G., Kamya, M. R., Nankabirwa, J. I., Briggs, J., Jagannathan, P., Dorsey, G. 1800; 21 (1): 22

  Abstract

  BACKGROUND: Routine malaria surveillance data in Africa primarily come from public health facilities reporting to national health management information systems. Although information on gender is routinely collected from patients presenting to these health facilities, stratification of malaria surveillance data by gender is rarely done. This study evaluated gender difference among patients diagnosed with parasitological confirmed malaria at public health facilities in Uganda.METHODS: This study utilized individual level patient data collected from January 2020 through April 2021 at 12 public health facilities in Uganda and cross-sectional surveys conducted in target areas around these facilities in April 2021. Associations between gender and the incidence of malaria and non-malarial visits captured at the health facilities from patients residing within the target areas were estimated using poisson regression models controlling for seasonality. Associations between gender and data on health-seeking behaviour from the cross-sectional surveys were estimated using poisson regression models controlling for seasonality.RESULTS: Overall, incidence of malaria diagnosed per 1000 person years was 735 among females and 449 among males (IRR=1.72, 95% CI 1.68-1.77, p<0.001), with larger differences among those 15-39years (IRR=2.46, 95% CI 2.34-2.58, p<0.001) and over 39years (IRR=2.26, 95% CI 2.05-2.50, p<0.001) compared to those under 15years (IRR=1.46, 95% CI 1.41-1.50, p<0.001). Female gender was also associated with a higher incidence of visits where malaria was not suspected (IRR=1.77, 95% CI 1.71-1.83, p<0.001), with a similar pattern across age strata. These associations were consistent across the 12 individual health centres. From the cross-sectional surveys, females were more likely than males to report fever in the past 2weeks and seek care at the local health centre (7.5% vs. 4.7%, p=0.001) with these associations significant for those 15-39years (RR=2.49, 95% CI 1.17-5.31, p=0.018) and over 39years (RR=2.56, 95% CI 1.00-6.54, p=0.049).CONCLUSIONS: Females disproportionately contribute to the burden of malaria diagnosed at public health facilities in Uganda, especially once they reach childbearing age. Contributing factors included more frequent visits to these facilities independent of malaria and a higher reported risk of seeking care at these facilities for febrile illnesses.

  View details for DOI 10.1186/s12936-022-04046-4

  View details for PubMedID 35062952

• Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity. Science translational medicine Chakraborty, S., Gonzalez, J. C., Sievers, B. L., Mallajosyula, V., Chakraborty, S., Dubey, M., Ashraf, U., Cheng, B. Y., Kathale, N., Tran, K. Q., Scallan, C., Sinnott, A., Cassidy, A., Chen, S. T., Gelbart, T., Gao, F., Golan, Y., Ji, X., Kim-Schulze, S., Prahl, M., Gaw, S. L., Gnjatic, S., Marron, T. U., Merad, M., Arunachalam, P. S., Boyd, S. D., Davis, M. M., Holubar, M., Khosla, C., Maecker, H. T., Maldonado, Y., Mellins, E. D., Nadeau, K. C., Pulendran, B., Singh, U., Subramanian, A., Utz, P. J., Sherwood, R., Zhang, S., Jagannathan, P., Tan, G. S., Wang, T. T. 1800: eabm7853

  Abstract

  A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc gamma receptor (FcgammaR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcgammaR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.

  View details for DOI 10.1126/scitranslmed.abm7853

  View details for PubMedID 35040666

• Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses. Science translational medicine Sievers, B. L., Chakraborty, S., Xue, Y., Gelbart, T., Gonzalez, J. C., Cassidy, A. G., Golan, Y., Prahl, M., Gaw, S. L., Arunachalam, P. S., Blish, C. A., Boyd, S. D., Davis, M. M., Jagannathan, P., Nadeau, K. C., Pulendran, B., Singh, U., Scheuermann, R. H., Frieman, M. B., Vashee, S., Wang, T. T., Tan, G. S. 1800: eabn7842

  Abstract

  Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that possess mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by pre-existing immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wildtype (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.

  View details for DOI 10.1126/scitranslmed.abn7842

  View details for PubMedID 35025672

• Long Term Accuracy of SARS-CoV-2 Interferon-γ Release Assay and its Application in Household Investigation. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Murugesan, K., Jagannathan, P., Altamirano, J., Maldonado, Y. A., Bonilla, H. F., Jacobson, K. B., Parsonnet, J., Andrews, J. R., Shi, R. Z., Boyd, S., Pinsky, B. A., Singh, U., Banaei, N. 2022

  Abstract

  An immunodiagnostic assay that sensitively detects a cell-mediated immune response to SARS-CoV-2 is needed for epidemiological investigation and for clinical assessment of T cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses.The performance of a whole blood interferon-gamma (IFN-γ) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific T cells was evaluated in COVID-19 convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen.The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI] 79.0-89.0) and 86.6% (123/142; 95% CI;80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI 64.4-89.2) at 10 months post-infection (P<0.01). The IFN-γ response remained relatively robust at 10 months post-infection (3.8 vs. 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of +50% (95% CI +25.4-+74.6) and +21.7% (95% CI, +9.23-+42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts.The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.

  View details for DOI 10.1093/cid/ciac045

  View details for PubMedID 35079772

• Piperaquine induced QTc prolongation decreases with repeated monthly dihydroartemisinin-piperaquine dosing in pregnant Ugandan women. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Hughes, E., Wallender, E., Kajubi, R., Jagannathan, P., Ochieng, T., Kakuru, A., Kamya, M. R., Clark, T. D., Rosenthal, P. J., Dorsey, G., Aweeka, F., Savic, R. M. 2021

  Abstract

  BACKGROUND: Intermittent preventive treatment with monthly dihydroartemisinin-piperaquine (DHA-PQ) is highly effective at preventing both malaria during pregnancy and placental malaria. Piperaquine prolongs the corrected QT interval (QTc), and it is possible that repeated monthly dosing could lead to progressive QTc prolongation. Intensive characterization of the relationship between piperaquine concentration and QTc interval throughout pregnancy can inform effective and safe prevention guidelines.METHODS: Data were collected from a randomized controlled trial, where pregnant Ugandan women received malaria chemoprevention with monthly DHA-PQ (120/960mg DHA/PQ; n=373) or sulfadoxine-pyrimethamine (1500/75mg S/P; n=375) during the second and third trimesters of pregnancy. Monthly trough piperaquine samples were collected throughout pregnancy and pre- and post-dose electrocardiograms were recorded at 20, 28 and 36 weeks gestation in each women. The PK-QTc relationship for piperaquine and QTc for SP was assessed using nonlinear mixed effects modeling.RESULTS: A positive linear relationship between piperaquine concentration and Frederica corrected QTc interval was identified. This relationship progressively decreased from a 4.42 to 3.28 to 2.13 msec increase per 100ng/mL increase in piperaquine concentration at 20, 28 and 36 weeks gestation, respectively. Furthermore, 61% (n=183) of women had a smaller change in QTc at week 36 compared to week 20. Nine women given DHA-PQ had grade 3-4 cardiac adverse events. SP was not associated with any change in QTc.CONCLUSIONS: Repeated DHA-PQ dosing did not result in an increased risk of QTc prolongation and the post-dose QTc intervals progressively decreased. Monthly dosing of DHA-PQ in pregnant women carries minimal risk of QTc prolongation.

  View details for DOI 10.1093/cid/ciab965

  View details for PubMedID 34864925

• Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children. Nature communications Wallender, E., Ali, A. M., Hughes, E., Kakuru, A., Jagannathan, P., Muhindo, M. K., Opira, B., Whalen, M., Huang, L., Duvalsaint, M., Legac, J., Kamya, M. R., Dorsey, G., Aweeka, F., Rosenthal, P. J., Savic, R. M. 2021; 12 (1): 6714

  Abstract

  Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n=4573), malaria incidence data (n=326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n=184) or every 4 weeks (n=96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84-99%). A PPQ level of 15.4ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.

  View details for DOI 10.1038/s41467-021-27051-8

  View details for PubMedID 34795281

• DIMINISHED V delta 2+delta gamma T CELL CYTOKINE PRODUCTION AND DEGRANULATION FOLLOWING IN VITRO MALARIA EXPOSURE Dantzler, K., Klemm, S., Rek, J., Nankya, F., Ssewanyana, I., Kamya, M., Greenhouse, B., Dorsey, G., Feeney, M., Greenleaf, W., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2021: 16

  View details for Web of Science ID 000778105601047

• MALARIA-DRIVEN EXPANSION OF MATURE, SHORT-LIVED FUNCTIONAL CD56NEG NK CELLS CORRELATES WITH CLINICAL IMMUNITY TO MALARIA Ty, M., de la Parte, L., Dantzler, K., van der Ploeg, K., Callaway, P., Tukwasibwe, S., Rek, J., Arinaitwe, E., Ssewanyana, I., Nankya, F., Musinguzi, K., Dorsey, G., Boyle, M., Feeney, M., Kamya, M., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2021: 16-17

  View details for Web of Science ID 000778105601048

• SEX-BASED IMMUNOLOGICAL DIFFERENCES AMONG MALARIA-EXPOSED UGANDANS INCLUDES ABERRANT HEMATOPOIESIS Nideffer, J., Ty, M., Nayebare, P., Nankya, F., Musinguzi, K., Briggs, J., Greenhouse, B., John, R., Kamya, M., Dorsey, G., Ssewanyana, I., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2021: 292

  View details for Web of Science ID 000778105603001

• IDENTIFYING AN OPTIMAL DIHYDROARTEMISININ-PIPERAQUINE DOSING REGIMEN FOR MALARIA PREVENTION IN YOUNG UGANDAN CHILDREN Wallender, E., Ali, A., Hughes, E., Kakuru, A., Jagannathan, P., Muhindo, M., Opira, B., Whalen, M., Huang, L., Kamya, M., Dorsey, G., Aweeka, F., Rosenthal, P. J., Savic, R. AMER SOC TROP MED & HYGIENE. 2021: 367

  View details for Web of Science ID 000778105603239

• PERIPHERAL PLASMODIUM FALCIPARUM INFECTION IN EARLY PREGNANCY IS ASSOCIATED WITH INCREASED MATERNAL MICROCHIMERISM IN THE OFFSPRING Simon, N., Shallat, J., Houck, J., Jagannathan, P., Prahl, M., Muhindo, M., Kakuru, A., Olwoch, P., Feeney, M., Harrington, W. AMER SOC TROP MED & HYGIENE. 2021: 7

  View details for Web of Science ID 000778105601020

• CELLULAR CORRELATES FOR PROTECTION AGAINST MALARIA ACQUIRED ACROSS MULTIPLE PREGNANCIES Kirosingh, A., De La Parte, L., Ty, M., Kakuru, A., Muhindo, M. K., Thulin, N., Kamya, M., Feeney, M., Dorsey, G., Wang, T., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2021: 219

  View details for Web of Science ID 000778105602375

• New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nature communications Chang, S. E., Feng, A., Meng, W., Apostolidis, S. A., Mack, E., Artandi, M., Barman, L., Bennett, K., Chakraborty, S., Chang, I., Cheung, P., Chinthrajah, S., Dhingra, S., Do, E., Finck, A., Gaano, A., GeSSner, R., Giannini, H. M., Gonzalez, J., Greib, S., Gundisch, M., Hsu, A. R., Kuo, A., Manohar, M., Mao, R., Neeli, I., Neubauer, A., Oniyide, O., Powell, A. E., Puri, R., Renz, H., Schapiro, J., Weidenbacher, P. A., Wittman, R., Ahuja, N., Chung, H., Jagannathan, P., James, J. A., Kim, P. S., Meyer, N. J., Nadeau, K. C., Radic, M., Robinson, W. H., Singh, U., Wang, T. T., Wherry, E. J., Skevaki, C., Luning Prak, E. T., Utz, P. J. 2021; 12 (1): 5417

  Abstract

  COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

  View details for DOI 10.1038/s41467-021-25509-3

  View details for PubMedID 34521836

• SARS-CoV-2 Antiviral Therapy. Clinical microbiology reviews Tao, K., Tzou, P. L., Nouhin, J., Bonilla, H., Jagannathan, P., Shafer, R. W. 2021: e0010921

  Abstract

  The development of effective antiviral therapy for COVID-19 is critical for those awaiting vaccination, as well as for those who do not respond robustly to vaccination. This review summarizes 1 year of progress in the race to develop antiviral therapies for COVID-19, including research spanning preclinical and clinical drug development efforts, with an emphasis on antiviral compounds that are in clinical development or that are high priorities for clinical development. The review is divided into sections on compounds that inhibit SARS-CoV-2 enzymes, including its polymerase and proteases; compounds that inhibit virus entry, including monoclonal antibodies; interferons; and repurposed drugs that inhibit host processes required for SARS-CoV-2 replication. The review concludes with a summary of the lessons to be learned from SARS-CoV-2 drug development efforts and the challenges to continued progress.

  View details for DOI 10.1128/CMR.00109-21

  View details for PubMedID 34319150

• Peripheral Plasmodium falciparum infection in early pregnancy is associated with increased maternal microchimerism in the offspring. The Journal of infectious diseases Simon, N., Shallat, J., Houck, J., Jagannathan, P., Prahl, M., Muhindo, M. K., Kakuru, A., Olwoch, P., Feeney, M. E., Harrington, W. E. 2021

  Abstract

  BACKGROUND: Placental malaria has been associated with increased cord blood maternal microchimerism (MMc), which in turn may affect susceptibility to malaria in the offspring. We sought to determine the impact of maternal peripheral Plasmodium falciparum parasitemia during pregnancy on MMc and to determine whether maternal cells expand during primary parasitemia in the offspring.METHODS: We conducted a nested cohort study of maternal-infant pairs from a prior pregnancy malaria chemoprevention study. MMc was measured by quantitative PCR targeting a maternal-specific marker in genomic DNA from cord blood, first P. falciparum parasitemia, and pre-parasitemia. Logistic and negative binomial regression were used to assess the impact of maternal peripheral parasitemia, symptomatic malaria, and placental malaria on cord blood MMc. Generalized estimating equations were used to assess predictors of MMc during infancy.RESULTS: Early maternal parasitemia was associated with increased detection of cord blood MMc (AOR=3.91, p=0.03), whereas late parasitemia, symptomatic malaria, and placental malaria were not. The first parasitemia episode in the infant was not associated with increased MMc relative to pre-parasitemia.CONCLUSIONS: Maternal parasitemia early in pregnancy may increase the amount of MMc acquired by the fetus. Future work should investigate the impact of this MMc on immune responses in the offspring.

