Dr. Cornelia Dekker is a Pediatric Infectious Diseases physician who came to Stanford after a 12-year career in vaccine clinical development at Lederle Biologicals and Chiron Vaccines where she served as Vice President, Clinical Research and Medical Affairs. In this position, she was responsible for the clinical development of 18 vaccine candidates, including those for HSV, HIV, meningococcus A and C, adjuvanted influenza, acellular pertussis-DT, hepatitis A, hepatitis B, hepatitis C, H. influenza type b and CMV. During her tenure, Chiron’s clinical program included testing of a recombinantly produced HSV gD2/gB2 vaccine with MF59 adjuvant for the amelioration of established genital herpes infection and the prevention of genital herpes in high-risk adults, and the first influenza vaccine combined with the MF59 adjuvant that was licensed intially in Europe and South America and just recently also in the US.
Dr. Dekker joined the Stanford University School of Medicine faculty in the Division of Pediatric Infectious Diseases and was named Medical Director of the Stanford-LPCH Vaccine Program in 1999. She has served as the Stanford PI on NIH-sponsored Vaccine and Treatment Evaluation Unit subcontracts to study new vaccine candidates and on a CDC-sponsored Clinical Immunization Safety Assessment Center contract evaluating safety of licensed vaccines. She leads the Stanford Clinical Core for NIH-sponsored studies looking at the detailed immune responses to influenza vaccines in children compared with young and elderly adults that has expanded to investigate genetic factors by also studying responses of identical and fraternal twins. Dr. Dekker’s expertise in vaccines has been tapped by NIH to serve on several vaccine safety and data monitoring boards, and she currently is Chair of the HIV Vaccine Trial Network Safety Monitoring Board. On the National Vaccine Advisory Committee, she served on the Vaccine Safety Working Group and H1N1 Vaccine Safety Subgroup among others. In 2016, she was named Medical Director for the Stanford Clinical and Translational Research Unit.
- Pediatric Infectious Disease
- Vaccine Clinical Trials
- Vaccine Safety
- Influenza, Human
- Clinical Research
Medical Director, Stanford-LPCH Vaccine Program (1999 - Present)
Medical Director, Stanford Clinical and Translational Research Unit (2016 - Present)
IRB Reviewer, Stanford Administrative Panel on Human Subjects in Medical Research, Panel 3 (2002 - Present)
Member, Stanford Institute for Immunity, Transplantation and Infection (2005 - Present)
Member, Department of Pediatrics Research Advisory Committee (2009 - 2015)
Member, Department of Pediatrics Administrative Advisory Committee (2008 - 2009)
Member, Stanford GCRC Advisory Committee (2006 - 2008)
Honors & Awards
Fellow, Infectious Diseases Society of America (1998-present)
Member, Pediatric Infectious Diseases Society (1998-present)
Junior Faculty Award, SmithKlein Beecham (07/05/00-07/04/02)
Excellence in Teaching, Stanford Univ. School of Medicine (06/23/08)
Boards, Advisory Committees, Professional Organizations
Chair, NIH DMID SMC: Phase I, Randomized, Double-blinded, Placebo-Controlled Dose De-escalation Study to Evaluate Safety and Immunogenicity of Alum Adjuvanted Zika Virus Purified Inactivated Vaccine (ZPIV) in Adults in a Flavivirus Endemic Area (2017 - Present)
Member, NIH DMID SMC: Phase 1, Double Blinded, Placebo Controlled, Dose Comparison Trial to Evaluate the Safety, Immunogenicity and Schedule of Measles-Vectored Chikungunya Virus Vaccine (MV-CHIK) in Healthy Adults (2017 - Present)
Chair, NIH DMID SMC: Phase I Placebo-Controlled Inactivated Whole Virus ZIKA Virus Vaccine in Flavivirus Naive Subjects (2016 - Present)
Chair, NIH DMID SMC: A Phase 1, First-in-human, Double-blinded, Randomized, Placebo-controlled Trial of a Zika Virus Purified Inactivated Vaccine (ZPIV) with Alum Adjuvant in Healthy Flavivirus-naive and Flavivirus-Primed Subjects (2016 - Present)
Chair, NIH DMID SMC: Phase I Study to Determine the Human Infectious Dose Causing 50% Infection with the GII.2 Snow Mountain Norovirus Filtrate, SNM (2013 - Present)
Chair, NIH DMID SMC: Phase I Study of the GII.4 Norovirus Filtrate, CIN 1 (2013 - 2015)
Member, NIH DMID SMC: 13-Valent Pneumococcal Conjugate Vaccine in Adults 55 through 74 Years of Age (2012 - Present)
Member, External Data Monitoring Committee for ACC-001 (vanutide cridificar) Alzheimer’s disease vaccine (2011 - 2014)
Member and Chair, HIV Vaccine Trial Network Safety Monitoring Board (Chair 2014-present) (2009 - Present)
Member, NVAC H1N1 Subgroup (2009 - 2010)
Member, NIH DMID SMC Evaluation of a Challenge Pool of Norwalk Virus Inocula in Human Subjects (2008 - Present)
Member, NVAC Vaccine Safety Working Group (2008 - 2011)
Member, NIH DMID Phase 1A Clinical Study with DAS181 Safety Monitoring Committee (2007 - 2010)
Member, National Vaccine Advisory Committee (NVAC) (2005 - 2010)
Co-chair, NVAC Subcommittee on Vaccine Development and Supply (2005 - 2008)
Chair (Pediatric), NIH DMID/Sanofi Pasteur Inactivated Influenza A/H5N1 Vaccine Data Safety Monitoring Board (2005 - 2007)
Co-chair, NVAC Working Group on Regulatory Harmonization (2005 - 2006)
Member, Trustee Committee, California Association of Independent Schools (2004 - 2007)
President, Bentley School Board of Trustees (2001 - 2004)
Trustee, Bentley School Board of Trustees (1997 - 2004)
Board Certification: Pediatrics, American Board of Pediatrics (1981)
Medical Education:Michigan State University (1976) MI
Fellowship:Duke University Medical Center (1982) NC
Residency:Duke University Medical Center (1979) NC
Internship:Duke University Medical Center (1977) NC
B.S., Michigan State University, Microbiology & Public Health, Human Clinical Medicine (1973)
M.D., Michigan State University, Medicine (1976)
Current Research and Scholarly Interests
The overarching theme of our research activities is human response to natural virus infection and to vaccines. We have conducted several studies of adult, toddler and infant immune response to initial infection with human cytomegalovirus (HCMV). Our largest was a project in which we screened 20,000 newborn infants at Stanford, El Camino and Santa Clara Valley Hospitals for evidence of congenital HCMV infection. Those infants identified as being infected were enrolled into a 3-year prospective study for medical, audiology and immunology screening. The hearing screening portion was designed to identify, as early as possible, infants who develop sensorineural hearing loss as a result of this infection.
A second area of clinical research is supported by Dr. Mark Davis' NIH-funded CCHI U19 project entitled "Protective Mechanisms Against Pandemic Respiratory Virus" and the HIPC U19 project entitled "Vaccination and Infection: Indicators of Immunological Health and Responsiveness". To provide samples for the lab projects we immunize children and adults (including elderly) with one of four different, licensed influenza vaccines (Fluzone, Fluzone high-dose, Fluzone Intradermal or FluMist) to study in detail the immune response to immunization given by various routes. Blood samples collected from study subjects are analyzed for influenza-specific B and T-cell responses as well as gene expression studies and cytokine analyses. Our latest studies have focused on genetic vs. environmental influences by enrolling fraternal and identical twins. Under the HIPC U19, we conducted a study of the shingles vaccine in twins and non-twin adults for a close examination of T-cell responses. We also have conducted a study of natural influenza infection for the past 4 years in children and adults to collect NP swabs and blood samples in collaboration with researchers in the Greenberg lab who study how B cells and T cells respond to influenza virus infection at these two sites.
Our group also was funded as part of the Vaccine Treatment and Evaluation Units by NIH through our collaborators at Vanderbilt University. We conducted studies of avian, novel H1N1 and seasonal influenza vaccines and a new malaria vaccine under this subcontract. A study of a new DNA vaccine against influenza was conducted under sponsorship by EMMES Corporation and the Vaccine Research Center at NIH.
A fourth area of interest has been vaccine safety. Stanford was one of six designated Centers for Immunization Safety Assessment (CISA) sponsored by the CDC for a 10 year period. The network provided consultation to CDC on evaluation and treatment of adverse events following immunization with licensed vaccines, developed protocols to study certain events that occur following immunization (including hypersensitivity reactions, safety of live viral vaccines in immunodeficient children, genetics study of Guillain-Barre syndrome patients). We also have collaborated with Dr. Greg Enns on an NIH-sponsored study of the safety of influenza vaccine and its metabolic effects in patients with the MELAS mtDNA polymorphisms.
For further information about ongoing studies, please refer to our website at http://vaccines.stanford.edu.
- Independent Studies (5)
Graduate and Fellowship Programs
Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging.
Proceedings of the National Academy of Sciences of the United States of America
2017; 114 (5): 1105–10
The elderly have reduced humoral immunity, as manifested by increased susceptibility to infections and impaired vaccine responses. To investigate the effects of aging on B-cell receptor (BCR) repertoire evolution during an immunological challenge, we used a phylogenetic distance metric to analyze Ig heavy-chain transcript sequences in both young and elderly individuals before and after influenza vaccination. We determined that BCR repertoires become increasingly specialized over a span of decades, but less plastic. In 50% of the elderly individuals, a large space in the repertoire was occupied by a small number of recall lineages that did not decline during vaccine response and contained hypermutated IgD(+) B cells. Relative to their younger counterparts, older subjects demonstrated a contracted naive repertoire and diminished intralineage diversification, signifying a reduced substrate for mounting novel responses and decreased fine-tuning of BCR specificities by somatic hypermutation. Furthermore, a larger proportion of the repertoire exhibited premature stop codons in some elderly subjects, indicating that aging may negatively affect the ability of B cells to discriminate between functional and nonfunctional receptors. Finally, we observed a decreased incidence of radical mutations compared with conservative mutations in elderly subjects' vaccine responses, which suggests that accumulating original antigenic sin may be limiting the accessible space for paratope evolution. Our findings shed light on the complex interplay of environmental and gerontological factors affecting immune senescence, and provide direct molecular characterization of the effects of senescence on the immune repertoire.