  View details for DOI 10.1093/infdis/jiab275

  View details for PubMedID 34010401

• Immunity after SARS-CoV-2 infections. Nature immunology Jagannathan, P., Wang, T. T. 2021

  View details for DOI 10.1038/s41590-021-00923-3

  View details for PubMedID 33875881

• Standardized and optimized preservation, extraction and quantification techniques for detection of fecal SARS-CoV-2 RNA. medRxiv : the preprint server for health sciences Natarajan, A., Han, A., Zlitni, S., Brooks, E. F., Vance, S. E., Wolfe, M., Singh, U., Jagannathan, P., Pinsky, B. A., Boehm, A., Bhatt, A. S. 2021

  Abstract

  COVID-19 patients shed SARS-CoV-2 viral RNA in their stool, sometimes well after they have cleared their respiratory infection. This feature of the disease may be significant for patient health, epidemiology, and diagnosis. However, to date, methods to preserve stool samples from COVID patients, and to extract and quantify viral RNA concentration have yet to be optimized. We sought to meet this urgent need by developing and benchmarking a standardized protocol for the fecal detection of SARS-CoV-2 RNA. We test three preservative conditions for their ability to yield detectable SARS-CoV-2 RNA: OMNIgene-GUT, Zymo DNA/RNA shield kit, and the most common condition, storage without any preservative. We test these in combination with three extraction kits: the QIAamp Viral RNA Mini Kit, Zymo Quick-RNA Viral Kit, and MagMAX Viral/Pathogen Kit. Finally, we also test the utility of two detection methods, ddPCR and RT-qPCR, for the robust quantification of SARS-CoV-2 viral RNA from stool. We identify that the Zymo DNA/RNA shield collection kit and the QiaAMP viral RNA mini kit yield more detectable RNA than the others, using both ddPCR and RT-qPCR assays. We also demonstrate key features of experimental design including the incorporation of appropriate controls and data analysis, and apply these techniques to effectively extract viral RNA from fecal samples acquired from COVID-19 outpatients enrolled in a clinical trial. Finally, we recommend a comprehensive methodology for future preservation, extraction and detection of RNA from SARS-CoV-2 and other coronaviruses in stool.

  View details for DOI 10.1101/2021.04.10.21255250

  View details for PubMedID 33880485

• Malaria PK/PD and the role pharmacometrics can play in the global health arena: Malaria treatment regimens for vulnerable populations. Clinical pharmacology and therapeutics Hughes, E., Wallender, E., Ali, A. M., Jagannathan, P., Savic, R. M. 2021

  Abstract

  Malaria is an infectious disease which disproportionately effects children and pregnant women. These vulnerable populations are often excluded from clinical trials resulting in one-size-fits-all treatment regimens based on those established for a non-pregnant adult population. Pharmacokinetic-pharmacodynamic (PK/PD) models can be used to optimize dose selection as they define the drug exposure-response relationship. Additionally, these models are able to identify patient characteristics which cause alterations in the expected PK/PD profiles and through simulations can recommend changes to dosing which compensate for the differences. In this review, we examine how PK/PD models have been applied to optimize antimalarial dosing recommendations for young children including those who are malnourished, pregnant women and individuals receiving concomitant therapies such as those for HIV treatment. The malaria field has had great success in utilizing PK/PD models as a foundation to update treatment guidelines and propose the next generation of dosing regimens to investigate in clinical trials. We propose how the malaria field can continue to use modeling to improve therapies by further integrating PK data into clinical studies and including data on drug resistance and host immunity in PK/PD models. Finally, we suggest that other disease areas can achieve similar success in applying pharmacometrics to improve outcomes by implementing three key principals.

  View details for DOI 10.1002/cpt.2238

  View details for PubMedID 33763871

• Diversity of KIR genes and their HLA-C ligands in Ugandan populations with historically varied malaria transmission intensity. Malaria journal Tukwasibwe, S., Traherne, J. A., Chazara, O., Jayaraman, J., Trowsdale, J., Moffett, A., Jiang, W., Nankabirwa, J. I., Rek, J., Arinaitwe, E., Nsobya, S. L., Atuheirwe, M., Frank, M., Godwin, A., Jagannathan, P., Cose, S., Kamya, M. R., Dorsey, G., Rosenthal, P. J., Colucci, F., Nakimuli, A. 2021; 20 (1): 111

  Abstract

  BACKGROUND: Malaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity. Several studies have shown that KIR and HLA-C genes influence the immune response to viral infections, but few studies have examined the role of KIR and HLA-C in malaria infection, and these have used low-resolution genotyping. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches.METHODS: High throughput multiplex quantitative real-time PCR method was used to genotype KIR genetic variants and copy number variation and a high-throughput real-time PCR method was developed to genotype HLA-C1 and C2 allotypes for 1344 participants, aged 6months to 10years, enrolled from Ugandan populations with historically high (Tororo District), medium (Jinja District) and low (Kanungu District) malaria transmission intensity.RESULTS: The prevalence of KIR3DS1, KIR2DL5, KIR2DS5, and KIR2DS1 genes was significantly lower in populations from Kanungu compared to Tororo (7.6 vs 13.2%: p=0.006, 57.2 vs 66.4%: p=0.005, 33.2 vs 46.6%: p<0.001, and 19.7 vs 26.7%: p=0.014, respectively) or Jinja (7.6 vs 18.1%: p<0.001, 57.2 vs 63.8%: p=0.048, 33.2 vs 43.5%: p=0.002, and 19.7 vs 30.4%: p<0.001, respectively). The prevalence of homozygous HLA-C2 was significantly higher in populations from Kanungu (31.6%) compared to Jinja (21.4%), p=0.043, with no significant difference between Kanungu and Tororo (26.7%), p=0.296.CONCLUSIONS: The KIR3DS1, KIR2DL5, KIR2DS5 and KIR2DS1 genes may partly explain differences in transmission intensity of malaria since these genes have been positively selected for in places with historically high malaria transmission intensity. The high-throughput, multiplex, real-time HLA-C genotyping PCR method developed will be useful in disease-association studies involving large cohorts.

  View details for DOI 10.1186/s12936-021-03652-y

  View details for PubMedID 33632228

• Gestational age dating using newborn metabolic screening: A validation study in Busia, Uganda. Journal of global health Oltman, S. P., Jasper, E. A., Kajubi, R. n., Ochieng, T. n., Kakuru, A. n., Adrama, H. n., Okitwi, M. n., Olwoch, P. n., Kamya, M. n., Bedell, B. n., McCarthy, M. n., Dagle, J. n., Jagannathan, P. n., Clark, T. D., Dorsey, G. n., Rand, L. n., Ruel, T. n., Rogers, E. E., Ryckman, K. K., Jelliffe-Pawlowski, L. L. 2021; 11: 04012

  View details for DOI 10.7189/jogh.11.04012

  View details for PubMedID 33692896

  View details for PubMedCentralID PMC7916447

• Standardized preservation, extraction and quantification techniques for detection of fecal SARS-CoV-2 RNA. Nature communications Natarajan, A., Han, A., Zlitni, S., Brooks, E. F., Vance, S. E., Wolfe, M., Singh, U., Jagannathan, P., Pinsky, B. A., Boehm, A., Bhatt, A. S. 2021; 12 (1): 5753

  Abstract

  Patients with COVID-19 shed SARS-CoV-2 RNA in stool, sometimes well after their respiratory infection has cleared. This may be significant for patient health, epidemiology, and diagnosis. However, methods to preserve stool, and to extract and quantify viral RNA are not standardized. We test the performance of three preservative approaches at yielding detectable SARS-CoV-2 RNA: the OMNIgene-GUT kit, Zymo DNA/RNA shield kit, and the most commonly applied, storage without preservative. We test these in combination with three extraction kits: QIAamp Viral RNA Mini Kit, Zymo Quick-RNA Viral Kit, and MagMAX Viral/Pathogen Kit. We also test the utility of ddPCR and RT-qPCR for the reliable quantification of SARS-CoV-2 RNA from stool. We identify that the Zymo DNA/RNA preservative and the QiaAMP extraction kit yield more detectable RNA than the others, using both ddPCR and RT-qPCR. Taken together, we recommend a comprehensive methodology for preservation, extraction and detection of RNA from SARS-CoV-2 and other coronaviruses in stool.

  View details for DOI 10.1038/s41467-021-25576-6

  View details for PubMedID 34599164

• Publisher Correction: Standardized preservation, extraction and quantification techniques for detection of fecal SARS-CoV-2 RNA. Nature communications Natarajan, A., Han, A., Zlitni, S., Brooks, E. F., Vance, S. E., Wolfe, M., Singh, U., Jagannathan, P., Pinsky, B. A., Boehm, A., Bhatt, A. S. 2021; 12 (1): 7100

  View details for DOI 10.1038/s41467-021-27392-4

  View details for PubMedID 34853336

• SARS-CoV-2 subgenomic RNA kinetics in longitudinal clinical samples Open Forum Infectious Diseases Verma, R., Kim, E., Martinez, G., Jagannathan, ., Rustagi, A., Parsonnet, J., Bonilla, H., Khosla, C., Holubar, M., Subramanian, A., Singh, ., Maldonado, Y., Blish, C., Andrews, J. 2021

  View details for DOI 10.1093/ofid/ofab310

• Inflammatory but not respiratory symptoms are associated with ongoing upper airway viral shedding in outpatients with uncomplicated COVID-19. Diagnostic microbiology and infectious disease Jacobson, K. B., Purington, N., Parsonnet, J., Andrews, J., Balasubramanian, V., Bonilla, H., Edwards, K., Desai, M., Singh, U., Hedlin, H., Jagannathan, P. 2021; 102 (3): 115612

  Abstract

  Although the vast majority of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections are uncomplicated, our understanding of predictors of symptom resolution and viral shedding cessation remains limited. We characterized symptom trajectories and oropharyngeal viral shedding among 120 outpatients with uncomplicated Coronavirus Disease of 2019 (COVID-19) enrolled in a clinical trial of Peginterferon Lambda, which demonstrated no clinical or virologic benefit compared with placebo. In the combined trial cohort, objective fever was uncommon, inflammatory symptoms (myalgias, fatigue) peaked at 4 to 5 days postsymptom onset, and cough peaked at 9 days. The median time to symptom resolution from earliest symptom onset was 17 days (95% confidence interval 14-18). SARS-CoV-2 IgG seropositivity at enrollment was associated with hastened resolution of viral shedding (hazard ratio 1.80, 95% confidence interval 1.05-3.1, P = 0.03), but not with symptom resolution. Inflammatory symptoms were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection; respiratory symptoms were not. These findings have important implications for COVID-19 screening approaches and trial design.

  View details for DOI 10.1016/j.diagmicrobio.2021.115612

  View details for PubMedID 34974350

• Exposure to pesticides in utero impacts the fetal immune system and response to vaccination in infancy. Nature communications Prahl, M., Odorizzi, P., Gingrich, D., Muhindo, M., McIntyre, T., Budker, R., Jagannathan, P., Farrington, L., Nalubega, M., Nankya, F., Sikyomu, E., Musinguzi, K., Naluwu, K., Auma, A., Kakuru, A., Kamya, M. R., Dorsey, G., Aweeka, F., Feeney, M. E. 2021; 12 (1): 132

  Abstract

  The use of pesticides to reduce mosquito vector populations is a cornerstone of global malaria control efforts, but the biological impact of most pesticides on human populations, including pregnant women and infants, is not known. Some pesticides, including carbamates, have been shown to perturb the human immune system. We measure the systemic absorption and immunologic effects of bendiocarb, a commonly used carbamate pesticide, following household spraying in a cohort of pregnant Ugandan women and their infants. We find that bendiocarb is present at high levels in maternal, umbilical cord, and infant plasma of individuals exposed during pregnancy, indicating that it is systemically absorbed and trans-placentally transferred to the fetus. Moreover, bendiocarb exposure is associated with numerous changes in fetal immune cell homeostasis and function, including a dose-dependent decrease in regulatory CD4 T cells, increased cytokine production, and inhibition of antigen-driven proliferation. Additionally, prenatal bendiocarb exposure is associated with higher post-vaccination measles titers at one year of age, suggesting that its impact on functional immunity may persist for many months after birth. These data indicate that in utero bendiocarb exposure has multiple previously unrecognized biological effects on the fetal immune system.

  View details for DOI 10.1038/s41467-020-20475-8

  View details for PubMedID 33420104

• Sex-based differences in clearance of chronic Plasmodium falciparum infection. eLife Briggs, J., Teyssier, N., Nankabirwa, J. I., Rek, J., Jagannathan, P., Arinaitwe, E., Bousema, T., Drakeley, C., Murray, M., Crawford, E., Hathaway, N., Staedke, S. G., Smith, D., Rosenthal, P. J., Kamya, M., Dorsey, G., Rodriguez-Barraquer, I., Greenhouse, B. 2020; 9

  Abstract

  Multiple studies have reported a male bias in incidence and/or prevalence of malaria infection in males compared to females. To test the hypothesis that sex-based differences in host-parasite interactions affect the epidemiology of malaria, we intensively followed Plasmodium falciparum infections in a cohort in a malaria endemic area of eastern Uganda and estimated both force of infection (FOI) and rate of clearance using amplicon deep-sequencing. We found no evidence of differences in behavioral risk factors, incidence of malaria, or FOI by sex. In contrast, females cleared asymptomatic infections at a faster rate than males (hazard ratio [HR]=1.82, 95% CI 1.20 to 2.75 by clone and HR = 2.07, 95% CI 1.24 to 3.47 by infection event) in multivariate models adjusted for age, timing of infection onset, and parasite density. These findings implicate biological sex-based differences as an important factor in the host response to this globally important pathogen.

  View details for DOI 10.7554/eLife.59872

  View details for PubMedID 33107430

• Opsonized antigen activates Vdelta2+ T cells via CD16/FCgammaRIIIa in individuals with chronic malaria exposure. PLoS pathogens Farrington, L. A., Callaway, P. C., Vance, H. M., Baskevitch, K., Lutz, E., Warrier, L., McIntyre, T. I., Budker, R., Jagannathan, P., Nankya, F., Musinguzi, K., Nalubega, M., Sikyomu, E., Naluwu, K., Arinaitwe, E., Dorsey, G., Kamya, M. R., Feeney, M. E. 2020; 16 (10): e1008997

  Abstract

  Vgamma9Vdelta2 T cells rapidly respond to phosphoantigens produced by Plasmodium falciparum in an innate-like manner, without prior antigen exposure or processing. Vdelta2 T cells have been shown to inhibit parasite replication in vitro and are associated with protection from P. falciparum parasitemia in vivo. Although a marked expansion of Vdelta2 T cells is seen after acute malaria infection in naive individuals, repeated malaria causes Vdelta2 T cells to decline both in frequency and in malaria-responsiveness, and to exhibit numerous transcriptional and phenotypic changes, including upregulation of the Fc receptor CD16. Here we investigate the functional role of CD16 on Vdelta2 T cells in the immune response to malaria. We show that CD16+ Vdelta2 T cells possess more cytolytic potential than their CD16- counterparts, and bear many of the hallmarks of mature NK cells, including KIR expression. Furthermore, we demonstrate that Vdelta2 T cells from heavily malaria-exposed individuals are able to respond to opsonized P.falciparum-infected red blood cells through CD16, representing a second, distinct pathway by which Vdelta2 T cells may contribute to anti-parasite effector functions. This response was independent of TCR engagement, as demonstrated by blockade of the phosphoantigen presenting molecule Butyrophilin 3A1. Together these results indicate that Vdelta2 T cells in heavily malaria-exposed individuals retain the capacity for antimalarial effector function, and demonstrate their activation by opsonized parasite antigen. This represents a new role both for Vdelta2 T cells and for opsonizing antibodies in parasite clearance, emphasizing cooperation between the cellular and humoral arms of the immune system.