View details for DOI 10.1073/pnas.1617959114
View details for PubMedID 28096374
Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states.
2017; 23 (2): 174–84
Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1β (IL-1β). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1β, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1β, who lack these characteristics. Adenine and N(4)-acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1β, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions.
View details for DOI 10.1038/nm.4267
View details for PubMedID 28092664
Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination.
Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro, they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine.
View details for DOI 10.1038/nm.4224
View details for PubMedID 27820605
Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans.
2016; 3 (4): 374-384 e4
Chronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. Here, we longitudinally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ. Baseline pSTAT levels tracked with circulating levels of C-reactive protein (CRP), and we derived a cytokine response score that negatively correlates with measures of cardiovascular disease, specifically diastolic dysfunction and atherosclerotic burden, outperforming CRP. Thus, we identified an immunological link between inflammation, decreased cell responsiveness in the JAK-STAT pathway, and cardiovascular aging. Targeting chronic inflammation may ameliorate this deficiency in cellular responsiveness and improve cardiovascular function.
View details for DOI 10.1016/j.cels.2016.09.009
View details for PubMedID 27746093
Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals.
2016; 12 (10)
Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B-cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population.
View details for DOI 10.1371/journal.ppat.1005892
View details for PubMedID 27764254
Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination.
Science translational medicine
2016; 8 (332): 332ra46-?
Diversity and size of the antigen-specific T cell receptor (TCR) repertoire are two critical determinants for successful control of chronic infection. Varicella zoster virus (VZV) that establishes latency during childhood can escape control mechanisms, in particular with increasing age. We examined the TCR diversity of VZV-reactive CD4 T cells in individuals older than 50 years by studying three identical twin pairs and three unrelated individuals before and after vaccination with live attenuated VZV. Although all individuals had a small number of dominant T cell clones, the breadth of the VZV-specific repertoire differed markedly. A genetic influence was seen for the sharing of individual TCR sequences from antigen-reactive cells but not for repertoire richness or the selection of dominant clones. VZV vaccination favored the expansion of infrequent VZV antigen-reactive TCRs, including those from naïve T cells with lesser boosting of dominant T cell clones. Thus, vaccination does not reinforce the in vivo selection that occurred during chronic infection but leads to a diversification of the VZV-reactive T cell repertoire. However, a single-booster immunization seems insufficient to establish new clonal dominance. Our results suggest that repertoire analysis of antigen-specific TCRs can be an important readout to assess whether a vaccination was able to generate memory cells in clonal sizes that are necessary for immune protection.
View details for DOI 10.1126/scitranslmed.aaf1725
View details for PubMedID 27030598
Longitudinal Kinetics of Cytomegalovirus-Specific T-Cell Immunity and Viral Replication in Infants With Congenital Cytomegalovirus Infection.
Journal of the Pediatric Infectious Diseases Society
2016; 5 (1): 14-20
Congenital cytomegalovirus (CMV) is reported to affect up to 1% of all live births in the United States. T-cell immunity may be important for controlling CMV replication in congenital CMV-infected infants. We describe the natural history of CMV-specific T-cell evolution and CMV replication in infants with congenital CMV infection.Cytomegalovirus viral load, CMV urine culture, and CMV-specific CD4 and CD8 T-cell responses were assessed in a prospective longitudinal cohort of 51 infants with congenital CMV infection who were observed from birth to 3 years of age.We found a kinetic pattern of decreasing urinary CMV replication and increasing CMV-specific CD4 and CD8 T-cell responses during the first 3 years of life. We also found higher CMV-specific CD8 T-cell responses were associated with subsequent reduction of urine CMV viral load.For infants with congenital CMV infection, our data suggest an age-related maturation of both CMV-specific CD4 and CD8 T-cell immunity that is associated with an age-related decline in urinary CMV replication.
View details for DOI 10.1093/jpids/piu089
View details for PubMedID 26908487
Expression of CD39 on Activated T Cells Impairs their Survival in Older Individuals.
2016; 14 (5): 1218-1231
In an immune response, CD4(+) T cells expand into effector T cells and then contract to survive as long-lived memory cells. To identify age-associated defects in memory cell formation, we profiled activated CD4(+) T cells and found an increased induction of the ATPase CD39 with age. CD39(+) CD4(+) T cells resembled effector T cells with signs of metabolic stress and high susceptibility to undergo apoptosis. Pharmacological inhibition of ATPase activity dampened effector cell differentiation and improved survival, suggesting that CD39 activity influences T cell fate. Individuals carrying a low-expressing CD39 variant responded better to vaccination with an increase in vaccine-specific memory T cells. Increased inducibility of CD39 after activation may contribute to the impaired vaccine response with age.
View details for DOI 10.1016/j.celrep.2016.01.002
View details for PubMedID 26832412
- Human B-cell isotype switching origins of IgE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2016; 137 (2): 579-?
Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells.
2016; 7: 11112-?
The adaptive immune system's capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, the influence of individual genetic and epigenetic differences on these repertoires is not typically measured. By leveraging the unique characteristics of B, CD4(+) T and CD8(+) T-lymphocyte subsets from monozygotic twins, we quantify the impact of heritable factors on both the V(D)J recombination process and on thymic selection. We show that the resulting biases in both V(D)J usage and N/P addition lengths, which are found in naïve and antigen experienced cells, contribute to significant variation in the CDR3 region. Moreover, we show that the relative usage of V and J gene segments is chromosomally biased, with ∼1.5 times as many rearrangements originating from a single chromosome. These data refine our understanding of the heritable mechanisms affecting the repertoire, and show that biases are evident on a chromosome-wide level.
View details for DOI 10.1038/ncomms11112
View details for PubMedID 27005435
Increased Proinflammatory Responses of Monocytes and Plasmacytoid Dendritic Cells to Influenza A Virus Infection During Pregnancy.
The Journal of infectious diseases
2016; 214 (11): 1666–71
Pregnancy-induced alterations in immunity may contribute to the increased morbidity associated with influenza A virus infection during pregnancy. We characterized the immune response of monocytes and plasmacytoid dendritic cells (pDCs) to influenza A virus infection in 21 pregnant and 21 nonpregnant women. In pregnant women, monocytes and pDCs exhibit an exaggerated proinflammatory immune response to 2 strains of influenza A virus, compared with nonpregnant women, characterized by increased expression of major histocompatibility complex class II (approximately 2.0-fold), CD69 (approximately 2.2-fold), interferon γ-induced protein 10 (approximately 2.0-fold), and macrophage inflammatory protein 1β (approximately 1.5-fold). This enhanced innate inflammatory response during pregnancy could contribute to pulmonary inflammation following influenza A virus infection.
View details for DOI 10.1093/infdis/jiw448
View details for PubMedID 27655870
Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching.
Antibody class switching is a feature of the adaptive immune system which enables diversification of the effector properties of antibodies. Even though class switching is essential for mounting a protective response to pathogens, the in vivo patterns and lineage characteristics of antibody class switching have remained uncharacterized in living humans. Here we comprehensively measured the landscape of antibody class switching in human adult twins using antibody repertoire sequencing. The map identifies how antibodies of every class are created and delineates a two-tiered hierarchy of class switch pathways. Using somatic hypermutations as a molecular clock, we discovered that closely related B cells often switch to the same class, but lose coherence as somatic mutations accumulate. Such correlations between closely related cells exist when purified B cells class switch in vitro, suggesting that class switch recombination is directed toward specific isotypes by a cell-autonomous imprinted state.
View details for DOI 10.7554/eLife.16578
View details for PubMedID 27481325
Mapping epitopes of U1-70K autoantibodies at single-amino acid resolution
2015; 48 (8): 513-523
The mechanisms underlying development of ribonucleoprotein (RNP) autoantibodies are unclear. The U1-70K protein is the predominant target of RNP autoantibodies, and the RNA binding domain has been shown to be the immunodominant autoantigenic region of U1-70K, although the specific epitopes are not known. To precisely map U1-70K epitopes, we developed silicon-based peptide microarrays with >5700 features, corresponding to 843 unique peptides derived from the U1-70K protein. The microarrays feature overlapping peptides, with single-amino acid resolution in length and location, spanning amino acids 110-170 within the U1-70K RNA binding domain. We evaluated the serum IgG of a cohort of patients with systemic lupus erythematosus (SLE; n = 26) using the microarrays, and identified multiple reactive epitopes, including peptides 116-121 and 143-148. Indirect peptide ELISA analysis of the sera of patients with SLE (n = 88) revealed that ∼14% of patients had serum IgG reactivity to 116-121, while reactivity to 143-148 appeared to be limited to a single patient. SLE patients with serum reactivity to 116-121 had significantly lower SLE Disease Activity Index (SLEDAI) scores at the time of sampling, compared to non-reactive patients. Minimal reactivity to the peptides was observed in the sera of healthy controls (n = 92). Competitive ELISA showed antibodies to 116-121 bind a common epitope in U1-70K (68-72) and the matrix protein M1 of human influenza B viruses. Institutional Review Boards approved this study. Knowledge of the precise epitopes of U1-70K autoantibodies may provide insight into the mechanisms of development of anti-RNP, identify potential clinical biomarkers and inform ongoing clinical trails of peptide-based therapeutics.