  View details for DOI 10.1371/journal.ppat.1008997

  View details for PubMedID 33085728

• Impact of intermittent preventive treatment of malaria in pregnancy with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine on the incidence of malaria in infancy: a randomized controlled trial. BMC medicine Kakuru, A., Jagannathan, P., Kajubi, R., Ochieng, T., Ochokoru, H., Nakalembe, M., Clark, T. D., Ruel, T., Staedke, S. G., Chandramohan, D., Havlir, D. V., Kamya, M. R., Dorsey, G. 2020; 18 (1): 207

  Abstract

  BACKGROUND: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) significantly reduces the burden of malaria during pregnancy compared to sulfadoxine-pyrimethamine (SP), the current standard of care, but its impact on the incidence of malaria during infancy is unknown.METHODS: We conducted a double-blind randomized trial to compare the incidence of malaria during infancy among infants born to HIV-uninfected pregnant women who were randomized to monthly IPTp with either DP or SP. Infants were followed for all their medical care in a dedicated study clinic, and routine assessments were conducted every 4weeks. At all visits, infants with fever and a positive thick blood smear were diagnosed and treated for malaria. The primary outcome was malaria incidence during the first 12months of life. All analyses were done by modified intention to treat.RESULTS: Of the 782 women enrolled, 687 were followed through delivery from December 9, 2016, to December 5, 2017, resulting in 678 live births: 339 born to mothers randomized to SP and 339 born to those randomized to DP. Of these, 581 infants (85.7%) were followed up to 12months of age. Overall, the incidence of malaria was lower among infants born to mothers randomized to DP compared to SP, but the difference was not statistically significant (1.71 vs 1.98 episodes per person-year, incidence rate ratio (IRR) 0.87, 95% confidence interval (CI) 0.73-1.03, p=0.11). Stratifying by infant sex, IPTp with DP was associated with a lower incidence of malaria among male infants (IRR 0.75, 95% CI 0.58-0.98, p=0.03) but not female infants (IRR 0.99, 95% CI 0.79-1.24, p=0.93).CONCLUSION: Despite the superiority of DP for IPTp, there was no evidence of a difference in malaria incidence during infancy in infants born to mothers who received DP compared to those born to mothers who received SP. Only male infants appeared to benefit from IPTp-DP suggesting that IPTp-DP may provide additional benefits beyond birth. Further research is needed to further explore the benefits of DP versus SP for IPTp on the health outcomes of infants.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02793622 . Registered on June 8, 2016.

  View details for DOI 10.1186/s12916-020-01675-x

  View details for PubMedID 32772921

• Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria. Cellular & molecular immunology Tukwasibwe, S., Nakimuli, A., Traherne, J., Chazara, O., Jayaraman, J., Trowsdale, J., Moffett, A., Jagannathan, P., Rosenthal, P. J., Cose, S., Colucci, F. 2020

  Abstract

  Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIRs and HLAs in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIRs and HLAs associated with immunity to malaria thus far.

  View details for DOI 10.1038/s41423-020-0482-z

  View details for PubMedID 32541835

• Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants. Cell reports Thulin, N. K., Brewer, R. C., Sherwood, R., Bournazos, S., Edwards, K. G., Ramadoss, N. S., Taubenberger, J. K., Memoli, M., Gentles, A. J., Jagannathan, P., Zhang, S., Libraty, D. H., Wang, T. T. 2020; 31 (6): 107642

  Abstract

  Infant mortality from dengue disease is a devastating global health burden that could be minimized with the ability to identify susceptibility for severe disease prior to infection. Although most primary infant dengue infections are asymptomatic, maternally derived anti-dengue immunoglobulin G (IgGs) present during infection can trigger progression to severe disease through antibody-dependent enhancement mechanisms. Importantly, specific characteristics of maternal IgGs that herald progression to severe infant dengue are unknown. Here, we define ≥10% afucosylation of maternal anti-dengue IgGs as a risk factor for susceptibility of infants to symptomatic dengue infections. Mechanistic experiments show that afucosylation of anti-dengue IgGs promotes FcgammaRIIIa signaling during infection, in turn enhancing dengue virus replication in FcgammaRIIIa+ monocytes. These studies identify a post-translational modification of anti-dengue IgGs that correlates with risk for symptomatic infant dengue infections and define a mechanism by which afucosylated antibodies and FcgammaRIIIa enhance dengue infections.

  View details for DOI 10.1016/j.celrep.2020.107642

  View details for PubMedID 32402275

• Relationships between measures of malaria at delivery and adverse birth outcomes in a high-transmission area of Uganda. The Journal of infectious diseases Ategeka, J., Kakuru, A., Kajubi, R., Wasswa, R., Ochokoru, H., Arinaitwe, E., Adoke, Y., Jagannathan, P., R Kamya, M., Muehlenbachs, A., Chico, R. M., Dorsey, G. 2020

  Abstract

  BACKGROUND: Clinical trials of interventions for preventing malaria in pregnancy often use measures of malaria at delivery as their primary outcome. Although the objective of these interventions is to improve birth outcomes, data on associations between different measures of malaria at delivery and adverse birth outcomes are limited.METHODS: Data came from 637 Ugandan women enrolled in a randomized controlled trial of intermittent preventive treatment of malaria in pregnancy. Malaria at delivery was detected using peripheral and placental blood microscopy, placental blood loop mediated isothermal amplification (LAMP) and placental histopathology. Multivariate analyses were used to estimate associations between measures of malaria at delivery and risks of low birth weight (LBW), small-for-gestational age (SGA) and preterm birth (PTB).RESULTS: Detection of malaria parasites by microscopy or LAMP was not associated with adverse birth outcomes. Presence of malaria pigment detected by histopathology in > 30% of high-powered fields was strongly associated with LBW (aRR=3.42, p=0.02) and SGA (aRR=4.24, p<0.001), but not preterm birth (aRR=0.88, p=0.87).CONCLUSIONS: A semi-quantitative classification system based on histopathologically detected malaria pigment provided the best surrogate measure of adverse birth outcomes in a high transmission setting and should be considered for use in malaria in pregnancy intervention studies.

  View details for DOI 10.1093/infdis/jiaa156

  View details for PubMedID 32249917

• FcRn, but not FcγRs, drives maternal-fetal transplacental transport of human IgG antibodies. Proceedings of the National Academy of Sciences of the United States of America Borghi, S. n., Bournazos, S. n., Thulin, N. K., Li, C. n., Gajewski, A. n., Sherwood, R. W., Zhang, S. n., Harris, E. n., Jagannathan, P. n., Wang, L. X., Ravetch, J. V., Wang, T. T. 2020

  Abstract

  The IgG Fc domain has the capacity to interact with diverse types of receptors, including the neonatal Fc receptor (FcRn) and Fcγ receptors (FcγRs), which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated by FcγRs, which upon cross-linking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and nonoverlapping functional properties of FcRn and FcγRs, recent studies have suggested that FcγRs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of FcγRs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter FcγRIIIa or FcRn binding, half-life, or their ability to deplete target cells in FcγR/FcRn humanized mice. Modeling maternal-fetal transport in FcγR/FcRn humanized mice confirmed that only FcRn contributed to transplacental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing FcγRIIIa binding did not result in enhanced maternal-fetal transport. These results argue against a role for FcγRs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to enhance only FcRn binding as a means to improve maternal-fetal transport of IgG.

  View details for DOI 10.1073/pnas.2004325117

  View details for PubMedID 32461366

• The Impact of Control Interventions on Malaria Burden in Young Children in a Historically High-Transmission District of Uganda: A Pooled Analysis of Cohort Studies from 2007 to 2018. The American journal of tropical medicine and hygiene Kamya, M. R., Kakuru, A. n., Muhindo, M. n., Arinaitwe, E. n., Nankabirwa, J. I., Rek, J. n., Bigira, V. n., Kapisi, J. n., Wanzira, H. n., Achan, J. n., Natureeba, P. n., Gasasira, A. n., Havlir, D. n., Jagannathan, P. n., Rosenthal, P. J., Rodriguez-Barraquer, I. n., Dorsey, G. n. 2020

  Abstract

  There is limited evidence on whether malaria elimination is feasible in high-transmission areas of Africa. Between 2007 and 2018, we measured the impact of malaria control interventions in young children enrolled in three clinical trials and two observational studies in Tororo, Uganda, a historically high-transmission area. Data were pooled from children aged 0.5-2 years. Interventions included individually assigned chemoprevention and repeated rounds of indoor residual spraying (IRS) of insecticide. All children received long-lasting insecticidal nets (LLINs) and treatment for symptomatic malaria with artemisinin-based combination therapy. Malaria incidence was measured using passive surveillance and parasite prevalence by microscopy and molecular methods at regular intervals. Poisson's generalized linear mixed-effects models were used to estimate the impact of various control interventions. In total, 939 children were followed over 1,221.7 person years. In the absence of chemoprevention and IRS (reference group), malaria incidence was 4.94 episodes per person year and parasite prevalence 47.3%. Compared with the reference group, implementation of IRS was associated with a 97.6% decrease (95% CI: 93.3-99.1%, P = 0.001) in the incidence of malaria and a 96.0% decrease (95% CI: 91.3-98.2%, P < 0.001) in parasite prevalence (both measured after the fifth and sixth rounds of IRS). The addition of chemoprevention with monthly dihydroartemisinin-piperaquine to IRS was associated with a 99.5% decrease (95% CI: 98.6-99.9%, P < 0.001) in the incidence of malaria. In a historically high-malaria burden area of Uganda, a combination of LLINs, effective case management, IRS, and chemoprevention was associated with almost complete elimination of malaria in young children.

  View details for DOI 10.4269/ajtmh.20-0100

  View details for PubMedID 32431280

• Symptomatic SARS-CoV-2 infections display specific IgG Fc structures. medRxiv : the preprint server for health sciences Chakraborty, S. n., Edwards, K. n., Buzzanco, A. S., Memoli, M. J., Sherwood, R. n., Mallajosyula, V. n., Xie, M. M., Gonzalez, J. n., Buffone, C. n., Kathale, N. n., Providenza, S. n., Jagannathan, P. n., Andrews, J. R., Blish, C. A., Krammer, F. n., Dugan, H. n., Wilson, P. C., Pham, T. D., Boyd, S. D., Zhang, S. n., Taubenberger, J. K., Morales, T. n., Schapiro, J. M., Parsonnet, J. n., Wang, T. T. 2020

  Abstract

  The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a public health crisis that is exacerbated by our poor understanding of correlates of immunity. SARS-CoV-2 infection can cause Coronavirus Disease 2019 (COVID-19), with a spectrum of symptoms ranging from asymptomatic carriage to life threatening pneumonia and cytokine dysregulation [1-3]. Although antibodies have been shown in a variety of in vitro assays to promote coronavirus infections through mechanisms requiring interactions between IgG antibodies and Fc gamma receptors (FcγRs), the relevance of these observations to coronavirus infections in humans is not known [4-7]. In light of ongoing clinical trials examining convalescent serum therapy for COVID-19 patients and expedited SARS-CoV-2 vaccine testing in humans, it is essential to clarify the role of antibodies in the pathogenesis of COVID-19. Here we show that adults with PCR-diagnosed COVID-19 produce IgG antibodies with a specific Fc domain repertoire that is characterized by reduced fucosylation, a modification that enhances interactions with the activating FcγR, FcγRIIIa. Fc fucosylation was reduced when compared with SARS-CoV-2-seropositive children and relative to adults with symptomatic influenza virus infections. These results demonstrate an antibody correlate of symptomatic SARS-CoV-2 infections in adults and have implications for novel therapeutic strategies targeting FcγRIIIa pathways.

  View details for DOI 10.1101/2020.05.15.20103341

  View details for PubMedID 32511463

  View details for PubMedCentralID PMC7252581

• Interferon-gamma release assay for accurate detection of SARS-CoV-2 T cell response. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Murugesan, K. n., Jagannathan, P. n., Pham, T. D., Pandey, S. n., Bonilla, H. F., Jacobson, K. n., Parsonnet, J. n., Andrews, J. R., Weiskopf, D. n., Sette, A. n., Pinsky, B. A., Singh, U. n., Banaei, N. n. 2020

  Abstract

  We investigated feasibility and accuracy of an interferon-gamma release assay (IGRA) for detection of T cell responses to SARS-CoV-2. Whole blood IGRA accurately distinguished between convalescents and uninfected healthy blood donors with a predominantly CD4+ T cell response. SARS-CoV-2 IGRA may serve as a useful diagnostic tool in managing the COVID-19 pandemic.

  View details for DOI 10.1093/cid/ciaa1537

  View details for PubMedID 33035306

• Piperaquine exposure is altered by pregnancy, HIV and nutritional status in Ugandan women. Antimicrobial agents and chemotherapy Hughes, E. n., Imperial, M. n., Wallender, E. n., Kajubi, R. n., Huang, L. n., Jagannathan, P. n., Zhang, N. n., Kakuru, A. n., Natureeba, P. n., Mwima, M. W., Muhindo, M. n., Mwebaza, N. n., Clark, T. D., Opira, B. n., Nakalembe, M. n., Havlir, D. n., Kamya, M. n., Rosenthal, P. J., Dorsey, G. n., Aweeka, F. n., Savic, R. M. 2020

  Abstract

  Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations >10.3 ng/mL have been associated with reduced maternal parasitemia, placental malaria and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post-hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks. The effects of covariates such as pregnancy, nutritional status (body mass index, BMI) and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to post-partum and HIV-uninfected pregnant women, respectively. Low BMI at 28-weeks gestation was associated with increased clearance (2% increase per unit decrease in BMI). Low BMI women given DHA-PQ every 8 weeks had a higher prevalence of parasitemia, malaria infection and placental malaria compared to women with higher BMIs. The reduced piperaquine exposure in women with low BMI as well as during EFV co-administration, compared to pregnant women with higher BMIs and not taking EFV, suggests that these populations could benefit from weekly instead of monthly dosing for prevention of malaria parasitemia. Simulations indicated that because of the BMI-clearance relationship, weight-based regimens would not improve protection compared to a 2880 mg fixed-dose regimen when provided monthly.