View details for DOI 10.3109/08916934.2015.1077233
View details for Web of Science ID 000366755000003
View details for PubMedID 26333287
Pregnancy Does Not Attenuate the Antibody or Plasmablast Response to Inactivated Influenza Vaccine.
journal of infectious diseases
2015; 212 (6): 861-870
Inactivated influenza vaccine (IIV) is recommended during pregnancy to prevent influenza infection and its complications in pregnant women and their infants. However, the extent to which pregnancy modifies the antibody response to vaccination remains unclear, and prior studies have focused primarily on hemagglutinin inhibition (HI) titers. A more comprehensive understanding of how pregnancy modifies the humoral immune response to influenza vaccination will aid in maximizing vaccine efficacy. Healthy pregnant women and control women were studied prior to, 7 days after, and 28 days after vaccination with IIV. HI titers, microneutralization (MN) titers, and the frequency of circulating plasmablasts were evaluated in pregnant versus control women. Pregnant women and control women mount similarly robust serologic immune responses to IIV, with no significant differences for any influenza strain in postvaccination geometric mean HI or MN titers. HI and MN titers correlate, though MN titers demonstrate more robust changes pre- versus postvaccination. The induction of circulating plasmablasts is increased in pregnant women versus controls (median fold-change 2.60 vs 1.49 [interquartile range, 0.94-7.53 vs 0.63-2.67]; P = .03). Pregnant women do not have impaired humoral immune responses to IIV and may have increased circulating plasmablast production compared to control women.
View details for DOI 10.1093/infdis/jiv138
View details for PubMedID 25740957
IgH sequences in common variable immune deficiency reveal altered B cell development and selection.
Science translational medicine
2015; 7 (302): 302ra135-?
Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted naïve and memory B cells from 13 of the CVID patients and 10 of the control subjects. The CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity-determining region 3 (CDR3). We observed a decreased selection against antibodies with long CDR3s in memory repertoires and decreased variable gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive from both decreased diversity of the naïve B cell pool and decreased somatic hypermutation in memory repertoires. The CVID patients also exhibited an abnormal clonal expansion of unmutated B cells relative to the controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro-B stage, cell and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.
View details for DOI 10.1126/scitranslmed.aab1216
View details for PubMedID 26311730
Cytomegalovirus infection enhances the immune response to influenza.
Science translational medicine
2015; 7 (281): 281ra43-?
Cytomegalovirus (CMV) is a β-herpesvirus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli, and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV status. In contrast, CMV-seropositive young adults exhibited enhanced antibody responses to influenza vaccination, increased CD8(+) T cell sensitivity, and elevated levels of circulating interferon-γ compared to seronegative individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the ubiquity of CMV infection in humans and many other species.
View details for DOI 10.1126/scitranslmed.aaa2293
View details for PubMedID 25834109
Distinct patterns of B-cell activation and priming by natural influenza virus infection versus inactivated influenza vaccination.
journal of infectious diseases
2015; 211 (7): 1051-1059
The human B-cell response to natural influenza virus infection has not been extensively investigated at the polyclonal level.The overall B-cell response of patients acutely infected with the 2009 pandemic influenza A(H1N1)pdm09 virus (A[H1N1]pdm09) was analyzed by determining the reactivity of plasmablast-derived polyclonal antibodies (PPAbs) to influenza proteins. Recipients of inactivated influenza vaccine containing the same A(H1N1)pdm09 strain were studied for comparison.During acute infection, robust plasmablast responses to the infecting virus were detected, characterized by a greater PPAb reactivity to the conserved influenza virus nuclear protein and to heterovariant and heterosubtypic hemagglutinins, in comparison to responses to the inactivated A(H1N1)pdm09 vaccine. In A(H1N1)pdm09 vaccinees, the presence of baseline serum neutralizing antibodies against A(H1N1)pdm09, suggesting previous exposure to natural A(H1N1)pdm09 infection, did not affect the plasmablast response to vaccination, whereas repeated immunization with inactivated A(H1N1)pdm09 vaccine resulted in significantly reduced vaccine-specific and cross-reactive PPAb responses.Natural A(H1N1)pdm09 infection and inactivated A(H1N1)pdm09 vaccination result in very distinct patterns of B-cell activation and priming. These differences are likely to be associated with differences in protective immunity, especially cross-protection against heterovariant and heterosubtypic influenza virus strains.
View details for DOI 10.1093/infdis/jiu580
View details for PubMedID 25336731
Variation in the human immune system is largely driven by non-heritable influences.
2015; 160 (1-2): 37-47
There is considerable heterogeneity in immunological parameters between individuals, but its sources are largely unknown. To assess the relative contribution of heritable versus non-heritable factors, we have performed a systems-level analysis of 210 healthy twins between 8 and 82 years of age. We measured 204 different parameters, including cell population frequencies, cytokine responses, and serum proteins, and found that 77% of these are dominated (>50% of variance) and 58% almost completely determined (>80% of variance) by non-heritable influences. In addition, some of these parameters become more variable with age, suggesting the cumulative influence of environmental exposure. Similarly, the serological responses to seasonal influenza vaccination are also determined largely by non-heritable factors, likely due to repeated exposure to different strains. Lastly, in MZ twins discordant for cytomegalovirus infection, more than half of all parameters are affected. These results highlight the largely reactive and adaptive nature of the immune system in healthy individuals.
View details for DOI 10.1016/j.cell.2014.12.020
View details for PubMedID 25594173
B-cell repertoire responses to varicella-zoster vaccination in human identical twins.
Proceedings of the National Academy of Sciences of the United States of America
2015; 112 (2): 500-505
Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual's genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicella-zoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B-cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall B-cell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus.
View details for DOI 10.1073/pnas.1415875112
View details for PubMedID 25535378
- The Split Virus Influenza Vaccine rapidly activates immune cells through Fc gamma receptors VACCINE 2014; 32 (45): 5989-5997
Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy.
Proceedings of the National Academy of Sciences of the United States of America
2014; 111 (40): 14506-14511
Pregnant women experience increased morbidity and mortality after influenza infection, for reasons that are not understood. Although some data suggest that natural killer (NK)- and T-cell responses are suppressed during pregnancy, influenza-specific responses have not been previously evaluated. Thus, we analyzed the responses of women that were pregnant (n = 21) versus those that were not (n = 29) immediately before inactivated influenza vaccination (IIV), 7 d after vaccination, and 6 wk postpartum. Expression of CD107a (a marker of cytolysis) and production of IFN-γ and macrophage inflammatory protein (MIP) 1β were assessed by flow cytometry. Pregnant women had a significantly increased percentage of NK cells producing a MIP-1β response to pH1N1 virus compared with nonpregnant women pre-IIV [median, 6.66 vs. 0.90% (P = 0.0149)] and 7 d post-IIV [median, 11.23 vs. 2.81% (P = 0.004)], indicating a heightened chemokine response in pregnant women that was further enhanced by the vaccination. Pregnant women also exhibited significantly increased T-cell production of MIP-1β and polyfunctionality in NK and T cells to pH1N1 virus pre- and post-IIV. NK- and T-cell polyfunctionality was also enhanced in pregnant women in response to the H3N2 viral strain. In contrast, pregnant women had significantly reduced NK- and T-cell responses to phorbol 12-myristate 13-acetate and ionomycin. This type of stimulation led to the conclusion that NK- and T-cell responses during pregnancy are suppressed, but clearly this conclusion is not correct relative to the more biologically relevant assays described here. Robust cellular immune responses to influenza during pregnancy could drive pulmonary inflammation, explaining increased morbidity and mortality.
View details for DOI 10.1073/pnas.1416569111
View details for PubMedID 25246558
Distinct Cross-reactive B-Cell Responses to Live Attenuated and Inactivated Influenza Vaccines.
journal of infectious diseases
2014; 210 (6): 865-874
Background. The immunological bases for the efficacies of the two currently licensed influenza vaccines, the live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV), are not fully understood. The goal of this study was to identify specific B-cell responses correlated with the known efficacies of these two vaccines.Methods. We compared the B-cell and antibody responses after immunization with 2010/2011 IIV versus LAIV in young adults, focusing on peripheral plasmablasts at days 6-8 post-vaccination.Results. The quantities of vaccine-specific plasmablasts and plasmablast-derived polyclonal antibodies (PPAb) were significantly higher in IIV recipients than in LAIV recipients. No significant difference was detected in the avidity of vaccine-specific PPAb between the two vaccine groups. Proportionally, LAIV induced a greater vaccine-specific IgA plasmablast response as well as a greater plasmablast response to the conserved influenza nuclear protein than did IIV. The cross-reactive plasmablast response to heterovariant strains, as indicated by the relative levels of cross-reactive plasmablasts and the cross-reactive PPAb binding reactivity, was also greater in the LAIV group.Conclusions. Distinct quantitative and qualitative patterns of plasmablast responses were induced by LAIV and IIV in young adults; a proportionally greater cross-reactive response was induced by LAIV.
View details for DOI 10.1093/infdis/jiu190
View details for PubMedID 24676204
Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements.
Cell host & microbe
2014; 16 (1): 105-114
B cells produce a diverse antibody repertoire by undergoing gene rearrangements. Pathogen exposure induces the clonal expansion of B cells expressing antibodies that can bind the infectious agent. To assess human B cell responses to trivalent seasonal influenza and monovalent pandemic H1N1 vaccination, we sequenced gene rearrangements encoding the immunoglobulin heavy chain, a major determinant of epitope recognition. The magnitude of B cell clonal expansions correlates with an individual's secreted antibody response to the vaccine, and the expanded clones are enriched with those expressing influenza-specific monoclonal antibodies. Additionally, B cell responses to pandemic influenza H1N1 vaccination and infection in different people show a prominent family of convergent antibody heavy chain gene rearrangements specific to influenza antigens. These results indicate that microbes can induce specific signatures of immunoglobulin gene rearrangements and that pathogen exposure can potentially be assessed from B cell repertoires.
View details for DOI 10.1016/j.chom.2014.05.013
View details for PubMedID 24981332
Live Vaccine Use and Safety in DiGeorge Syndrome.
2014; 133 (4): e946-54
Live vaccines are generally contraindicated in patients with DiGeorge syndrome (DGS), a congenital disorder characterized by cellular immune deficiency. Vaccine utilization and safety in this population are not well described. This study examined vaccination patterns and adverse events following live immunization (AEFLI) in these individuals.A multicenter retrospective cohort study was conducted in subjects with DGS confirmed by fluorescence in situ hybridization assay (chromosome 22q11.2 microdeletion). Live vaccine-preventable illnesses, vaccination coverage and timeliness, and AEFLIs in the 56-day window after live vaccination were examined. Bivariate and multivariable analyses assessed the impact of demographics medical history, timing of diagnostic confirmation, and preceding immune function on vaccination patterns and AEFLIs.Of 194 subjects, 77% and 75% received measles-mumps-rubella (MMR) and varicella vaccines, respectively; 58% completed recommended vaccinations by age 19 to 35 months. Adverse events occurred after 14% and 20% of MMR and varicella vaccine doses, respectively. Most events were minor, few were serious, and no deaths were reported in post-live vaccination windows. Although early diagnostic confirmation negatively affected live vaccination coverage and timeliness (P < .001), baseline CD4% did not differ between subjects who did or did not receive live vaccines by 12 to 18 months. Among varicella vaccine recipients, those with a subsequent adverse event had a lower preceding CD4% (24.8% ± 7.3%) than those without (35.5% ± 11.7%) (P < .05); no CD4% differences were observed with MMR vaccination. Fourteen unvaccinated subjects experienced live vaccine-preventable illnesses.Live vaccines were frequently given and generally well-tolerated among patients with DGS with mild-to-moderate immunosuppression.
View details for DOI 10.1542/peds.2013-0831
View details for PubMedID 24685951
Effects of Aging, Cytomegalovirus Infection, and EBV Infection on Human B Cell Repertoires
JOURNAL OF IMMUNOLOGY
2014; 192 (2): 603-611
Elderly humans show decreased humoral immunity to pathogens and vaccines, yet the effects of aging on B cells are not fully known. Chronic viral infection by CMV is implicated as a driver of clonal T cell proliferations in some aging humans, but whether CMV or EBV infection contributes to alterations in the B cell repertoire with age is unclear. We have used high-throughput DNA sequencing of IGH gene rearrangements to study the BCR repertoires over two successive years in 27 individuals ranging in age from 20 to 89 y. Some features of the B cell repertoire remain stable with age, but elderly subjects show increased numbers of B cells with long CDR3 regions, a trend toward accumulation of more highly mutated IgM and IgG Ig genes, and persistent clonal B cell populations in the blood. Seropositivity for CMV or EBV infection alters B cell repertoires, regardless of the individual's age: EBV infection correlates with the presence of persistent clonal B cell expansions, whereas CMV infection correlates with the proportion of highly mutated Ab genes. These findings isolate effects of aging from those of chronic viral infection on B cell repertoires and provide a baseline for understanding human B cell responses to vaccination or infectious stimuli.
View details for DOI 10.4049/jimmunol.1301384
View details for Web of Science ID 000329224000006
View details for PubMedID 24337376
Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination.
Proceedings of the National Academy of Sciences of the United States of America
2014; 111 (2): 869-874
Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.
View details for DOI 10.1073/pnas.1321060111
View details for PubMedID 24367114
- Apoptosis and other immune biomarkers predict influenza vaccine responsiveness. Molecular systems biology 2014; 10: 750-?
Immediate hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines: Reports to VAERS
2013; 31 (51): 6107-6112
Hypersensitivity disorders following vaccinations are a cause for concern.To determine the type and rate by age, gender, and vaccine received for reported hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines.A systematic review of reports to the Vaccine Adverse Event Reporting System (VAERS) following monovalent 2009 pandemic influenza A (H1N1) vaccines.US Civilian reports following vaccine received from October 1, 2009 through May 31, 2010.Age, gender, vaccines received, diagnoses, clinical signs, and treatment were reviewed by nurses and physicians with expertise in vaccine adverse events. A panel of experts, including seven allergists reviewed complex illnesses and those with conflicting evidence for classification of the event.Of 1984 reports, 1286 were consistent with immediate hypersensitivity disorders and 698 were attributed to anxiety reactions, syncope, or other illnesses. The female-to-male ratio was ≥4:1 for persons 20-to-59 years of age, but approximately equal for children under 10. One hundred eleven reports met Brighton Collaboration criteria for anaphylaxis; only one-half received epinephrine for initial therapy. The overall rate of reported hypersensitivity reactions was 10.7 per million vaccine doses distributed, with a 2-fold higher rate for live vaccine.Underreporting, especially of mild events, would result in an underestimate of the true rate of immediate hypersensitivity reactions. Selective reporting of events in adult females could have resulted in higher rates than reported for males.Adult females may be at higher risk of hypersensitivity reactions after influenza vaccination than men. Although the risk of hypersensitivity reactions following 2009 pandemic influenza A (H1N1) vaccines was low, all clinics administering vaccines should be familiar with treatment guidelines for these adverse events, including the use of intramuscular epinephrine early in the course of serious hypersensitivity reactions.
View details for DOI 10.1016/j.vaccine.2013.09.066
View details for Web of Science ID 000329010400012
View details for PubMedID 24120547
Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults.
Human vaccines & immunotherapeutics
2013; 9 (12): 2548-2557
Malaria results in over 650 000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.
View details for DOI 10.4161/hv.26038
View details for PubMedID 23955431
Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry.
Science translational medicine
2013; 5 (208): 208ra145-?
Natural killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood major lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 37 parameters, including 28 NK cell receptors, on peripheral blood NK cells from 5 sets of monozygotic twins and 12 unrelated donors of defined human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6000 to 30,000 phenotypic populations within an individual and >100,000 phenotypes in the donor panel. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation.
View details for DOI 10.1126/scitranslmed.3006702
View details for PubMedID 24154599
Genetic measurement of memory B-cell recall using antibody repertoire sequencing
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (33): 13463-13468
Annual influenza vaccinations aim to protect against seasonal infections, and vaccine strain compositions are updated every year. This protection is based on antibodies that are produced by either newly activated or memory B cells recalled from previous encounters with influenza vaccination or infection. The extent to which the B-cell repertoire responds to vaccination and recalls antibodies has so far not been analyzed at a genetic level-which is to say, at the level of antibody sequences. Here, we developed a consensus read sequencing approach that incorporates unique barcode labels on each starting RNA molecule. These labels allow one to combine multiple sequencing reads covering the same RNA molecule to reduce the error rate to a desired level, and they also enable accurate quantification of RNA and isotype levels. We validated this approach and analyzed the differential response of the antibody repertoire to live-attenuated or trivalent-inactivated influenza vaccination. Additionally, we analyzed the antibody repertoire in response to repeated yearly vaccinations with trivalent-inactivated influenza vaccination. We found antibody sequences that were present in both years, providing a direct genetic measurement of B-cell recall.
View details for DOI 10.1073/pnas.1312146110
View details for Web of Science ID 000323069200060
View details for PubMedID 23898164
- Comprehensive assessment of serious adverse events following immunization by health care providers. journal of pediatrics 2013; 162 (6): 1276-?
Lineage structure of the human antibody repertoire in response to influenza vaccination.
Science translational medicine
2013; 5 (171): 171ra19-?
The human antibody repertoire is one of the most important defenses against infectious disease, and the development of vaccines has enabled the conferral of targeted protection to specific pathogens. However, there are many challenges to measuring and analyzing the immunoglobulin sequence repertoire, including that each B cell's genome encodes a distinct antibody sequence, that the antibody repertoire changes over time, and the high similarity between antibody sequences. We have addressed these challenges by using high-throughput long read sequencing to perform immunogenomic characterization of expressed human antibody repertoires in the context of influenza vaccination. Informatic analysis of 5 million antibody heavy chain sequences from healthy individuals allowed us to perform global characterizations of isotype distributions, determine the lineage structure of the repertoire, and measure age- and antigen-related mutational activity. Our analysis of the clonal structure and mutational distribution of individuals' repertoires shows that elderly subjects have a decreased number of lineages but an increased prevaccination mutation load in their repertoire and that some of these subjects have an oligoclonal character to their repertoire in which the diversity of the lineages is greatly reduced relative to younger subjects. We have thus shown that global analysis of the immune system's clonal structure provides direct insight into the effects of vaccination and provides a detailed molecular portrait of age-related effects.
View details for DOI 10.1126/scitranslmed.3004794
View details for PubMedID 23390249
Clinical Assessment of Serious Adverse Events in Children Receiving 2009 H1N1 Vaccination
PEDIATRIC INFECTIOUS DISEASE JOURNAL
2013; 32 (2): 163-168
Monovalent 2009 H1N1 influenza vaccines were licensed and administered in the United States during the H1N1 influenza pandemic between 2009 and 2013.Vaccine Adverse Event Reporting System received reports of adverse events following immunization (AEFI) after H1N1 vaccination. Selected reports were referred to the Centers for Disease Control and Prevention's Clinical Immunization Safety Assessment network for additional review. We assessed causality using modified World Health Organization criteria.There were 3,928 reports of AEFI in children younger than age 18 years after 2009 H1N1 vaccination received by January 31, 2010. Of these, 214 (5.4%) were classified as serious nonfatal and 109 were referred to Clinical Immunization Safety Assessment for further evaluation. Ninety-nine (91%) had sufficient initial information to begin investigation and are described here. The mean age was 8 years (range, 6 months-17 years) and 38% were female. Median number of days between vaccination and symptom onset was 2 (range, -11 days to +41 days). Receipt of inactivated, live attenuated, or unknown type of 2009 H1N1 vaccines was reported by 68, 26 and 5 cases, respectively. Serious AEFI were categorized as neurologic events in 47 cases, as hypersensitivity in 15 cases and as respiratory events in 10 cases. At the time of evaluation, recovery was described as complete (61), partial (16), no improvement (1), or unknown (21). Causality assessment yielded the following likelihood of association with 2009 H1N1 vaccination: 8 definitely; 8 probably; 21 possibly; 43 unlikely; 17 unrelated; and 2 unclassifiable.Most AEFI in children evaluated were not causally related to vaccine and resolved without sequelae. Detailed clinical assessment of individual serious AEFI can provide reassurance of vaccine safety.