  View details for DOI 10.1128/AAC.01013-20

  View details for PubMedID 33020153

• Proinflammatory IgG Fc structures in patients with severe COVID-19 Nature Immunology Chakraborty, S., Gonzales, J., Edwards, K., Mallajosyulla, V., Buzzanco, A. S., Sherwood, R., Buffone, C., Kathale, N., Providenza, S., Xie, M. M., Andrews, J. R., Blish, C. A., Singh, U., Dugan, H., Wilson, P. C., Pham, T. D., Boyd, S. D., Nadeau, K. C., Pinsky, B. A., Zhang, S., Memoli, M. J., Taubenberger, J. K., Morales, T., Schapiro, J. M., Tan, G. S., et al 2020

  View details for DOI 10.1038/s41590-020-00828-7

• Infant sex modifies associations between placental malaria and risk of malaria in infancy. Malaria journal Kakuru, A. n., Roh, M. E., Kajubi, R. n., Ochieng, T. n., Ategeka, J. n., Ochokoru, H. n., Nakalembe, M. n., Clark, T. D., Ruel, T. n., Staedke, S. G., Chandramohan, D. n., Havlir, D. V., Kamya, M. R., Dorsey, G. n., Jagannathan, P. n. 2020; 19 (1): 449

  Abstract

  Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM.Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin-piperaquine (DP) or Sulfadoxine-pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0-20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM.There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622.

  View details for DOI 10.1186/s12936-020-03522-z

  View details for PubMedID 33272281

• Generation of a malaria negative Ugandan birth weight standard for the diagnosis of small for gestational age. PloS one Zakama, A. K., Weekes, T., Kajubi, R., Kakuru, A., Ategeka, J., Kamya, M., Muhindo, M. K., Havlir, D., Jagannathan, P., Dorsey, G., Gaw, S. L. 2020; 15 (10): e0240157

  Abstract

  OBJECTIVE: Placental malaria is a known risk factor for small for gestational age (SGA) neonates. However, currently utilized international and African birthweight standards have not controlled for placental malaria and/or lack obstetrical ultrasound dating. We developed a neonatal birthweight standard based on obstetrically dated pregnancies that excluded individuals with clinical malaria, asymptomatic parasitemia, and placental malaria infection. We hypothesized that current curves underestimate true ideal birthweight and the prevalence of SGA.STUDY DESIGN: Participants were pooled from two double-blind randomized control trials of intermittent preventive therapy during pregnancy in Uganda. HIV-negative women without comorbidities were enrolled from 12-20 weeks gestation. Gestational age was confirmed by ultrasound dating. Women were followed through pregnancy and delivery for clinical malaria, asymptomatic parasitemia, and placental malaria. Women without malaria, asymptomatic parasitemia, or placental malaria formed the malaria negative cohort and generated the Ugandan birthweight standard. The Ugandan standard was then used to estimate the prevalence of SGA neonates in the malaria positive cohort. These findings were compared to international (Williams, World Health Organization (WHO), and INTERGROWTH-21st) and regional standards (Tanzanian and Malawi).RESULTS: 926 women had complete delivery data; 393 (42.4%) met criteria for the malaria negative cohort and 533 (57.6%) were malaria positive. The Ugandan standard diagnosed SGA in 17.1% of malaria positive neonates; similar to the INTERGROWTH-21st and Schmiegelow curves. The WHO curve diagnosed SGA in significantly more neonates (32.1%, p = <0.001), and the Malawi curve diagnosed SGA in significantly fewer neonates (8.3%, p <0.001).CONCLUSION: Exclusion of women with subclinical placental malaria in malaria-endemic areas created birth weight norms at higher values and increased the detection of SGA. Birth weight standards that fail to account for endemic illness may underestimate the true growth potential of healthy neonates.

  View details for DOI 10.1371/journal.pone.0240157

  View details for PubMedID 33007041

• Impact of Microscopic and Submicroscopic Parasitemia During Pregnancy on Placental Malaria in a High-Transmission Setting in Uganda JOURNAL OF INFECTIOUS DISEASES Briggs, J., Ategeka, J., Kajubi, R., Ochieng, T., Kakuru, A., Ssemanda, C., Wasswa, R., Jagannathan, P., Greenhouse, B., Rodriguez-Barraquer, I., Kamya, M., Dorsey, G. 2019; 220 (3): 457–66

  View details for DOI 10.1093/infdis/jiz130

  View details for Web of Science ID 000477595700015

• Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomised, controlled, superiority trial LANCET Kajubi, R., Ochieng, T., Kakuru, A., Jagannathan, P., Nakalembe, M., Ruel, T., Opira, B., Ochokoru, H., Ategeka, J., Nayebare, P., Clark, T. D., Havlir, D. V., Kamya, M. R., Dorsey, G. 2019; 393 (10179): 1428–39

  View details for DOI 10.1016/S0140-6736(18)32224-4

  View details for Web of Science ID 000463561000028

• Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomised, controlled, superiority trial. Lancet (London, England) Kajubi, R., Ochieng, T., Kakuru, A., Jagannathan, P., Nakalembe, M., Ruel, T., Opira, B., Ochokoru, H., Ategeka, J., Nayebare, P., Clark, T. D., Havlir, D. V., Kamya, M. R., Dorsey, G. 2019

  Abstract

  BACKGROUND: Intermittent treatment with sulfadoxine-pyrimethamine, recommended for prevention of malaria in pregnant women throughout sub-Saharan Africa, is threatened by parasite resistance. We assessed the efficacy and safety of intermittent preventive treatment with dihydroartemisinin-piperaquine as an alternative to sulfadoxine-pyrimethamine.METHODS: We did a double-blind, randomised, controlled, superiority trial at one rural site in Uganda with high malaria transmission and sulfadoxine-pyrimethamine resistance. HIV-uninfected pregnant women between 12 and 20 weeks gestation were randomly assigned (1:1) to monthly intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine. The primary endpoint was the risk of a composite adverse birth outcome defined as low birthweight, preterm birth, or small for gestational age in livebirths. Protective efficacy was defined as 1-prevalence ratio or 1-incidence rate ratio. All analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02793622.FINDINGS: Between Sept 6, 2016, and May 29, 2017, 782 women were enrolled and randomly assigned to receive sulfadoxine-pyrimethamine (n=391) or dihydroartemisinin-piperaquine (n=391); 666 (85·2%) women who delivered livebirths were included in the primary analysis. There was no significant difference in the risk of our composite adverse birth outcome between the dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine treatment group (54 [16%] of 337 women vs 60 [18%] of 329 women; protective efficacy 12% [95% CI -23 to 37], p=0·45). Both drug regimens were well tolerated, with no significant differences in adverse events between the groups, with the exception of asymptomatic corrected QT interval prolongation, which was significantly higher in the dihydroartemisinin-piperaquine group (mean change 13 ms [SD 23]) than in the sulfadoxine-pyrimethamine group (mean change 0 ms [SD 23]; p<0·0001).INTERPRETATION: Monthly intermittent preventive treatment with dihydroartemisinin-piperaquine was safe but did not lead to significant improvements in birth outcomes compared with sulfadoxine-pyrimethamine.FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Bill & Melinda Gates Foundation.

  View details for PubMedID 30910321

• Impact of microscopic and submicroscopic parasitemia during pregnancy on placental malaria in a high-transmission setting in Uganda. The Journal of infectious diseases Briggs, J., Ategeka, J., Kajubi, R., Ochieng, T., Kakuru, A., Ssemanda, C., Wasswa, R., Jagannathan, P., Greenhouse, B., Rodriquez-Barraquer, I., Kamya, M., Dorsey, G. 2019

  Abstract

  BACKGROUND: Placental malaria is a major cause of adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of parasitemia during pregnancy and placental malaria.METHODS: Data come from 637 women enrolled in a randomized controlled trial of intermittent preventive treatment of malaria in pregnancy (IPTp) from Uganda. Plasmodium falciparum parasitemia was assessed using microscopy and ultrasensitive quantitative PCR at intervals of 28 days from 12-20 weeks gestation through delivery. Multivariate analysis was used to measure associations between characteristics of parasitemia during pregnancy and the risk of placental malaria based on histopathology.RESULTS: Overall risk of placental malaria was 44.6%. None of the 34 women without parasitemia detected during pregnancy had evidence of placental malaria. Increasing proportion of interval assessments with parasitemia and higher parasite densities were independently associated with an increased risk of placental malaria. Higher gravidity and more effective IPTp were associated with a decreased risk of placental malaria. Women with parasitemia only detected before the 3rd trimester still had an increased risk of placental malaria.CONCLUSIONS: The frequency, density, and timing of parasitemia are all important risk factors for placental malaria. Interventions should target the prevention of all levels of parasitemia throughout pregnancy.

  View details for PubMedID 30891605

• Modeling Prevention of Malaria and Selection of Drug Resistance with Different Dosing Schedules of Dihydroartemisinin-Piperaquine Preventive Therapy during Pregnancy in Uganda ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Wallender, E., Zhang, N., Conrad, M., Kakuru, A., Muhindo, M., Tumwebaze, P., Kajubi, R., Mota, D., Legac, J., Jagannathan, P., Havlir, D., Kamya, M., Dorsey, G., Aweeka, F., Rosenthal, P. J., Savic, R. M. 2019; 63 (2)

  View details for DOI 10.1128/AAC.01393-18

  View details for Web of Science ID 000457110200039

• Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins. The American journal of tropical medicine and hygiene Conroy, A. L., Bangirana, P., Muhindo, M. K., Kakuru, A., Jagannathan, P., Opoka, R. O., Liechty, E. A., Nakalembe, M., Kamya, M. R., Dorsey, G., John, C. C. 2019

  Abstract

  Maternal infection during pregnancy can have lasting effects on neurodevelopment, but the impact of malaria in pregnancy on child neurodevelopment is unknown. We present a case of a 24-year-old gravida three woman enrolled at 14 weeks 6 days of gestation in a clinical trial evaluating malaria prevention strategies in pregnancy. She had two blood samples test positive for Plasmodium falciparum using loop-mediated isothermal amplification before 20 weeks of gestation. At 31 weeks 4 days of gestation, the woman presented with preterm premature rupture of membranes, and the twins were delivered by cesarean section. Twin A was 1,920 g and Twin B was 1,320 g. Both placentas tested negative for malaria by microscopy, but the placenta of Twin B had evidence of past malaria by histology. The twins' development was assessed using the Bayley Scales of Infant and Toddler Development-Third Edition. At 1 year chronologic age, Twin B had lower scores across all domains (composite scores: cognitive, Twin A [100], Twin B [70]; motor, Twin A [88], Twin B [73]; language, Twin A [109], Twin B [86]). This effect persisted at 2 years chronologic age (composite scores: cognitive, Twin A [80], Twin B [60]; motor, Twin A [76], Twin B [67]; language, Twin A [77], Twin B [59]). Infant health was similar over the first 2 years of life. We report differences in neurodevelopmental outcomes in placental malaria-discordant dizygotic twins. Additional research is needed to evaluate the impact of placental malaria on neurodevelopmental complications. Trial registration number: ClinicalTrials.gov number, NCT02163447. Registered: June 2014, https://clinicaltrials.gov/ct2/show/NCT02163447.

  View details for PubMedID 30628574

• Emerging role of gammadelta T cells in vaccine-mediated protection from infectious diseases. Clinical & translational immunology Dantzler, K. W., de la Parte, L., Jagannathan, P. 2019; 8 (8): e1072

  Abstract

  gammadelta T cells are fascinating cells that bridge the innate and adaptive immune systems. They have long been known to proliferate rapidly following infection; however, the identity of the specific gammadelta T cell subsets proliferating and the role of this expansion in protection from disease have only been explored more recently. Several recent studies have investigated gammadelta T-cell responses to vaccines targeting infections such as Mycobacterium, Plasmodium and influenza, and studies in animal models have provided further insight into the association of these responses with improved clinical outcomes. In this review, we examine the evidence for a role for gammadelta T cells in vaccine-induced protection against various bacterial, protozoan and viral infections. We further discuss results suggesting potential mechanisms for protection, including cytokine-mediated direct and indirect killing of infected cells, and highlight remaining open questions in the field. Finally, building on current efforts to integrate strategies targeting gammadelta T cells into immunotherapies for cancer, we discuss potential approaches to improve vaccines for infectious diseases by inducing gammadelta T-cell activation and cytotoxicity.

  View details for DOI 10.1002/cti2.1072

  View details for PubMedID 31485329

• Reduced exposure to piperaquine in young children, compared to adults, in children receiving dihydroartemisinin-piperaquine as malaria chemoprevention. Clinical pharmacology and therapeutics Whalen, M. E., Kajubi, R. n., Chamankhah, N. n., Huang, L. n., Orukan, F. n., Wallender, E. n., Kamya, M. R., Dorsey, G. n., Jagannathan, P. n., Rosenthal, P. J., Mwebaza, N. n., Aweeka, F. T. 2019

  Abstract

  Dihydroartemisinin (DHA)-piperaquine is being evaluated as intermittent preventive therapy for malaria, but dosing has not been optimized for children. We assessed exposure to DHA and piperaquine in Ugandan children at two ages during infancy. Intensive sampling was performed in 32 children at 32 weeks of age, 31 children at 104 weeks, and 30 female adult controls. Compared to adults, DHA area under the concentration time curve (AUC0-8hr ) was 52% higher at 32 weeks and comparable at 104 weeks. Compared to adults, piperaquine AUC0-21d was 35% lower at 32 weeks and 53% lower at 104 weeks. Terminal piperaquine concentrations on Days 7, 14, and 21 were lower in children compared to adults and lower at 104 compared to 32 weeks. Piperaquine exposure was lower in young children compared to adults, and lower at 104 compared to 32 weeks of age, suggesting a need for age-based DHA-piperaquine dose optimization for chemoprevention. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/cpt.1534

  View details for PubMedID 31173649

• Malaria smear positivity among Kenyan children peaks at intermediate temperatures as predicted by ecological models. Parasites & vectors Shah, M. M., Krystosik, A. R., Ndenga, B. A., Mutuku, F. M., Caldwell, J. M., Otuka, V. n., Chebii, P. K., Maina, P. W., Jembe, Z. n., Ronga, C. n., Bisanzio, D. n., Anyamba, A. n., Damoah, R. n., Ripp, K. n., Jagannathan, P. n., Mordecai, E. A., LaBeaud, A. D. 2019; 12 (1): 288

  Abstract

  Ambient temperature is an important determinant of malaria transmission and suitability, affecting the life-cycle of the Plasmodium parasite and Anopheles vector. Early models predicted a thermal malaria transmission optimum of 31 °C, later revised to 25 °C using experimental data from mosquito and parasite biology. However, the link between ambient temperature and human malaria incidence remains poorly resolved.To evaluate the relationship between ambient temperature and malaria risk, 5833 febrile children (<18 years-old) with an acute, non-localizing febrile illness were enrolled from four heterogenous outpatient clinic sites in Kenya (Chulaimbo, Kisumu, Msambweni and Ukunda). Thick and thin blood smears were evaluated for the presence of malaria parasites. Daily temperature estimates were obtained from land logger data, and rainfall from National Oceanic and Atmospheric Administration (NOAA)'s Africa Rainfall Climatology (ARC) data. Thirty-day mean temperature and 30-day cumulative rainfall were estimated and each lagged by 30 days, relative to the febrile visit. A generalized linear mixed model was used to assess relationships between malaria smear positivity and predictors including temperature, rainfall, age, sex, mosquito exposure and socioeconomic status.Malaria smear positivity varied between 42-83% across four clinic sites in western and coastal Kenya, with highest smear positivity in the rural, western site. The temperature ranges were cooler in the western sites and warmer in the coastal sites. In multivariate analysis controlling for socioeconomic status, age, sex, rainfall and bednet use, malaria smear positivity peaked near 25 °C at all four sites, as predicted a priori from an ecological model.This study provides direct field evidence of a unimodal relationship between ambient temperature and human malaria incidence with a peak in malaria transmission occurring at lower temperatures than previously recognized clinically. This nonlinear relationship with an intermediate optimal temperature implies that future climate warming could expand malaria incidence in cooler, highland regions while decreasing incidence in already warm regions with average temperatures above 25 °C. These findings support efforts to further understand the nonlinear association between ambient temperature and vector-borne diseases to better allocate resources and respond to disease threats in a future, warmer world.