View details for DOI 10.1097/INF.0b013e318271b90a
View details for Web of Science ID 000313874500020
View details for PubMedID 23334340
Heterovariant Cross-Reactive B-Cell Responses Induced by the 2009 Pandemic Influenza Virus A Subtype H1N1 Vaccine
JOURNAL OF INFECTIOUS DISEASES
2013; 207 (2): 288-296
The generation of heterovariant immunity is a highly desirable feature of influenza vaccines. The goal of this study was to compare the heterovariant B-cell response induced by the monovalent inactivated 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) vaccine with that induced by the 2009 seasonal trivalent influenza vaccine (sTIV) containing a seasonal influenza A virus subtype H1N1 (A[H1N1]) component in young and elderly adults.Plasmablast-derived polyclonal antibodies (PPAb) from young and elderly recipients of A(H1N1)pdm09 vaccine or sTIV were tested for binding activity to various influenza antigens.In A(H1N1)pdm09 recipients, the PPAb titers against homotypic A(H1N1)pdm09 vaccine were similar to those against the heterovariant seasonal A(H1N1) vaccine and were similar between young and elderly subjects. The PPAb avidity was higher among elderly individuals, compared with young individuals. In contrast, the young sTIV recipients had 10-fold lower heterovariant PPAb titers against the A(H1N1)pdm09 vaccine than against the homotypic seasonal A(H1N1) vaccine. In binding assays with recombinant head and stalk domains of hemagglutinin, PPAb from the A(H1N1)pdm09 recipients but not PPAb from the sTIV recipients bound to the conserved stalk domain.The A(H1N1)pdm09 vaccine induced production of PPAb with heterovariant reactivity, including antibodies targeting the conserved hemagglutinin stalk domain.
View details for DOI 10.1093/infdis/jis664
View details for Web of Science ID 000312886400015
View details for PubMedID 23107783
Characterization of influenza vaccine immunogenicity using influenza antigen microarrays.
2013; 8 (5)
Existing methods to measure influenza vaccine immunogenicity prohibit detailed analysis of epitope determinants recognized by immunoglobulins. The development of highly multiplex proteomics platforms capable of capturing a high level of antibody binding information will enable researchers and clinicians to generate rapid and meaningful readouts of influenza-specific antibody reactivity.We developed influenza hemagglutinin (HA) whole-protein and peptide microarrays and validated that the arrays allow detection of specific antibody reactivity across a broad dynamic range using commercially available antibodies targeted to linear and conformational HA epitopes. We derived serum from blood draws taken from 76 young and elderly subjects immediately before and 28±7 days post-vaccination with the 2008/2009 trivalent influenza vaccine and determined the antibody reactivity of these sera to influenza array antigens.Using linear regression and correcting for multiple hypothesis testing by the Benjamini and Hochberg method of permutations over 1000 resamplings, we identified antibody reactivity to influenza whole-protein and peptide array features that correlated significantly with age, H1N1, and B-strain post-vaccine titer as assessed through a standard microneutralization assay (p<0.05, q <0.2). Notably, we identified several peptide epitopes that were inversely correlated with regard to age and seasonal H1N1 and B-strain neutralization titer (p<0.05, q <0.2), implicating reactivity to these epitopes in age-related defects in response to H1N1 influenza. We also employed multivariate linear regression with cross-validation to build models based on age and pre-vaccine peptide reactivity that predicted vaccine-induced neutralization of seasonal H1N1 and H3N2 influenza strains with a high level of accuracy (84.7% and 74.0%, respectively).Our methods provide powerful tools for rapid and accurate measurement of broad antibody-based immune responses to influenza, and may be useful in measuring response to other vaccines and infectious agents.
View details for DOI 10.1371/journal.pone.0064555
View details for PubMedID 23734205
Apoptosis and other immune biomarkers predict influenza vaccine responsiveness.
Molecular systems biology
2013; 9: 659-?
Despite the importance of the immune system in many diseases, there are currently no objective benchmarks of immunological health. In an effort to identifying such markers, we used influenza vaccination in 30 young (20-30 years) and 59 older subjects (60 to >89 years) as models for strong and weak immune responses, respectively, and assayed their serological responses to influenza strains as well as a wide variety of other parameters, including gene expression, antibodies to hemagglutinin peptides, serum cytokines, cell subset phenotypes and in vitro cytokine stimulation. Using machine learning, we identified nine variables that predict the antibody response with 84% accuracy. Two of these variables are involved in apoptosis, which positively associated with the response to vaccination and was confirmed to be a contributor to vaccine responsiveness in mice. The identification of these biomarkers provides new insights into what immune features may be most important for immune health.
View details for DOI 10.1038/msb.2013.15
View details for PubMedID 23591775
Biologically plausible and evidence-based risk intervals in immunization safety research
2012; 31 (1): 271-277
In immunization safety research, individuals are considered at risk for the development of certain adverse events following immunization (AEFI) within a specific period of time referred to as the risk interval. These intervals should ideally be determined based on biologic plausibility considering features of the AEFI, presumed or known pathologic mechanism, and the vaccine. Misspecification of the length and timing of these intervals may result in introducing bias in epidemiologic and clinical studies of immunization safety. To date, little work has been done to formally assess and determine biologically plausible and evidence-based risk intervals in immunization safety research. In this report, we present a systematic process to define biologically plausible and evidence-based risk interval estimates for two specific AEFIs, febrile seizures and acute disseminated encephalomyelitis. In addition, we review methodologic issues related to the determination of risk intervals for consideration in future studies of immunization safety.
View details for DOI 10.1016/j.vaccine.2012.07.024
View details for Web of Science ID 000313306400038
View details for PubMedID 22835735
Causality assessment of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS)
2012; 30 (50): 7253-7259
Adverse events following immunization (AEFI) reported to the national Vaccine Adverse Event Reporting System (VAERS) represent true causally related events, as well as events that are temporally, but not necessarily causally related to vaccine.We sought to determine if the causal relationships between the vaccine and the AEFI reported to VAERS could be assessed through expert review.A stratified random sample of 100 VAERS reports received in 2004 contained 13 fatal cases, 19 cases with non-fatal disabilities, 39 other serious non-fatal cases and 29 non-serious cases. Experts knowledgeable about vaccines and clinical outcomes, reviewed each VAERS report and available medical records.Modified World Health Organization criteria were used to classify the causal relationship between vaccines and AEFI as definite, probable, possible, unlikely or unrelated. Five independent reviewers evaluated each report. If they did not reach a majority agreement on causality after initial review, the report was discussed on a telephone conference to achieve agreement.108 AEFIs were identified in the selected 100 VAERS reports. After initial review majority agreement was achieved for 83% of the AEFI and 17% required further discussion. In the end, only 3 (3%) of the AEFI were classified as definitely causally related to vaccine received. Of the remaining AEFI 22 (20%) were classified as probably and 22 (20%) were classified as possibly related to vaccine received; a majority (53%) were classified as either unlikely or unrelated to a vaccine received.Using VAERS reports and additional documentation, causality could be assessed by expert review in the majority of VAERS reports. Assessment of VAERS reports identified that causality was thought to be probable or definite in less than one quarter of reports, and these were dominated by local reactions, allergic reactions, or symptoms known to be associated with the vaccine administered.
View details for DOI 10.1016/j.vaccine.2012.09.074
View details for Web of Science ID 000312523600024
View details for PubMedID 23063829
Immunogenicity and Safety of Varying Dosages of a Monovalent 2009 H1N1 Influenza Vaccine Given With and Without AS03 Adjuvant System in Healthy Adults and Older Persons
JOURNAL OF INFECTIOUS DISEASES
2012; 206 (6): 811-820
Adjuvanted vaccines have the potential to improve influenza pandemic response. AS03 adjuvant has been shown to enhance the immune response to inactivated influenza vaccines. Methods: This trial was designed to evaluate the immunogenicity and safety of an inactivated 2009 H1N1 influenza vaccine at varying dosages of hemagglutinin with and without extemporaneously mixed AS03 adjuvant system in adults ≥ 18 years of age. Adults were randomized to receive 2 doses of 1 of 5 vaccine formulations (3.75 µg, 7.5 µg, or 15 µg with AS03 or 7.5 µg or 15 µg without adjuvant). Results: The study population included 544 persons <65 years of age and 245 persons ≥ 65 years of age. Local adverse events tended to be more frequent in the adjuvanted vaccine groups, but severe reactions were uncommon. In both age groups, hemagglutination inhibition antibody geometric mean titers after dose one were higher in the adjuvanted groups, compared with the 15 µg unadjuvanted group, and this difference was statistically significant for the comparison of the 15 µg adjuvanted group with the 15 µg unadjuvanted group. Conclusions: AS03 adjuvant system improves the immune response to inactivated 2009 H1N1 influenza vaccine in both younger and older adults and is generally well tolerated. ClinicalTrials.gov NCT00963157.