  View details for DOI 10.1186/s13071-019-3547-z

  View details for PubMedID 31171037

• Case Report: Birth Outcome and Neurodevelopment in Placental Malaria Discordant Twins AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Conroy, A. L., Bangirana, P., Muhindo, M. K., Kakuru, A., Jagannathan, P., Opoka, R. O., Liechty, E. A., Nakalembe, M., Kamya, M. R., Dorsey, G., John, C. C. 2019; 100 (3): 552–55

  View details for DOI 10.4269/ajtmh.18-0659

  View details for Web of Science ID 000460416400018

• SEVERITY OF MALARIA IN A BIRTH COHORT OF INFANTS LIVING IN A HIGHLY ENDEMIC AREA OF UGANDA Zehner, N., Andra, T., Kajubi, R., Ssewanyana, I., Conrad, M., Nankya, F., Adrama, H., Clark, T. D., Kamya, M., Dorsey, G., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2019: 291–92

  View details for Web of Science ID 000507364503307

• VALIDATION OF PIPERAQUINE CONCENTRATIONS PROTECTIVE AGAINST PLASMODIUM FALCIPARUM INFECTION WHEN DIHYDROARTEMISININ-PIPERAQUINE IS GIVEN ASINTERMITTENT PREVENTIVE TREATMENT DURING PREGNANCY Hughes, E., Kajubi, R., Wallender, E., Huang, L., Ochieng, T., Kakuru, A., Jagannathan, P., Nakalembe, M., Opira, B., Ategeka, J., Nayebare, P., Clark, T. D., Kamya, M., Rosenthal, P., Dorsey, G., Aweeka, F., Savic, R. AMER SOC TROP MED & HYGIENE. 2019: 113

  View details for Web of Science ID 000507364502368

• PHARMACOKINETIC/PHARMACODYNAMIC MODELING TO IDENTIFY OPTIMAL DIHYDROARTEMISININ-PIPERAQUINE INTERMITTENT PREVENTIVE TREATMENT REGIMENS FOR YOUNG UGANDAN CHILDREN Wallender, E., Hughes, E., Kakuru, A., Jagannathan, P., Muhindo, M., Opira, B., Whalen, M., Kamya, M., Dorsey, G., Aweeka, F., Rosenthal, P. J., Savic, R. M. AMER SOC TROP MED & HYGIENE. 2019: 521

  View details for Web of Science ID 000507364504408

• ASSOCIATION BETWEEN PLACENTAL MALARIA AND THE INCIDENCE OF MALARIA IN INFANTS BORN TO HIV-UNINFECTED UGANDAN MOTHERS LIVING IN A HIGH MALARIA TRANSMISSION SETTING Kakuru, A., Staedke, S., Chandramohan, D., Kajubi, R., Andra, T., Adrama, H., Nakalembe, M., Clark, T. D., Ruel, T., Havlir, D. V., Kamya, M. R., Dorsey, G., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2019: 518

  View details for Web of Science ID 000507364504398

• MECHANISMS DRIVING ALTERED V Delta 2+Gamma Delta T CELL FUNCTION DURING RECURRENT MALARIA INFECTION Dantzler, K. W., Klemm, S., Polidoro, R., Rao, A., Junquiera, C., Dvorak, M., Rek, J., Kamya, M., Cheung, P., Kuo, A., Dorsey, G., Feeney, M., Lieberman, J., Khatri, P., Greenleaf, W., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2019: 111

  View details for Web of Science ID 000507364502362

• Modeling prevention of malaria and selection of drug resistance with different dosing schedules of dihydroartemisinin-piperaquine preventive therapy during pregnancy in Uganda. Antimicrobial agents and chemotherapy Wallender, E., Zhang, N., Conrad, M., Kakuru, A., Muhindo, M., Tumwebaze, P., Kajubi, R., Mota, D., Legac, J., Jagannathan, P., Havlir, D., Kamya, M., Dorsey, G., Aweeka, F., Rosenthal, P. J., Savic, R. M. 2018

  Abstract

  Dihydroartemisinin-piperaquine (DHA-PQ) is under study for intermittent preventive treatment during pregnancy (IPTp), but it may accelerate selection for drug resistance. Understanding the relationships between piperaquine concentration, prevention of parasitemia, and selection for decreased drug sensitivity can inform control policies and optimization of DHA-PQ dosing. Piperaquine concentrations, measures of parasitemia, and Plasmodium falciparum genotypes associated with decreased aminoquinoline sensitivity in Africa (pfmdr1 86Y, pfcrt 76T) were obtained from pregnant Ugandan women randomized to IPTp with sulfadoxine-pyrimethamine (SP) or DHA-PQ. Joint pharmacokinetic/pharmacodynamic models described relationships between piperaquine concentration and probability of genotypes of interest using nonlinear mixed effects modeling. Increasing piperaquine plasma concentration was associated with a log-linear decrease in risk of parasitemia. Our models predicted that higher median piperaquine concentrations would be required to provide 99% protection against mutant compared to wild type infections (pfmdr1 N86: 9.6 ng/mL, 86Y: 19.6 ng/mL; pfcrt K76: 6.5 ng/mL, 76T: 19.6 ng/mL). Comparing monthly, weekly, and daily dosing, daily low dose DHA-PQ was predicted to result in the fewest infections and the fewest mutant infections per 1,000 pregnancies (predicted mutant infections for pfmdr1 86Y: SP monthly: 607, DHA-PQ monthly: 198, DHA-PQ daily: 1; for pfcrt 76T: SP monthly: 1564, DHA-PQ monthly: 283, DHA-PQ daily: 1). Our models predict that higher piperaquine concentrations are needed to prevent infections with pfmdr1/pfcrt mutant compared to wild type parasites and that, despite selection for mutants by DHA-PQ, the overall burden of mutant infections is lower for IPTp with DHA-PQ than for IPTp with SP.

  View details for PubMedID 30530597

• How does malaria in pregnancy impact malaria risk in infants? BMC medicine Jagannathan, P. 2018; 16 (1): 212

  Abstract

  Malaria in pregnancy not only exerts profound negative consequences on the health of the mother and developing fetus, but may also alter the risk of malaria during infancy. Although mechanisms driving this altered risk remain unclear, in utero exposure to malaria antigens may impact the development of fetal and infant innate immunity. In an article in BMC Medicine, Natama et al. describe an ambitious analysis of basal and TLR-stimulated cord blood responses among a birth cohort in Burkina Faso. Basal levels of several cytokines, chemokines, and growth factors were shown to be significantly lower in cord blood with histopathologic evidence of placental malaria. Additionally, following TLR7/8 stimulation, samples obtained from infants of mothers with placental malaria were hyper-responsive compared to those without evidence of prenatal malaria exposure. Furthermore, several responses impacted by placental malaria were associated with differential malaria risk in infancy. Understanding how malaria in pregnancy shapes immune responses in infants will provide critical insight into the rational design of malaria control strategies during pregnancy, including intermittent preventative treatment in pregnancy and vaccines.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1187-3.

  View details for PubMedID 30454004

• γδ T Cells in Antimalarial Immunity: New Insights Into Their Diverse Functions in Protection and Tolerance. Frontiers in immunology Dantzler, K. W., Jagannathan, P. 2018; 9: 2445

  Abstract

  Uniquely expressing diverse innate-like and adaptive-like functions, γδ T cells exist as specialized subsets, but are also able to adapt in response to environmental cues. These cells have long been known to rapidly proliferate following primary malaria infection in humans and mice, but exciting new work is shedding light into their diverse functions in protection and following repeated malaria infection. In this review, we examine the current knowledge of functional specialization of γδ T cells in malaria, and the mechanisms dictating recognition of malaria parasites and resulting proliferation. We discuss γδ T cell plasticity, including changing interactions with other immune cells during recurrent infection and potential for immunological memory in response to repeated stimulation. Building on recent insights from human and murine experimental studies and vaccine trials, we propose areas for future research, as well as applications for therapeutic development.

  View details for DOI 10.3389/fimmu.2018.02445

  View details for PubMedID 30405634

  View details for PubMedCentralID PMC6206268

• gamma delta T Cells in Antimalarial Immunity: New Insights Into Their Diverse Functions in Protection and Tolerance FRONTIERS IN IMMUNOLOGY Dantzler, K. W., Jagannathan, P. 2018; 9

  View details for DOI 10.3389/fimmu.2018.02445

  View details for Web of Science ID 000447973300001

• In utero priming of highly functional effector T cell responses to human malaria. Science translational medicine Odorizzi, P. M., Jagannathan, P., McIntyre, T. I., Budker, R., Prahl, M., Auma, A., Burt, T. D., Nankya, F., Nalubega, M., Sikyomu, E., Musinguzi, K., Naluwu, K., Kakuru, A., Dorsey, G., Kamya, M. R., Feeney, M. E. 2018; 10 (463)

  Abstract

  Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, we assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. We found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria-exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

  View details for PubMedID 30333241

• Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure. eLife Rodriguez-Barraquer, I., Arinaitwe, E., Jagannathan, P., Kamya, M. R., Rosenthal, P. J., Rek, J., Dorsey, G., Nankabirwa, J., Staedke, S. G., Kilama, M., Drakeley, C., Ssewanyana, I., Smith, D. L., Greenhouse, B. 2018; 7

  Abstract

  Fundamental gaps remain in our understanding of how immunity to malaria develops. We used detailed clinical and entomological data from parallel cohort studies conducted across the malaria transmission spectrum in Uganda to quantify the development of immunity against symptomatic P. falciparum as a function of age and transmission intensity. We focus on: anti-parasite immunity (i.e; ability to control parasite densities) and anti-disease immunity (i.e; ability to tolerate higher parasite densities without fever). Our findings suggest a strong effect of age on both types of immunity, not explained by cumulative-exposure. They also show an independent effect of exposure, where children living in moderate/high transmission settings develop immunity faster as transmission increases. Surprisingly, children in the lowest transmission setting appear to develop immunity more efficiently than those living in moderate transmission settings. Anti-parasite and anti-disease immunity develop in parallel, reducing the probability of experiencing symptomatic malaria upon each subsequent P. falciparum infection.

  View details for PubMedID 30044224

• Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure ELIFE Rodriguez-Barraquer, I., Arinaitwe, E., Jagannathan, P., Kamya, M. R., Rosenthal, P. J., Rek, J., Dorsey, G., Nankabirwa, J., Staedke, S. G., Kilama, M., Drakeley, C., Ssewanyana, I., Smith, D. L., Greenhouse, B. 2018; 7

  View details for DOI 10.7554/eLife.35832

  View details for Web of Science ID 000442198400001

• Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Savic, R. M., Jagannathan, P., Kajubi, R., Huang, L., Zhang, N., Were, M., Kakuru, A., Muhindo, M. K., Mwebaza, N., Wallender, E., Clark, T. D., Opira, B., Kamya, M., Havlir, D. V., Rosenthal, P. J., Dorsey, G., Aweeka, F. T. 2018

  Abstract

  Background: Dihydroartemsinin-piperaquine is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies.Methods: HIV-uninfected pregnant women were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks gestation and randomized to: sulfadoxine-pyrimethamine every 8 weeks (n=106), dihydroartemsinin-piperaquine every 8 weeks (n=94), or dihydroartemsinin-piperaquine every 4 weeks (n=100) during pregnancy. Pharmacokinetic sampling for piperaquine was performed every 4 weeks, and an intensive pharmacokinetic sub-study was performed in 30 women at 28 weeks gestation. Concentration-effect relationships were assessed between exposure to piperaquine; the prevalence of P. falciparum infection during pregnancy; outcomes at delivery including placental malaria, low birthweight, and preterm birth; and risks for toxicity. Simulations of new dosing scenarios were performed.Results: Model-defined piperaquine target venous plasma concentrations of 13.9 ng/ml provided 99% protection from P. falciparum infection during pregnancy. Each 10 day increase in time>target piperaquine concentrations was associated with reduced odds of placental parasitemia (0∙67, P<0.0001), preterm birth (0.74, P<0.01), and low birthweight (0.74, P<0.05), though increases in piperaquine concentrations were associated with QTc prolongation (5 msec increase per 100 ng/ml). Modeling suggests that daily or weekly administration of lower dosages of piperaquine, compared to standard dosing, will maintain piperaquine trough levels above target concentrations with reduced piperaquine peak levels, potentially limiting toxicity.Conclusions: The protective efficacy of IPTp with dihydroartemsinin-piperaquine was strongly associated with higher drug exposure. Studies of the efficacy and safety of alternative dihydroartemsinin-piperaquine IPTp dosing strategies are warranted.Clinical Trials Registration: NCT02163447.

  View details for PubMedID 29547881

• Response to "Antiretroviral Therapy With Efavirenz in HIV-Infected Pregnant Women: Understanding the Possible Mechanisms for Drug-Drug Interaction". Clinical pharmacology and therapeutics Jagannathan, P. n., Kajubi, R. n., Aweeka, F. T. 2018

  View details for PubMedID 29322501

• EVALUATION OF ACCURACY OF MAGNETO-OPTICAL METHOD FOR THE DETECTION OF MALARIA PARASITES Jagannathan, P., Adrama, H., Kajubi, R., Clark, T., Dorsey, G., Kamya, M., Greenhouse, B., Thota, P. AMER SOC TROP MED & HYGIENE. 2018: 538

  View details for Web of Science ID 000461386604412

• Malaria in pregnancy shapes the development of fetal and infant immunity. Parasite immunology Harrington, W. E., Kakuru, A. n., Jagannathan, P. n. 2018: e12573

  Abstract

  Malaria in pregnancy remains one of the most important causes of adverse birth outcomes. In addition to the profoundly deleterious impact of maternal malaria on the health of the mother and fetus, malaria infection in pregnancy has been shown to affect the development of the fetal and infant immune system and may alter the risk of malaria and non-malarial outcomes during infancy. This review summarizes our current understanding of how malaria infection in pregnancy shapes the protective components of the maternal immune system transferred to the fetus and how fetal exposure to parasite antigens impacts the development of fetal and infant immunity. It also reviews existing evidence linking malaria infection in pregnancy to malaria and non-malarial outcomes in infancy and how preventing malaria in pregnancy may alter these outcomes. A better understanding of the consequences of malaria infection in pregnancy on the development of fetal and infant immunity will inform control strategies, including intermittent preventative treatment in pregnancy and vaccine development. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30019470

• Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Scientific reports Jagannathan, P., Lutwama, F., Boyle, M. J., Nankya, F., Farrington, L. A., McIntyre, T. I., Bowen, K., Naluwu, K., Nalubega, M., Musinguzi, K., Sikyomu, E., Budker, R., Katureebe, A., Rek, J., Greenhouse, B., Dorsey, G., Kamya, M. R., Feeney, M. E. 2017; 7 (1): 11487

  Abstract

  Vδ2(+) γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2(+) T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2(+) counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2(+) T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2(+) T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria.