View details for DOI 10.1093/infdis/jis427
View details for Web of Science ID 000308233500004
View details for PubMedID 22782949
Algorithm to assess causality after individual adverse events following immunizations
2012; 30 (39): 5791-5798
Assessing individual reports of adverse events following immunizations (AEFI) can be challenging. Most published reviews are based on expert opinions, but the methods and logic used to arrive at these opinions are neither well described nor understood by many health care providers and scientists. We developed a standardized algorithm to assist in collecting and interpreting data, and to help assess causality after individual AEFI. Key questions that should be asked during the assessment of AEFI include: Is the diagnosis of the AEFI correct? Does clinical or laboratory evidence exist that supports possible causes for the AEFI other than the vaccine in the affected individual? Is there a known causal association between the AEFI and the vaccine? Is there strong evidence against a causal association? Is there a specific laboratory test implicating the vaccine in the pathogenesis? An algorithm can assist with addressing these questions in a standardized, transparent manner which can be tracked and reassessed if additional information becomes available. Examples in this document illustrate the process of using the algorithm to determine causality. As new epidemiologic and clinical data become available, the algorithm and guidelines will need to be modified. Feedback from users of the algorithm will be invaluable in this process. We hope that this algorithm approach can assist with educational efforts to improve the collection of key information on AEFI and provide a platform for teaching about causality assessment.
View details for DOI 10.1016/j.vaccine.2012.04.005
View details for Web of Science ID 000308382000016
View details for PubMedID 22507656
Lack of association between childhood immunizations and encephalitis in California, 1998-2008
2012; 30 (2): 247-253
A number of new and combination vaccines have been introduced for children in the past two decades. Encephalitis cases occurring within defined time windows following administration of pertussis- or measles-containing vaccines are eligible for compensation by the Vaccine Injury Compensation Program. Due to increased parental concerns about vaccine safety and potential neurologic adverse events following immunization with new and multiple vaccines administered at the same visit, our aim was to determine whether immunizations are associated with an increased risk of encephalitis within defined risk windows.We reviewed immunization records from 246 pediatric encephalitis cases referred to the California Encephalitis Project between July 1998 and December 2008. We included data on 110 cases who had been immunized in the year prior to the onset of encephalitis (observation period) and had complete immunization records. We used the case-centered method to test whether cases were more likely to have developed encephalitis in defined risk windows-42, 30 and 21 days after any vaccination, 3 days after pertussis-containing vaccines and 5-15 days after measles-virus containing vaccines-compared with the rest of the observation period.All vaccines recommended in the current immunization schedule were represented in our sample. No increased risk of encephalitis was seen following administration of pertussis-containing vaccines, measles-containing vaccines or any number of vaccines administered in a single visit (vaccine episode); the odds ratios and 95% confidence intervals for encephalitis after a vaccine episode were: 1.0 (0.6-1.8) in a 42-day risk window, 0.9 (0.5-1.6) in a 30-day risk window and 1.2 (0.7-2.2) in a 21-day risk window.No association between receipt of currently recommended immunizations and subsequent development of encephalitis was observed in this study.
View details for DOI 10.1016/j.vaccine.2011.10.104
View details for Web of Science ID 000299971800022
View details for PubMedID 22080172
- Developing the next generation of vaccinologists VACCINE 2011; 29 (50): 9296-9297
Safety and Immunogenicity of LC16m8, an Attenuated Smallpox Vaccine in Vaccinia-Naive Adults
JOURNAL OF INFECTIOUS DISEASES
2011; 204 (9): 1395-1402
LC16m8 is an attenuated cell culture-adapted Lister vaccinia smallpox vaccine missing the B5R protein and licensed for use in Japan.We conducted a phase I/II clinical trial that compared the safety and immunogenicity of LC16m8 with Dryvax in vaccinia-naive participants. Adverse events were assessed, as were electrocardiography and laboratory testing for cardiotoxicity and viral culturing of the vaccination sites. Neutralization titers to vaccinia, monkeypox, and variola major were assessed and cell-mediated immune responses were measured by interferon (IFN)-γ enzyme-linked immunosorbent spot and lymphoproliferation assays.Local and systemic reactions after vaccination with LC16m8 were similar to those reported after Dryvax. No clinically significant abnormalities consistent with cardiac toxicity were seen for either vaccine. Both vaccines achieved antivaccinia, antivariola, and antimonkeypox neutralizing antibody titers >1:40, although the mean plaque reduction neutralization titer of LC16m8 at day 30 after vaccination was significantly lower than Dryvax for anti-NYCBH vaccinia (P < .01), antimonkeypox (P < .001), and antivariola (P < .001). LC16m8 produced robust cellular immune responses that trended higher than Dryvax for lymphoproliferation (P = .06), but lower for IFN-γ ELISPOT (P = .02).LC16m8 generates neutralizing antibody titers to multiple poxviruses, including vaccinia, monkeypox, and variola major, and broad T-cell responses, indicating that LC16m8 may have efficacy in protecting individuals from smallpox. Clinical Trials Registration. NCT00103584.
View details for DOI 10.1093/infdis/jir527
View details for Web of Science ID 000295509300013
View details for PubMedID 21921208
Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination
2011; 29 (46): 8302-8308
Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009-2010 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) network sought to characterize these SAEs and to assess their possible causal relationship to vaccination.Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR§314.80) after receipt of H1N1 vaccine reported to VAERS between October 1, 2009 and March 31, 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined.212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barré Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as "possibly" related (33%), 108 as "unlikely" related (51%), and 20 as "unrelated" (9%) to H1N1 vaccination; none were classified as "probable" or "definite" and 12 were unclassifiable (6%).The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols for providers to use in evaluation of adverse events following immunization, and rapid identification and follow-up of VAERS reports could improve causality assessment.
View details for DOI 10.1016/j.vaccine.2011.08.093
View details for Web of Science ID 000296988500019
View details for PubMedID 21893148
Rotavirus shedding in premature infants following first immunization
2011; 29 (45): 8141-8146
There is limited data regarding rotavirus vaccine shedding in premature infants. We describe the natural history of rotavirus shedding in premature infants in the 2-week period following first immunization with RotaTeq(®), the pentavalent rotavirus vaccine (RV5), and the risk for symptomatic transmission to household contacts (HHC).A prospective pilot study of 15 premature infants of gestational ages 26-34 weeks immunized with RV5 between 6 and 14 weeks chronological age on discharge from the NICU was conducted. Stool samples collected in the following 2 weeks and analyzed for rotavirus antigen by enzyme immunoassay (EIA), cell culture, and RT-PCR. Solicited adverse events were collected on study subjects and any symptoms of fever, vomiting and diarrhea in HHC.Rotavirus antigen shedding after immunization was detected, with positive rotavirus EIA results in 53.3% of premature infants and in 22.1% of 86 stool samples collected. Shedding rates by RT-PCR were higher with 86.7% of infants and 76.7% of samples being positive. Only 42% of EIA positive samples were positive by cell culture (8/86 total samples, 9.3%). None of 53 HHC reported symptoms of rotavirus infection during the 4 weeks following immunization of the infants.The findings of this study demonstrate that premature infants have positive stools by EIA, viral culture, and RT-PCR at varying time points during 2 weeks following first-dose immunization with RV5. RT-PCR shedding rates need to be clinically evaluated in the context of virus quantification by cell culture, which was low. No symptomatic transmission to HHC was detected in this study, supporting low transmissibility of vaccine virus shed by these infants born prematurely.
View details for DOI 10.1016/j.vaccine.2011.08.028
View details for Web of Science ID 000296683700036
View details for PubMedID 21856359
Overview of the Clinical Consult Case Review of adverse events following immunization: Clinical Immunization Safety Assessment (CISA) network 2004-2009
2011; 29 (40): 6920-6927
In 2004 the Clinical Consult Case Review (CCCR) working group was formed within the CDC-funded Clinical Immunization Safety Assessment (CISA) Network to review individual cases of adverse events following immunizations (AEFI).Cases were referred by practitioners, health departments, or CDC employees. Vaccine Adverse Event Reporting System (VAERS) searches and literature reviews for similar cases were performed prior to review. After CCCR discussion, AEFI were assessed for a causal relationship with vaccination and recommendations regarding future immunizations were relayed back to the referring physicians. In 2010, surveys were sent to referring physicians to determine the utility and effectiveness of the CCCR service.CISA investigators reviewed 76 cases during 68 conference calls between April 2004 and December 2009. Almost half of the cases (35/76) were neurological in nature. Similar AEFI for the specific vaccines received were discovered for 63 cases through VAERS searches and for 38 cases through PubMed searches. Causality assessment using the modified WHO criteria resulted in classifying 3 cases as definitely related to vaccine administration, 12 as probably related, 16 as possibly related, 18 as unlikely related, 10 as unrelated, and 17 had insufficient information to assign causality. The physician satisfaction survey was returned by 30 (57.7%) of those surveyed and a majority of respondents (93.3%) felt that the CCCR service was useful.The CCCR provides advice about AEFI to practitioners, assigns potential causality, and contributes to an improved understanding of adverse health events following immunizations.