  View details for DOI 10.1038/s41598-017-10624-3

  View details for PubMedID 28904345

• Intermittent Preventive Treatment with Dihydroartemisinin-piperaquine for the Prevention of Malaria among HIV-infected Pregnant Women. journal of infectious diseases Natureeba, P., Kakuru, A., Muhindo, M., Littmann, E., Ochieng, T., Ategeka, J., Koss, C. A., Plenty, A., Charlebois, E. D., Clark, T. D., Nzarubara, B., Nakalembe, M., Cohan, D., Rizzuto, G., Muehlenbachs, A., Ruel, T., Jagannathan, P., Havlir, D. V., Kamya, M. R., Dorsey, G. 2017

  Abstract

  Daily trimethoprim-sulfamethoxazole (TMP-SMX) and insecticide treated nets (ITNs) remain the main interventions for prevention of malaria in HIV-infected pregnant women in Africa. However, antifolate and pyrethroid resistance threaten the effectiveness of these intervention and new ones are needed.We conducted a double-blind randomized placebo-controlled trial comparing daily TMP-SMX plus monthly dihydroartemisinin-piperaquine (DP) to daily TMP-SMX alone in HIV-infected pregnant women in an area of Uganda where indoor residual spraying of insecticide (IRS) had recently been implemented. Participants were enrolled between 12-28 weeks gestation and provided an ITN. The primary outcome was placental malaria by histopathology (active or past infection). Secondary outcomes included incidence of malaria; parasite prevalence; and adverse birth outcomes.All 200 women enrolled were followed through delivery and the primary outcome was assessed in 194. There was no statistically significant difference in the risk of placental malaria by histopathology between the daily TMP-SMX plus DP and daily TMP-SMX alone arms (6.1 vs. 3.1%, RR=1.96, 95%CI 0.50-7.61, P=0.50). Similarly, there were no differences in secondary outcomes.Among HIV-infected pregnant women in the setting of IRS, adding monthly DP to daily TMP-SMX did not reduce the risk of placental or maternal malaria or improve birth outcomes.

  View details for DOI 10.1093/infdis/jix110

  View details for PubMedID 28329368

• Antiretroviral Therapy With Efavirenz Accentuates Pregnancy-Associated Reduction of Dihydroartemisinin-Piperaquine Exposure During Malaria Chemoprevention. Clinical pharmacology & therapeutics Kajubi, R., Huang, L., Jagannathan, P., Chamankhah, N., WERE, M., Ruel, T., Koss, C. A., Kakuru, A., Mwebaza, N., Kamya, M., Havlir, D., Dorsey, G., Rosenthal, P. J., Aweeka, F. T. 2017

  Abstract

  Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected non-pregnant women. DHA peak concentration and area under the concentration time curve (AUC0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC0-21d was 40% lower in pregnant women compared to non-pregnant women. DHA AUC0-8hr and piperaquine AUC0-21d were 27% and 38% lower, respectively in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/cpt.664

  View details for PubMedID 28187497

• CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero. Open forum infectious diseases Prahl, M., Jagannathan, P., McIntyre, T. I., Auma, A., Wamala, S., Nalubega, M., Musinguzi, K., Naluwu, K., Sikyoma, E., Budker, R., Odorizzi, P., Kakuru, A., Havlir, D. V., Kamya, M. R., Dorsey, G., Feeney, M. E. 2017; 4 (1): ofx022-?

  Abstract

  Sex differences in the immune response and in infectious disease susceptibility have been well described, although the mechanisms underlying these differences remain incompletely understood. We evaluated the frequency of cord blood CD4 T cell subsets in a highly malaria-exposed birth cohort of mother-infant pairs in Uganda by sex. We found that frequencies of cord blood regulatory T cell ([Treg] CD4(+)CD25(+)FoxP3(+)CD127(lo/-)) differed by infant sex, with significantly lower frequencies of Tregs in female than in male neonates (P = .006). When stratified by in utero malaria exposure status, this difference was observed in the exposed, but not in the unexposed infants.

  View details for DOI 10.1093/ofid/ofx022

  View details for PubMedID 28480292

  View details for PubMedCentralID PMC5414097

• Predicting optimal dihydroartemisinin-piperaquine regimens to prevent malaria during pregnancy for HIV-infected women receiving efavirenz. The Journal of infectious diseases Wallender, E. n., Vucicevic, K. n., Jagannathan, P. n., Huang, L. n., Natureeba, P. n., Kakura, A. n., Muhindo, M. n., Nakalembe, M. n., Havlir, D. n., Kamya, M. n., Aweeka, F. n., Dorsey, G. n., Rosenthal, P. J., Savic, R. M. 2017

  Abstract

  A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population.Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal pharmacokinetic and QTc (25 women) data. Population PK and PK-QTc models for piperaquine were developed to consider the benefits (protective piperaquine coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective piperaquine coverage was defined as maintaining a concentration >10 ng/ml for >95% of the chemoprevention period.Piperaquine clearance was 4,540 L/day. With monthly DHA-PQ (2,880 mg piperaquine), <1% of women achieved defined protective piperaquine coverage. Weekly (960 mg piperaquine) or low dose daily (320 or 160 mg piperaquine) regimens, achieved protective piperaquine coverage for 34% and >96% of women respectively. All regimens were safe, with ≤2% of women predicted to have ≥ 30 msec QTc increase.For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing.

  View details for PubMedID 29272443

• Both inflammatory and regulatory cytokine responses to malaria are blunted with increasing age in highly exposed children. Malaria journal Farrington, L. n., Vance, H. n., Rek, J. n., Prahl, M. n., Jagannathan, P. n., Katureebe, A. n., Arinaitwe, E. n., Kamya, M. R., Dorsey, G. n., Feeney, M. E. 2017; 16 (1): 499

  Abstract

  Young children are at greatest risk for malaria-associated morbidity and mortality. The immune response of young children differs in fundamental ways from that of adults, and these differences likely contribute to the increased susceptibility of children to severe malaria and to their delayed development of immunity. Elevated levels of pro-inflammatory cytokines and chemokines in the peripheral blood during acute infection contribute to the control of parasitaemia, but are also responsible for much of the immunopathology seen during symptomatic disease. Clinical immunity to malaria may depend upon the ability to regulate these pro-inflammatory responses, possibly through mechanisms of immunologic tolerance. In order to explore the effect of age on the immune response to malaria and the development of clinical immunity, cytokines and chemokines were measured in the plasma of children at day 0 of an acute malaria episode and during convalescence.Younger children presenting with acute malaria exhibited much higher levels of TNF, IL2, and IL6, as well as increased Th1 associated chemokines IP10, MIG, and MCP1, compared to older children with acute malaria. Additionally, the regulatory cytokines IL10 and TNFRI were dramatically elevated in younger children compared to older children during acute infection, indicating that regulatory as well as pro-inflammatory cytokine responses are dampened in later childhood.Together these data suggest that there is a profound blunting of the cytokine and chemokine response to malaria among older children residing in endemic settings, which may be due to repeated malaria exposure, intrinsic age-based differences in the immune response, or both.

  View details for PubMedID 29284469

• The Development of Plasmodium falciparum-Specific IL10 CD4 T Cells and Protection from Malaria in Children in an Area of High Malaria Transmission. Frontiers in immunology Boyle, M. J., Jagannathan, P. n., Bowen, K. n., McIntyre, T. I., Vance, H. M., Farrington, L. A., Schwartz, A. n., Nankya, F. n., Naluwu, K. n., Wamala, S. n., Sikyomu, E. n., Rek, J. n., Greenhouse, B. n., Arinaitwe, E. n., Dorsey, G. n., Kamya, M. R., Feeney, M. E. 2017; 8: 1329

  Abstract

  Cytokine-producing CD4 T cells have important roles in immunity against Plasmodium falciparum (Pf) malaria. However, the factors influencing functional differentiation of Pf-specific CD4 T cells in naturally exposed children are not well understood. Moreover, it is not known which CD4 T-cell cytokine-producing subsets are most critical for protection. We measured Pf-specific IFNγ-, IL10-, and TNFα-producing CD4 T-cell responses by multi-parametric flow cytometry in 265 children aged 6 months to 10 years enrolled in a longitudinal observational cohort in a high malaria transmission site in Uganda. We found that both age and parasite burden were independently associated with cytokine production by CD4 T cells. IL10 production by IFNγ+ CD4 T cells was higher in younger children and in those with high-parasite burden during recent infection. To investigate the role of CD4 T cells in immunity to malaria, we measured associations of Pf-specific CD4 cytokine-producing cells with the prospective risk of Pf infection and clinical malaria, adjusting for household exposure to Pf-infected mosquitos. Overall, the prospective risk of infection was not associated with the total frequency of Pf-specific CD4 T cells, nor of any cytokine-producing CD4 subset. However, the frequency of CD4 cells producing IL10 but not inflammatory cytokines (IFNγ and TNFα) was associated with a decreased risk of clinical malaria once infected. These data suggest that functional polarization of the CD4 T-cell response may modulate the clinical manifestations of malaria and play a role in naturally acquired immunity.

  View details for PubMedID 29097996

  View details for PubMedCentralID PMC5653696

• Impact of intermittent preventive treatment during pregnancy on Plasmodium falciparum drug resistance-mediating polymorphisms in Uganda. The Journal of infectious diseases Conrad, M. D., Mota, D. n., Foster, M. n., Tukwasibwe, S. n., Legac, J. n., Tumwebaze, P. n., Whalen, M. n., Kakuru, A. n., Nayebare, P. n., Wallender, E. n., Havlir, D. V., Jagannathan, P. n., Huang, L. n., Aweeka, F. n., Kamya, M. R., Dorsey, G. n., Rosenthal, P. J. 2017

  Abstract

  In a recent trial of intermittent preventive treatment in pregnancy (IPTp) in Uganda, dihydroartemisinin-piperaquine (DP) was superior to sulfadoxine-pyrimethamine (SP) in preventing maternal and placental malaria.We compared genotypes using sequencing, fluorescent microsphere, and qPCR assays at loci associated with drug resistance in Plasmodium falciparum isolated from subjects receiving DP or SP.Considering aminoquinoline resistance, DP was associated with increased prevalences of mutations at pfmdr1 N86Y, pfmdr1 Y184F, and pfcrt K76T compared to SP (64.6% vs 27.4%, p<0.001; 93.9% vs 59.2%, p<0.001; and 87.7% vs 75.4%, p=0.03, respectively). Increasing plasma piperaquine concentration at the time of parasitemia was associated with increasing pfmdr1 86Y prevalence; no infections with the N86 genotype occurred with piperaquine >2.75 ng/ml. pfkelch13 propeller domain polymorphisms previously associated with artemisinin resistance were not identified. Recently identified markers of piperaquine resistance were uncommon and not associated with DP. Considering antifolate resistance, SP was associated with increased prevalence of a 5 mutation haplotype (pfdhfr 51I, 59R, and 108N; pfdhps 437G and 581G) compared to DP (90.8% vs 60.0%, p=0.001).IPTp selected for genotypes associated with decreased sensitivity to treatment regimens, but genotypes associated with clinically relevant DP resistance in Asia have not emerged in Uganda.

  View details for PubMedID 28968782

• Protective effect of indoor residual spraying of insecticide on preterm birth among pregnant women with HIV in Uganda: A secondary data analysis. The Journal of infectious diseases Roh, M. E., Shiboski, S. n., Natureeba, P. n., Kakuru, A. n., Muhindo, M. n., Ochieng, T. n., Plenty, A. n., Koss, C. A., Clark, T. D., Awori, P. n., Nakalambe, M. n., Cohan, D. n., Jagannathan, P. n., Gosling, R. n., Havlir, D. V., Kamya, M. R., Dorsey, G. n. 2017

  Abstract

  Recent evidence demonstrated improved birth outcomes among HIV-uninfected pregnant women protected by indoor residual spraying of insecticide (IRS). Evidence regarding its impact on HIV-infected pregnant women is lacking.Data were pooled from two studies conducted before-and-after an IRS campaign in Tororo, Uganda among HIV-infected pregnant women who received bednets, daily trimethoprim-sulfamethoxazole (TMP-SMX), and combination antiretroviral therapy (c-ART) at enrollment. Exposure was the proportion of pregnancy protected by IRS. Adverse birth outcomes included preterm birth, low birthweight, and fetal/neonatal death. Multivariate Poisson regression with robust standard errors was used to estimate risk ratios (RR).Of 565 women in our analysis, 380 (67%), 88 (16%), and 97 (17%) women were protected by IRS for 0%, >0-90%, and >90% of their pregnancy, respectively. Any IRS protection significantly reduced malaria incidence during pregnancy and placental malaria risk. Compared to no IRS protection, >90% IRS protection reduced preterm birth risk (RR=0.35; 95% CI: 0.15-0.84), with non-significant decreases in the risk of low birthweight (RR=0.68; 95% CI: 0.29-1.57) and fetal/neonatal death (RR=0.24; 95% CI: 0.04-1.52).Our exploratory analyses support the hypothesis that IRS may significantly reduce malaria and preterm birth risk among pregnant women with HIV receiving bednets, daily TMP-SMX, and c-ART.

  View details for PubMedID 29029337

• Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes. Malaria journal Kapisi, J. n., Kakuru, A. n., Jagannathan, P. n., Muhindo, M. K., Natureeba, P. n., Awori, P. n., Nakalembe, M. n., Ssekitoleko, R. n., Olwoch, P. n., Ategeka, J. n., Nayebare, P. n., Clark, T. D., Rizzuto, G. n., Muehlenbachs, A. n., Havlir, D. V., Kamya, M. R., Dorsey, G. n., Gaw, S. L. 2017; 16 (1): 400

  Abstract

  Malaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes.This is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12-20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants.The 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0-1 episodes of symptomatic malaria and < 50% of samples LAMP+), and 73 (25.9%) had high malaria burden during pregnancy (≥ 2 episodes of symptomatic malaria or ≥ 50% of samples LAMP+). Women with high malaria burden had increased risks of placental malaria by blood microscopy and LAMP [aRR 14.2 (1.80-111.6) and 4.06 (1.73-9.51), respectively], compared to the other two groups combined. Compared with women with no malaria exposure during pregnancy, the risk of placental malaria by histopathology was higher among low and high burden groups [aRR = 3.27 (1.32-8.12) and aRR = 7.07 (2.84-17.6), respectively]. Detection of placental parasites by any method was significantly associated with PTB [aRR 5.64 (1.46-21.8)], and with a trend towards increased risk for LBW and SGA irrespective of the level of malaria burden during pregnancy.Higher malaria burden during pregnancy was associated with placental malaria and together with the detection of parasites in the placenta were associated with increased risk for adverse birth outcomes. Trial Registration Current Controlled Trials Identifier NCT02163447.