View details for DOI 10.1016/j.vaccine.2011.07.044
View details for Web of Science ID 000295300500014
View details for PubMedID 21801776
Comparison of the immunogenicity and safety of a split-virion, inactivated, trivalent influenza vaccine (Fluzone (R)) administered by intradermal and intramuscular route in healthy adults
2011; 29 (34): 5666-5674
The aim of the study was to determine whether reduced doses of trivalent inactivated influenza vaccine (TIV) administered by the intradermal (ID) route generated similar immune responses to standard TIV given intramuscularly (IM) with comparable safety profiles. Recent changes in immunization recommendations have increased the number of people for whom influenza vaccination is recommended. Thus, given this increased need and intermittent vaccine shortages, means to rapidly expand the vaccine supply are needed. Previously healthy subjects 18-64 years of age were randomly assigned to one of four TIV vaccine groups: standard 15 μg HA/strain TIV IM, either 9 μg or 6 μg HA/strain of TIV ID given using a new microinjection system (BD Soluvia™ Microinjection System), or 3 μg HA/strain of TIV ID given by Mantoux technique. All vaccines contained A/New Caledonia (H1N1), A/Wyoming (H3N2) and B/Jiangsu strains of influenza. Sera were obtained 21 days after vaccination and hemagglutination inhibition (HAI) assays were performed and geometric mean titers (GMT) were compared among the groups. Participants were queried immediately following vaccination regarding injection pain and quality of the experience. Local and systemic reactions were collected for 7 days following vaccination and compared. Ten study sites enrolled 1592 subjects stratified by age; 18-49 years [N=814] and 50-64 years [N=778]. Among all subjects, for each of the three vaccine strains, the GMTs at 21 days post-vaccination for both the 9 μg and the 6 μg doses of each strain given ID were non inferior to GMTs generated after standard 15 μg doses/strain IM. However, for the 3 μg ID dose, only the A/Wyoming antigen produced a GMT that was non-inferior to the standard IM dose. Additionally, in the subgroup of subjects 50-64 years of age, the 6μg dose given ID induced GMTs that were inferior to the standard IM TIV for the A/H1N1 and B strains. No ID dose produced a GMT superior to that seen after standard IM TIV. Local erythema and swelling were significantly more common in the ID groups but the reactions were mild to moderate and short-lived. No significant safety issues related to intradermal administration were identified. Participants given TIV ID provided favorable responses to questions about their experiences with ID administration. In conclusion, for the aggregated cohorts of adults 18-64 years of age, reduced doses (6 μg and 9 μg) of TIV delivered ID using a novel microinjection system stimulated comparable HAI antibody responses to standard TIV given IM. The reduced 3 μg dose administered ID by needle and syringe, as well as the 6 μg ID for subjects aged 50-64 years of age generated poorer immune responses as compared to the 15 μg IM dose.
View details for DOI 10.1016/j.vaccine.2011.06.010
View details for Web of Science ID 000294145800013
View details for PubMedID 21699951
Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies
JOURNAL OF CLINICAL INVESTIGATION
2011; 121 (8): 3109-3119
During seasonal influenza epidemics, disease burden is shouldered predominantly by the very young and the elderly. Elderly individuals are particularly affected, in part because vaccine efficacy wanes with age. This has been linked to a reduced ability to induce a robust serum antibody response. Here, we show that this is due to reduced quantities of vaccine-specific antibodies, rather than a lack of antibody avidity or affinity. We measured levels of vaccine-specific plasmablasts by ELISPOT 1 week after immunization of young and elderly adults with inactivated seasonal influenza vaccine. Plasmablast-derived polyclonal antibodies (PPAbs) were generated from bulk-cultured B cells, while recombinant monoclonal antibodies (re-mAbs) were produced from single plasmablasts. The frequency of vaccine-specific plasmablasts and the concentration of PPAbs were lower in the elderly than in young adults, whereas the yields of secreted IgG per plasmablast were not different. Differences were not detected in the overall vaccine-specific avidity or affinity of PPAbs and re-mAbs between the 2 age groups. In contrast, reactivity of the antibodies induced by the inactivated seasonal influenza vaccine toward the 2009 pandemic H1N1 virus, which was not present in the vaccine, was higher in the elderly than in the young. These results indicate that the inferior antibody response to influenza vaccination in the elderly is primarily due to reduced quantities of vaccine-specific antibodies. They also suggest that exposure history affects the cross-reactivity of vaccination-induced antibodies.
View details for DOI 10.1172/JCI57834
View details for Web of Science ID 000293495500022
View details for PubMedID 21785218
Attitudes and Beliefs of Parents Concerned About Vaccines: Impact of Timing of Immunization Information
2011; 127: S120-S126
To determine if giving vaccine-information materials before the 2-month vaccination visit to mothers with concerns about vaccine safety positively changed their attitudes and beliefs about vaccine safety.Mothers who indicated concerns about infant vaccinations were recruited from 2 separate sites in Tennessee and California and were given vaccine information at 1 of 3 times: during a prenatal visit; a 1-week postpartum well-child visit; or a 2-month vaccination visit. A separate group of concerned mothers was assigned to be followed longitudinally at all 3 time points and was analyzed separately. The mothers reviewed a new vaccine-information pamphlet and Vaccine Information Statements (VIS) from the Centers for Disease Control and Prevention. Attitudes and beliefs about immunization were assessed both before and after the review of materials with written surveys.A total of 272 mothers with immunization concerns participated in the study. After review of the materials, mothers in all groups were significantly more likely to respond positively to questions and statements supporting the safety and importance of vaccines. Mothers who received this information at earlier visits were not significantly more likely to respond positively than mothers who received the information at the child's 2-month vaccination visit; however, participating mothers did indicate a preference for receiving vaccine information before the first vaccination visit.Distribution of the vaccine-information pamphlet and Vaccine Information Statements significantly improved attitudes about vaccination regardless of at what visit they were provided. Allowing adequate time to review vaccine information, even if done at the vaccination visit, may benefit concerned mothers.
View details for DOI 10.1542/peds.2010-1722R
View details for Web of Science ID 000296918100018
View details for PubMedID 21502250
Understanding the Role of Human Variation in Vaccine Adverse Events: The Clinical Immunization Safety Assessment Network
2011; 127: S65-S73
The Clinical Immunization Safety Assessment (CISA) Network is a collaboration between the Centers for Disease Control and Prevention (CDC) and 6 academic medical centers to provide support for immunization safety assessment and research. The CISA Network was established by the CDC in 2001 with 4 primary goals: (1) develop research protocols for clinical evaluation, diagnosis, and management of adverse events following immunization (AEFI); (2) improve the understanding of AEFI at the individual level, including determining possible genetic and other risk factors for predisposed people and subpopulations at high risk; (3) develop evidence-based algorithms for vaccination of people at risk of serious AEFI; and (4) serve as subject-matter experts for clinical vaccine-safety inquiries. CISA Network investigators bring in-depth clinical, pathophysiologic, and epidemiologic expertise to assessing causal relationships between vaccines and adverse events and to understanding the pathogenesis of AEFI. CISA Network researchers conduct expert reviews of clinically significant adverse events and determine the validity of the recorded diagnoses on the basis of clinical and laboratory criteria. They also conduct special studies to investigate the possible pathogenesis of adverse events, assess relationships between vaccines and adverse events, and maintain a centralized repository for clinical specimens. The CISA Network provides specific clinical guidance to both health care providers who administer vaccines and those who evaluate and treat patients with possible AEFI. The CISA Network plays an important role in providing critical immunization-safety data and expertise to inform vaccine policy-makers. The CISA Network serves as a unique resource for vaccine-safety monitoring efforts conducted at the CDC.
View details for DOI 10.1542/peds.2010-1722J
View details for Web of Science ID 000296918100010
View details for PubMedID 21502239
Plasmablast-derived polyclonal antibody response after influenza vaccination
JOURNAL OF IMMUNOLOGICAL METHODS
2011; 365 (1-2): 67-75
Conventional measurement of antibody responses to vaccines largely relies on serum antibodies, which are primarily produced by bone marrow plasma cells and may not represent the entire vaccine-induced B cell repertoire, including important functional components such as those targeted to mucosal sites. After immunization or infection, activated B cells differentiate into plasmablasts in local lymphoid organs, then traffic through circulation to the target sites where they further develop into plasma cells. On day 7 after influenza vaccination, a burst of plasmablasts, highly enriched for vaccine-specific antibody secreting cells, appears in the peripheral blood. This provides a unique window to the overall B cell response to the vaccine, without interference of pre-existing cross-reactive serum antibody. In this study we isolated B cells from volunteers on day 7 after immunization with the inactivated influenza vaccine and cultured them ex vivo to collect plasmablast-derived polyclonal antibodies (PPAb). The PPAb contained secreted IgG and IgA, which was approximately 0.2ng per antibody secreting cell. Influenza-specific IgG and IgA binding activity was detected in PPAb at dilutions up to 10(5) by ELISA. The ratio of the titers of influenza-specific IgA to IgG by ELISA was 4-fold higher in PPAb than in day 28 post-vaccination sera, suggesting that vaccine-induced IgA is enriched in PPAb compared to sera. Functional activity was also detected in PPAb as determined by microneutralization and hemagglutination inhibition assays. In addition to bulk B cell cultures, we also cultured plasmablast subsets sorted by cell surface markers to generate PPAb. These results suggest that PPAb better reflects the mucosal IgA response than serum samples. Since PPAb are exclusively produced by recently activated B cells, it allows assessing vaccine-induced antibody response without interference from pre-existing cross-reactive serum antibodies and permits an assessment of antibody avidity based on antigen specific binding and antibody quantity. Therefore this assay is particularly useful for studying vaccine/infection-induced antibodies against antigens that might have previously circulated, such as antibody responses to rotavirus, dengue or influenza viruses in which cross-reactive antibodies against different virus serotypes/subtypes play a critical role in immunity and/or pathogenesis.
View details for DOI 10.1016/j.jim.2010.12.008
View details for Web of Science ID 000288620600007
View details for PubMedID 21182843
Varicella Zoster Disease of the Central Nervous System: Epidemiological, Clinical, and Laboratory Features 10 Years after the Introduction of the Varicella Vaccine
JOURNAL OF INFECTIOUS DISEASES
2011; 203 (3): 316-323
Since the introduction of live attenuated varicella zoster virus (VZV) vaccine in 1995 there has been a significant reduction in varicella incidence and its associated complications, but the impact on VZV-associated central nervous system (CNS) disease has not been assessed.In this descriptive study we evaluated patients referred to the California Encephalitis Project from 1998 to 2009 with VZV PCR-positive cerebrospinal fluid (CSF). Epidemiological, clinical, and laboratory data were collected using a standardized case form. Specimens were genotyped using multi-single nucleotide polymorphism (SNP) analysis.Twenty-six specimens were genotyped from patients 12-85 years of age (median, 46 years). Clinical presentations included meningitis (50%), encephalitis (42%), and acute disseminated encephalomyelitis (ADEM) (8%). Only 11 patients (42%) had a concomitant herpes zoster rash. Genotype analysis identified 20 European Group (Clade1, Clade 3) strains; 4 Asian (Clade 2) strains, and 2 Mosaic Group (Clade 4, Clade VI) strains. One specimen was recognized as vaccine strain by identifying vaccine-associated SNPs.VZV continues to be associated with CNS disease, with meningitis being the most frequent clinical presentation. CNS VZV disease often presented without accompanying zoster rash. Sequencing data revealed multiple genotypes, including 1 vaccine strain detected in the CSF of a young patient with meningitis.