  View details for PubMedID 28982374

  View details for PubMedCentralID PMC5629777

• Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation MALARIA JOURNAL Prahl, M., Jagannathan, P., McIntyre, T. I., Auma, A., Farrington, L., Wamala, S., Nalubega, M., Musinguzi, K., Naluwu, K., Sikyoma, E., Budker, R., Vance, H., Odorizzi, P., Nayebare, P., Ategeka, J., Kakuru, A., Havlir, D. V., Kamya, M. R., Dorsey, G., Feeney, M. E. 2016; 15

  Abstract

  In malaria-endemic areas, the first exposure to malaria antigens often occurs in utero when the fetal immune system is poised towards the development of tolerance. Children exposed to placental malaria have an increased risk of clinical malaria in the first few years of life compared to unexposed children. Recent work has suggested the potential of pregnancy-associated malaria to induce immune tolerance in children living in malaria-endemic areas. A study was completed to evaluate the effect of malaria exposure during pregnancy on fetal immune tolerance and effector responses.Using cord blood samples from a cohort of mother-infant pairs followed from early in pregnancy until delivery, flow cytometry analysis was completed to assess the relationship between pregnancy-associated malaria and fetal cord blood CD4 and dendritic cell phenotypes.Cord blood FoxP3(+) Treg counts were higher in infants born to mothers with Plasmodium parasitaemia early in pregnancy (12-20 weeks of gestation; p = 0.048), but there was no association between Treg counts and the presence of parasites in the placenta at the time of delivery (by loop-mediated isothermal amplification (LAMP); p = 0.810). In contrast, higher frequencies of activated CD4 T cells (CD25(+)FoxP3(-)CD127(+)) were observed in the cord blood of neonates with active placental Plasmodium infection at the time of delivery (p = 0.035). This population exhibited evidence of effector memory differentiation, suggesting priming of effector T cells in utero. Lastly, myeloid dendritic cells were higher in the cord blood of infants with histopathologic evidence of placental malaria (p < 0.0001).Together, these data indicate that in utero exposure to malaria drives expansion of both regulatory and effector T cells in the fetus, and that the timing of this exposure has a pivotal role in determining the polarization of the fetal immune response.

  View details for DOI 10.1186/s12936-016-1545-6

  View details for Web of Science ID 000384846400001

  View details for PubMedID 27717402

  View details for PubMedCentralID PMC5055709

• Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children. journal of infectious diseases Rodriguez-Barraquer, I., Arinaitwe, E., Jagannathan, P., Boyle, M. J., Tappero, J., Muhindo, M., Kamya, M. R., Dorsey, G., Drakeley, C., Ssewanyana, I., Smith, D. L., Greenhouse, B. 2016; 214 (7): 1072-1080

  Abstract

  Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure.We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease.Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%-12%) for each additional year of age and by 2% (95% CI, 1%-3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether-lumefantrine.Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity.

  View details for DOI 10.1093/infdis/jiw301

  View details for PubMedID 27481862

  View details for PubMedCentralID PMC5021229

• Characterizing microscopic and submicroscopic malaria parasitaemia at three sites with varied transmission intensity in Uganda MALARIA JOURNAL Rek, J., Katrak, S., Obasi, H., Nayebare, P., Katureebe, A., Kakande, E., Arinaitwe, E., Nankabirwa, J. I., Jagannathan, P., Drakeley, C., Staedke, S. G., Smith, D. L., Bousema, T., Kamya, M., Rosenthal, P. J., Dorsey, G., Greenhouse, B. 2016; 15

  Abstract

  Parasite prevalence is a key metric used to quantify the burden of malaria and assess the impact of control strategies. Most published estimates of parasite prevalence are based on microscopy and likely underestimate true prevalence.Thick smear microscopy was performed in cohorts of children (aged 6 month to 10 years) and adults every 90 days over 2 years, at three sites of varying transmission intensity in Uganda. Microscopy-negative samples were tested for sub-microscopic parasitaemia using loop-mediated isothermal amplification (LAMP). Generalized estimating equation models were used to evaluate associations between age and parasitaemia, factors associated with sub-microscopic infection and associations between parasitaemia and haemoglobin.A total of 9260 samples were collected from 1245 participants. Parasite prevalence among children across the three sites was 7.4, 9.4 and 28.8 % by microscopy and 21.3, 31.8 and 69.0 % by microscopy plus LAMP. Parasite prevalence among adults across the three sites was 3.1, 3.0 and 5.2 % by microscopy and 18.8, 24.2 and 53.5 % by microscopy plus LAMP. Among those with parasitaemia, adults and persons recently treated with anti-malarial therapy had the highest prevalence of sub-microscopic infection. Children with sub-microscopic or microscopic parasitaemia had lower mean haemoglobin levels compared to children with no detectable parasites.Across a range of transmission intensities in Uganda, microscopy vastly underestimated parasite prevalence, especially among adults.

  View details for DOI 10.1186/s12936-016-1519-8

  View details for Web of Science ID 000383665400001

  View details for PubMedID 27628178

  View details for PubMedCentralID PMC5024471

• Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda MALARIA JOURNAL Muhindo, M. K., Kakuru, A., Natureeba, P., Awori, P., Olwoch, P., Ategeka, J., Nayebare, P., Clark, T. D., Muehlenbachs, A., Roh, M., Mpeka, B., Greenhouse, B., Havlir, D. V., Kamya, M. R., Dorsey, G., Jagannathan, P. 2016; 15

  Abstract

  Indoor residual spraying of insecticide (IRS) is a key intervention for reducing the burden of malaria in Africa. However, data on the impact of IRS on malaria in pregnancy and birth outcomes is limited.An observational study was conducted within a trial of intermittent preventive therapy during pregnancy in Tororo, Uganda. Women were enrolled at 12-20 weeks of gestation between June and October 2014, provided with insecticide-treated bed nets, and followed through delivery. From December 2014 to February 2015, carbamate-containing IRS was implemented in Tororo district for the first time. Exact spray dates were collected for each household. The exposure of interest was the proportion of time during a woman's pregnancy under protection of IRS, with three categories of protection defined: no IRS protection, >0-20 % IRS protection, and 20-43 % IRS protection. Outcomes assessed included malaria incidence and parasite prevalence during pregnancy, placental malaria, low birth weight (LBW), pre-term delivery, and fetal/neonatal deaths.Of 289 women followed, 134 had no IRS protection during pregnancy, 90 had >0-20 % IRS protection, and 65 had >20-43 % protection. During pregnancy, malaria incidence (0.49 vs 0.10 episodes ppy, P = 0.02) and parasite prevalence (20.0 vs 8.9 %, P < 0.001) were both significantly lower after IRS. At the time of delivery, the prevalence of placental parasitaemia was significantly higher in women with no IRS protection (16.8 %) compared to women with 0-20 % (1.1 %, P = 0.001) or >20-43 % IRS protection (1.6 %, P = 0.006). Compared to women with no IRS protection, those with >20-43 % IRS protection had a lower risk of LBW (20.9 vs 3.1 %, P = 0.002), pre-term birth (17.2 vs 1.5 %, P = 0.006), and fetal/neonatal deaths (7.5 vs 0 %, P = 0.03).In this setting, IRS was temporally associated with lower malaria parasite prevalence during pregnancy and at delivery, and improved birth outcomes. IRS may represent an important tool for combating malaria in pregnancy and for improving birth outcomes in malaria-endemic settings. Trial Registration Current Controlled Trials Identifier NCT02163447.

  View details for DOI 10.1186/s12936-016-1489-x

  View details for Web of Science ID 000382535500004

  View details for PubMedID 27566109

• Effective Antimalarial Chemoprevention in Childhood Enhances the Quality of CD4(+) T Cells and Limits Their Production of Immunoregulatory Interleukin 10 JOURNAL OF INFECTIOUS DISEASES Jagannathan, P., Bowen, K., Nankya, F., McIntyre, T. I., Auma, A., Wamala, S., Sikyomu, E., Naluwu, K., Nalubega, M., Boyle, M. J., Farrington, L. A., Bigira, V., Kapisi, J., Aweeka, F., Greenhouse, B., Kamya, M., Dorsey, G., Feeney, M. E. 2016; 214 (2): 329-338

  Abstract

  Experimental inoculation of viable Plasmodium falciparum sporozoites administered with chemoprevention targeting blood-stage parasites results in protective immunity. It is unclear whether chemoprevention similarly enhances immunity following natural exposure to malaria.We assessed P. falciparum-specific T-cell responses among Ugandan children who were randomly assigned to receive monthly dihydroartemisinin-piperaquine (DP; n = 87) or no chemoprevention (n = 90) from 6 to 24 months of age, with pharmacologic assessments for adherence, and then clinically followed for an additional year.During the intervention, monthly DP reduced malaria episodes by 55% overall (P < .001) and by 97% among children who were highly adherent to DP (P < .001). In the year after the cessation of chemoprevention, children who were highly adherent to DP had a 55% reduction in malaria incidence as compared to children given no chemoprevention (P = .004). Children randomly assigned to receive DP had higher frequencies of blood-stage specific CD4(+) T cells coproducing interleukin-2 and tumor necrosis factor α (P = .003), which were associated with protection from subsequent clinical malaria and parasitemia, and fewer blood-stage specific CD4(+) T cells coproducing interleukin-10 and interferon γ (P = .001), which were associated with increased risk of malaria.In this setting, effective antimalarial chemoprevention fostered the development of CD4(+) T cells that coproduced interleukin 2 and tumor necrosis factor α and were associated with prospective protection, while limiting CD4(+) T-cell production of the immunoregulatory cytokine IL-10.

  View details for DOI 10.1093/infdis/jiw147

  View details for Web of Science ID 000379822900021

  View details for PubMedID 27067196

  View details for PubMedCentralID PMC4918829

• Frequent Malaria Drives Progressive V delta 2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood JOURNAL OF INFECTIOUS DISEASES Farrington, L. A., Jagannathan, P., McIntyre, T. I., Vance, H. M., Bowen, K., Boyle, M. J., Nankya, F., Wamala, S., Auma, A., Nalubega, M., Sikyomu, E., Naluwu, K., Bigira, V., Kapisi, J., Dorsey, G., Kamya, M. R., Feeney, M. E. 2016; 213 (9): 1483-1490

  Abstract

  γδ T cells expressing Vδ2 may be instrumental in the control of malaria, because they inhibit the replication of blood-stage parasites in vitro and expand during acute malaria infection. However, Vδ2 T-cell frequencies and function are lower among children with heavy prior malaria exposure. It remains unclear whether malaria itself is driving this loss. Here we measure Vδ2 T-cell frequency, cytokine production, and degranulation longitudinally in Ugandan children enrolled in a malaria chemoprevention trial from 6 to 36 months of age. We observed a progressive attenuation of the Vδ2 response only among children incurring high rates of malaria. Unresponsive Vδ2 T cells were marked by expression of CD16, which was elevated in the setting of high malaria transmission. Moreover, chemoprevention during early childhood prevented the development of dysfunctional Vδ2 T cells. These observations provide insight into the role of Vδ2 T cells in the immune response to chronic malaria.

  View details for DOI 10.1093/infdis/jiv600

  View details for Web of Science ID 000376295800018

  View details for PubMedID 26667315

  View details for PubMedCentralID PMC4813738

• B cell sub-types following acute malaria and associations with clinical immunity (vol 15, 139, 2016) MALARIA JOURNAL Sullivan, R. T., Ssewanyana, I., Wamala, S., Nankya, F., Jagannathan, P., Tappero, J. W., Mayanja-Kizza, H., Muhindo, M. K., Arinaitwe, E., Kamya, M., Dorsey, G., Feeney, M. E., Riley, E. M., Drakeley, C. J., Greenhouse, B. 2016; 15

  View details for DOI 10.1186/s12936-016-1236-3

  View details for Web of Science ID 000373485200005

• Erratum to: B cell sub-types following acute malaria and associations with clinical immunity. Malaria journal Sullivan, R. T., Ssewanyana, I., Wamala, S., Nankya, F., Jagannathan, P., Tappero, J. W., Mayanja-Kizza, H., Muhindo, M. K., Arinaitwe, E., Kamya, M., Dorsey, G., Feeney, M. E., Riley, E. M., Drakeley, C. J., Greenhouse, B. 2016; 15: 188

  View details for DOI 10.1186/s12936-016-1236-3

  View details for PubMedID 27036294

  View details for PubMedCentralID PMC4818512

• B cell sub-types following acute malaria and associations with clinical immunity. Malaria journal Sullivan, R. T., Ssewanyana, I., Wamala, S., Nankya, F., Jagannathan, P., Tappero, J. W., Mayanja-Kizza, H., Muhindo, M. K., Arinaitwe, E., Kamya, M., Dorsey, G., Feeney, M. E., Riley, E. M., Drakeley, C. J., Greenhouse, B., Sullivan, R. 2016; 15: 139

  Abstract

  Repeated exposure to Plasmodium falciparum is associated with perturbations in B cell sub-set homeostasis, including expansion atypical memory B cells. However, B cell perturbations immediately following acute malaria infection have been poorly characterized, especially with regard to their relationship with immunity to malaria.To better understand the kinetics of B cell sub-sets following malaria, the proportions of six B cell sub-sets were assessed at five time points following acute malaria in four to 5 years old children living in a high transmission region of Uganda. B cell sub-set kinetics were compared with measures of clinical immunity to malaria-lower parasite density at the time of malaria diagnosis and recent asymptomatic parasitaemia.Atypical memory B cell and transitional B cell proportions increased following malaria. In contrast, plasmablast proportions were highest at the time of malaria diagnosis and rapidly declined following treatment. Increased proportions of atypical memory B cells were associated with greater immunity to malaria, whereas increased proportions of transitional B cells were associated with evidence of less immunity to malaria.These findings highlight the dynamic changes in multiple B cell sub-sets following acute, uncomplicated malaria, and how these sub-sets are associated with developing immunity to malaria.

  View details for DOI 10.1186/s12936-016-1190-0

  View details for PubMedID 26939776

  View details for PubMedCentralID PMC4778296

• Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children MALARIA JOURNAL Sundell, K., Jagannathan, P., Huang, L., Bigira, V., Kapisi, J., Kakuru, M. M., Savic, R., Kamya, M. R., Dorsey, G., Aweeka, F. 2015; 14

  Abstract

  Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure.Children were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored.The incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39-66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6-49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54-76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89-99 %, P < 0.001).The protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy.Current Controlled Trials Identifier NCT00948896.

  View details for DOI 10.1186/s12936-015-0908-8

  View details for Web of Science ID 000361786600002

  View details for PubMedID 26403465

• Effector Phenotype of Plasmodium falciparum-Specific CD4(+) T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations JOURNAL OF INFECTIOUS DISEASES Boyle, M. J., Jagannathan, P., Bowen, K., McIntyre, T. I., Vance, H. M., Farrington, L. A., Greenhouse, B., Nankya, F., Rek, J., Katureebe, A., Arinaitwe, E., Dorsey, G., Kamya, M. R., Feeney, M. E. 2015; 212 (3): 416-425

  Abstract

  Mechanisms mediating immunity to malaria remain unclear, but animal data and experimental human vaccination models suggest a critical role for CD4(+) T cells. Advances in multiparametric flow cytometry have revealed that the functional quality of pathogen-specific CD4(+) T cells determines immune protection in many infectious models. Little is known about the functional characteristics of Plasmodium-specific CD4(+) T-cell responses in immune and nonimmune individuals.We compared T-cell responses to Plasmodium falciparum among household-matched children and adults residing in settings of high or low malaria transmission in Uganda. Peripheral blood mononuclear cells were stimulated with P. falciparum antigen, and interferon γ (IFN-γ), interleukin 2, interleukin 10, and tumor necrosis factor α (TNF-α) production was analyzed via multiparametric flow cytometry.We found that the magnitude of the CD4(+) T-cell responses was greater in areas of high transmission but similar between children and adults in each setting type. In the high-transmission setting, most P. falciparum-specific CD4(+) T-cells in children produced interleukin 10, while responses in adults were dominated by IFN-γ and TNF-α. In contrast, in the low-transmission setting, responses in both children and adults were dominated by IFN-γ and TNF-α.These findings highlight major differences in the CD4(+) T-cell response of immune adults and nonimmune children that may be relevant for immune protection from malaria.

  View details for DOI 10.1093/infdis/jiv054

  View details for Web of Science ID 000357824300011

  View details for PubMedID 25646355

  View details for PubMedCentralID PMC4539911

• Decline of FoxP3+Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria PLOS PATHOGENS Boyle, M. J., Jagannathan, P., Farrington, L. A., Eccles-James, I., Wamala, S., McIntyre, T. I., Vance, H. M., Bowen, K., Nankya, F., Auma, A., Nalubega, M., Sikyomu, E., Naluwu, K., Rek, J., Katureebe, A., Bigira, V., Kapisi, J., Tappero, J., Muhindo, M. K., Greenhouse, B., Arinaitwe, E., Dorsey, G., Kamya, M. R., Feeney, M. E. 2015; 11 (7)

  Abstract

  FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.

  View details for DOI 10.1371/journal.ppat.1005041

  View details for Web of Science ID 000359365200048

  View details for PubMedID 26182204

  View details for PubMedCentralID PMC4504515

• IFN gamma Responses to Pre-erythrocytic and Blood-stage Malaria Antigens Exhibit Differential Associations With Past Exposure and Subsequent Protection JOURNAL OF INFECTIOUS DISEASES Jagannathan, P., Nankya, F., Stoyanov, C., Eccles-James, I., Sikyomu, E., Naluwu, K., Wamala, S., Nalubega, M., Briggs, J., Bowen, K., Bigira, V., Kapisi, J., Kamya, M. R., Dorsey, G., Feeney, M. E. 2015; 211 (12): 1987-1996

  Abstract

  The malaria-specific T-cell response is believed to be important for protective immunity. Antimalarial chemoprevention may affect this response by altering exposure to malaria antigens.We performed interferon γ (IFNγ) ELISpot assays to assess the cellular immune response to blood-stage and pre-erythrocytic antigens longitudinally from 1 to 3 years of age in 196 children enrolled in a randomized trial of antimalarial chemoprevention in Tororo, Uganda, an area of high transmission intensity.IFNγ responses to blood-stage antigens, particularly MSP1, were frequently detected, strongly associated with recent malaria exposure, and lower in those adherent to chemoprevention compared to nonadherent children and those randomized to no chemoprevention. IFNγ responses to pre-erythrocytic antigens were infrequent and similar between children randomized to chemoprevention or no chemoprevention. Responses to blood-stage antigens were not associated with subsequent protection from malaria (aHR 0.96, P = .83), but responses to pre-erythrocytic antigens were associated with protection after adjusting for prior malaria exposure (aHR 0.52, P = .009).In this high transmission setting, IFNγ responses to blood-stage antigens were common and associated with recent exposure to malaria but not protection from subsequent malaria. Responses to pre-erythrocytic antigens were uncommon, not associated with exposure but were associated with protection from subsequent malaria.

  View details for DOI 10.1093/infdis/jiu814

  View details for Web of Science ID 000355675600017

  View details for PubMedID 25520427

• FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure PLOS PATHOGENS Sullivan, R. T., Kim, C. C., Fontana, M. F., Feeney, M. E., Jagannathan, P., Boyle, M. J., Drakeley, C. J., Ssewanyana, I., Nankya, F., Mayanja-Kizza, H., Dorsey, G., Greenhouse, B. 2015; 11 (5)

  Abstract

  Exposure to Plasmodium falciparum is associated with circulating "atypical" memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.

  View details for DOI 10.1371/journal.ppat.1004894

  View details for Web of Science ID 000355269300038

  View details for PubMedID 25993340

• Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial AIDS Kamya, M. R., Kapisi, J., Bigira, V., Clark, T. D., Kinara, S., Mwangwa, F., Muhindo, M. K., Kakuru, A., Aweeka, F. T., Huang, L., Jagannathan, P., Achan, J., Havlir, D. V., Rosenthal, P. J., Dorsey, G. 2014; 28 (18): 2701-2709

  Abstract

  Trimethoprim-sulfamethoxazole prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children.An open-label, randomized controlled trial.Tororo, Uganda, a rural area with intense, year-round, malaria transmission.Two hundred infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age).No chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole or monthly dihydroartemisinin-piperaquine given from randomization to 24 months of age.The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrhoeal illness, or respiratory tract infection; prevalence of anaemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped.During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% [95% confidence interval (95% CI) 53-80, P < 0.001] for dihydroartemisinin-piperaquine, 49% (95% CI 23-66, P = 0.001) for trimethoprim-sulfamethoxazole and 9% for sulfadoxine-pyrimethamine (95% CI -35 to 38, P = 0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the dihydroartemisinin-piperaquine arm.Monthly chemoprevention with dihydroartemisinin-piperaquine was well tolerated and associated with a significant reduction in malaria in young HIV-exposed children.

  View details for DOI 10.1097/QAD.0000000000000497

  View details for Web of Science ID 000345277300008

  View details for PubMedID 25493596

• Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria MALARIA JOURNAL Muhindo, M. K., Kakuru, A., Jagannathan, P., Talisuna, A., Osilo, E., Orukan, F., Arinaitwe, E., Tappero, J. W., Kaharuza, F., Kamya, M. R., Dorsey, G. 2014; 13

  Abstract

  Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance.Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient.A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR = 1.34, 95% CI 1.20-1.50, p < 0.001), having a temperature ≥38.0°C vs < 37.0°C (RR = 1.19, 95% CI 1.05-1.35, p = 0.007) and having a parasite density >20,000/μL vs <4,000/μL (RR = 3.37, 95% CI 2.44-4.49, p < 0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected.Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy.Current Controlled Trials Identifier NCT00527800.

  View details for DOI 10.1186/1475-2875-13-32

  View details for Web of Science ID 000331402500001

  View details for PubMedID 24468007

• The Effects of ACT Treatment and TS Prophylaxis on Plasmodium falciparum Gametocytemia in a Cohort of Young Ugandan Children AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Kakuru, A., Jagannathan, P., Arinaitwe, E., Wanzira, H., Muhindo, M., Bigira, V., Osilo, E., Homsy, J., Kamya, M. R., Tappero, J. W., Dorsey, G. 2013; 88 (4): 736-743

  Abstract

  Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P < 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P < 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.

  View details for DOI 10.4269/ajtmh.12-0654

  View details for Web of Science ID 000317024700023

  View details for PubMedID 23382157

• Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda MALARIA JOURNAL Jagannathan, P., Muhindo, M. K., Kakuru, A., Arinaitwe, E., Greenhouse, B., Tappero, J., Rosenthal, P. J., Kaharuza, F., Kamya, M. R., Dorsey, G. 2012; 11

  Abstract

  The burden of malaria has decreased in parts of Africa following the scaling up of control interventions. However, similar data are limited from high transmission settings.A cohort of 100 children, aged six weeks to 10 months of age, were enrolled in an area of high malaria transmission intensity and followed through 48 months of age. Children were given a long-lasting insecticide-treated bed net (LLIN) at enrolment and received all care, including monthly blood smears and treatment with artemisinin-based combination therapy (ACT) for uncomplicated malaria, at a dedicated clinic. The incidence of malaria was estimated by passive surveillance and associations between malaria incidence and age, calendar time and season were measured using generalized estimating equations.Reported compliance with LLINs was 98% based on monthly routine evaluations. A total of 1,633 episodes of malaria were observed, with a median incidence of 5.3 per person-year (PPY). There were only six cases of complicated malaria, all single convulsions. Malaria incidence peaked at 6.5 PPY at 23 months of age before declining to 3.5 PPY at 48 months. After adjusting for age and season, the risk of malaria increased by 52% from 2008 to 2011 (RR 1.52, 95% CI 1.10-2.09). Asymptomatic parasitaemia was uncommon (monthly prevalence <10%) and rarely observed prior to 24 months of age.In Tororo, despite provision of LLINs and prompt treatment with ACT, the incidence of malaria is very high and appears to be rising. Additional malaria control interventions in high transmission settings are likely needed.Current Controlled Trials Identifier NCT00527800.

  View details for DOI 10.1186/1475-2875-11-435

  View details for Web of Science ID 000313871300002

  View details for PubMedID 23273022

• Pantoea agglomerans pneumonia in a heart-lung transplant recipient: case report and a review of an emerging pathogen in immunocompromised hosts TRANSPLANT INFECTIOUS DISEASE Shubov, A., Jagannathan, P., Chin-Hong, P. V. 2011; 13 (5): 536-539

  Abstract

  Pantoea agglomerans is a gram-negative rod that is frequently found on the exterior of many plants, fruits, vegetables, and in soil, and it is used as a biopesticide in the agriculture industry. Recent reports have implicated P. agglomerans in systemic infections of immunocompromised hosts and neonates, as well as more localized infections in healthy hosts. P. agglomerans as a cause of hospital-acquired pneumonia has not been well characterized. We report a case of P. agglomerans pneumonia in a heart-lung transplant recipient following transplantation. The organism was susceptible to multiple antimicrobial agents and treated successfully with ertapenem. We review the patient's course and the relevant literature, and discuss implications for the future.

  View details for DOI 10.1111/j.1399-3062.2011.00630.x

  View details for Web of Science ID 000295837900017

  View details for PubMedID 21504526

• Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis pneumonia: a cautionary case series AIDS Jagannathan, P., Davis, E., Jacobson, M., Huang, L. 2009; 23 (13): 1794-1796

  View details for DOI 10.1097/QAD.0b013e32832d9b20

  View details for Web of Science ID 000269333900024

  View details for PubMedID 19684486

• Comparisons of CD8(+) T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness JOURNAL OF VIROLOGY Jagannathan, P., Osborne, C. M., Royce, C., Manion, M. M., Tilton, J. C., Li, L., Fischer, S., Hallahan, C. W., Metcalf, J. A., McLaughlin, M., Pipeling, M., McDyer, J. F., Manley, T. J., Meier, J. L., Altman, J. D., Hertel, L., Davey, R. T., Connors, M., Migueles, S. A. 2009; 83 (6): 2728-2742

  Abstract

  To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8(+) T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8(+) T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8(+) T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8(+) T cells were predominantly CD27(+)45RO(+) for HIV and CD27(-)45RA(+) for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8(+) T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8(+) T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8(+) T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained.

  View details for DOI 10.1128/JVI.02128-08

  View details for Web of Science ID 000263650500032

  View details for PubMedID 19129459

• Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda MALARIA JOURNAL Staedke, S. G., Jagannathan, P., Yeka, A., Bukirwa, H., Banek, K., Maiteki-Sebuguzi, C., Clark, T. D., Nzarubara, B., Njama-Meya, D., Mpimbaza, A., Rosenthal, P. J., Kamya, M. R., Wabwire-Mangen, F., Dorsey, G., Talisuna, A. O. 2008; 7

  Abstract

  New antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials.Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity.Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported.Although the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.

  View details for DOI 10.1186/1475-2875-7-107

  View details for Web of Science ID 000257609000001

  View details for PubMedID 18547416

• Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children MALARIA JOURNAL Maiteki-Sebuguzi, C., Jagannathan, P., Yau, V. M., Clark, T. D., Njama-Meya, D., Nzarubara, B., Talisuna, A. O., Kamya, M. R., Rosenthal, P. J., Dorsey, G., Staedke, S. G. 2008; 7

  Abstract

  Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children.A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment.Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 - 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 - 9.17; weakness: RR 5.40, 95% CI 1.86 - 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 - 4.23; weakness: RR 2.26, 95% CI 1.01 - 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings.This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential.Current Controlled Trials Identifier ISRCTN37517549.

  View details for DOI 10.1186/1475-2875-7-106

  View details for Web of Science ID 000257163700001

  View details for PubMedID 18547415

• Limitations in knowledge of HIV transmission among HIV-positive patients accessing case management services in a resource-poor setting AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV Fawzi, M. C., Jagannathan, P., Cabral, J., Banares, R., Salazar, J., Farmer, P., BEHFOROUZ, H. 2006; 18 (7): 764-771

  Abstract

  HIV has increasingly become an infection of poverty. Adequate HIV transmission knowledge among HIV-positive patients is necessary to reduce the risk of secondary infection and protect those who are uninfected from transmission. This study was conducted among individuals enrolled in a program that serves impoverished HIV patients in the Boston area. Although the mean HIV transmission knowledge score was 80% for this group, a significant proportion of patients demonstrated limitations in knowledge of HIV transmission. Highly vulnerable patients, such as those who reported not accessing HIV medications, a history of sexual abuse, or problems getting clothing, had lower levels of HIV knowledge. This paper hopes to alert providers that their most vulnerable patients may be at an increased risk of re-infection or transmission due to limited HIV knowledge. Programs that serve HIV-positive patients coping with poverty and other serious problems need to ensure adequate knowledge of HIV transmission to reduce the overall burden of HIV in resource-poor settings.

  View details for DOI 10.1080/09540120500373844

  View details for Web of Science ID 000240620300017

  View details for PubMedID 16971286