View details for DOI 10.1093/infdis/jiq066
View details for Web of Science ID 000286611800006
View details for PubMedID 21177308
Vaccine effectiveness against laboratory-confirmed influenza in infants A matched case control study
2010; 6 (9): 729-735
Influenza is a common and potentially serious infection in infants. Previous studies of influenza vaccine in this age group have reported widely varying estimates of vaccine effectiveness, and few have used laboratory confirmation of influenza diagnoses. We evaluated the effectiveness of 1 and 2 doses of the trivalent inactivated vaccine against laboratory-confirmed influenza in children aged 6 to 23 months within the Kaiser Permanente Northern California Medical Care Program for the 2003-2004, 2004-2005 and 2005-2006 influenza seasons. 1,648 children were included in the analyses, with an average of 4.5 controls matched to each of the 300 cases (213, 29 and 58 cases identified for each of the influenza seasons, respectively) based on birth month/year and zip code. Vaccination status was determined as of 14 days prior to the case patient's positive test result. Conditional logistic regression was used to calculate vaccine effectiveness for each season, adjusting for chronic medical conditions and other possible confounders. During the 2005-2006 influenza season, when predominant circulating virus strains and vaccine strains were well matched, vaccination was 76% [95% CI: 37-91%] effective against laboratory-confirmed infection. There was no statistically significant effect of vaccination, however, for the 2003-2004 or 2004-2005 seasons. Our results highlight the need for further study of influenza vaccine effectiveness in this age group.
View details for DOI 10.4161/hv.6.9.12470
View details for Web of Science ID 000282760400017
View details for PubMedID 20855940
Preterm Infants' T Cell Responses to Inactivated Poliovirus Vaccine
JOURNAL OF INFECTIOUS DISEASES
2010; 201 (2): 214-222
The antigen-specific T cell responses of preterm infants to immunization are not well understood. The aim of the present study was to compare the T cell responses of preterm infants after inactivated poliovirus vaccination with those of term infants.We prospectively enrolled 2-month-old preterm (gestational age, 33 weeks) and term (gestational age, 37 weeks) infants to receive 3 doses of diphtheria-tetanus toxoids-acellular pertussis-hepatitis B virus-inactivated poliovirus vaccine. Whole blood and peripheral blood mononuclear cells (PBMCs) were stimulated with poliovirus vaccine, and memory T cell activation was analyzed by flow cytometry and lymphoproliferation, respectively. Levels of poliovirus neutralizing antibodies were measured in serum.We enrolled 33 preterm and 50 term infants. Preterm infants had fewer circulating CD4(+)CD45RO(+) memory (P = .005) and CD4(+)CD69(+)IFN-gamma(+) cells activated by staphylococcus enterotoxin B at 2 (P = .015) and 7 (P = .05) months of age. After immunization, preterm and term infants had comparable frequencies of poliovirus-specific CD4(+)CD45RO(+)CD69(+)IFN-gamma(+) memory T cells (P = .79). PBMCs from preterm infants had diminished poliovirus-specific lymphoproliferation (P<.001). Although all infants developed seroprotective poliovirus antibody titers, serotype 1 titers were lower among preterm infants (P = .03).Preterm infants develop poliovirus-specific T cell responses that are comparable to those of term infants. However, they demonstrate nonspecific and poliovirus-specific functional T cell limitations, suggesting that investigations into whether T cell differences remain as preterm infants mature are warranted.
View details for DOI 10.1086/649590
View details for Web of Science ID 000273051200008
View details for PubMedID 20017631
Differential maternal responses to a newly developed vaccine information pamphlet
2009; 28 (2): 323-328
We compared the response to a new vaccine information pamphlet with the current CDC Vaccine Information Statements (VIS) among recently delivered mothers who were screened to identify those with concerns about immunization. Eligible mothers (n=226) were randomly assigned to one of three equal groups; those reviewing only the new pamphlet, those receiving only VIS, or those receiving both. Among those mothers reviewing both, 61% preferred the new pamphlet for its visual appeal (P<0.0001) and ease of understanding (P=0.005). Overall, mothers expressed increased confidence and fewer concerns regarding multiple injections after reviewing the pamphlet. However, older, more-highly educated mothers were less likely to report improved vaccine confidence after reviewing either the pamphlet or the VIS. Mothers in all three groups stated a preference for receiving the vaccine information during pregnancy or prior to the actual immunization visit. These data suggest that early provision of tailored immunization material along with the VIS to new mothers may enhance their overall confidence in vaccines and that additional strategies targeted toward certain mothers may be needed.
View details for DOI 10.1016/j.vaccine.2009.10.046
View details for Web of Science ID 000274869300006
View details for PubMedID 19879994
Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults
2009; 27 (47): 6642-6648
Dosage-sparing strategies, adjuvants and alternative substrates for vaccine production are being explored for influenza vaccine development. We assessed the safety and immunogenicity of a Vero cell culture-grown inactivated whole virus influenza A/H5N1 vaccine with or without aluminum hydroxide adjuvant [Al(OH)(3)] in healthy young adults. Vaccines were well tolerated, but injection site discomfort was more frequent in groups receiving Al(OH)(3). Dose-related increases in serum antibody levels were observed. Neutralizing antibody titers varied significantly when tested by two different laboratories. Al(OH)(3) did not enhance HAI or neutralizing antibody responses, and contributed to increased injection site pain. Because influenza antibody titers vary significantly between different laboratories, international standardization of assays is warranted.
View details for DOI 10.1016/j.vaccine.2009.03.015
View details for Web of Science ID 000272056300022
View details for PubMedID 19773098
- One Step Closer to a CMV Vaccine NEW ENGLAND JOURNAL OF MEDICINE 2009; 360 (12): 1250-1252
- Adolescent Vaccination Recommendations from the National Vaccine Advisory Committee AMERICAN JOURNAL OF PREVENTIVE MEDICINE 2009; 36 (3): 278-279
Recurrent sterile abscesses following aluminium adjuvant-containing vaccines.
BMJ case reports
Abscess formation following immunisation is a previously reported complication, generally associated with microbial contamination of the vaccine. Less commonly, such abscesses have been sterile. Here we describe two children evaluated in the Center for Disease Control and Prevention (CDC)-funded Clinical Immunization Safety Assessment (CISA) network who developed recurrent sterile abscesses after administration of vaccines containing aluminium adjuvant, either individually or in combination. Although the abscesses healed without sequelae, these occurrences support an association between receipt of aluminium adjuvant and sterile abscesses in susceptible patients. For patients with similar symptoms, clinicians may wish to choose a vaccine formulation containing the least amount of aluminium adjuvant.
View details for DOI 10.1136/bcr.09.2008.0951
View details for PubMedID 21686546
An algorithm for treatment of patients with hypersensitivity reactions after vaccines
2008; 122 (3): E771-E777
Concerns about possible allergic reactions to immunizations are raised frequently by both patients/parents and primary care providers. Estimates of true allergic, or immediate hypersensitivity, reactions to routine vaccines range from 1 per 50000 doses for diphtheria-tetanus-pertussis to approximately 1 per 500000 to 1000000 doses for most other vaccines. In a large study from New Zealand, data were collected during a 5-year period on 15 marketed vaccines and revealed an estimated rate of 1 immediate hypersensitivity reaction per 450000 doses of vaccine administered. Another large study, conducted within the Vaccine Safety Datalink, described a range of reaction rates to >7.5 million doses. Depending on the study design and the time after the immunization event, reaction rates varied from 0.65 cases per million doses to 1.53 cases per million doses when additional allergy codes were included. For some vaccines, particularly when allergens such as gelatin are part of the formulation (eg, Japanese encephalitis), higher rates of serious allergic reactions may occur. Although these per-dose estimates suggest that true hypersensitivity reactions are quite rare, the large number of doses that are administered, especially for the commonly used vaccines, makes this a relatively common clinical problem. In this review, we present background information on vaccine hypersensitivity, followed by a detailed algorithm that provides a rational and organized approach for the evaluation and treatment of patients with suspected hypersensitivity. We then include 3 cases of suspected allergic reactions to vaccines that have been referred to the Clinical Immunization Safety Assessment network to demonstrate the practical application of the algorithm.
View details for DOI 10.1542/peds.2008-1002
View details for Web of Science ID 000258822600086
View details for PubMedID 18762513
Influence of Prior Influenza Vaccination on Antibody and B-Cell Responses
2008; 3 (8)
Currently two vaccines, trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV), are licensed in the USA. Despite previous studies on immune responses induced by these two vaccines, a comparative study of the influence of prior influenza vaccination on serum antibody and B-cell responses to new LAIV or TIV vaccination has not been reported. During the 2005/6 influenza season, we quantified the serum antibody and B-cell responses to LAIV or TIV in adults with differing influenza vaccination histories in the prior year: LAIV, TIV, or neither. Blood samples were collected on days 0, 7-9 and 21-35 after immunization and used for serum HAI assay and B-cell assays. Total and influenza-specific circulating IgG and IgA antibody secreting cells (ASC) in PBMC were detected by direct ELISPOT assay. Memory B cells were also tested by ELISPOT after polyclonal stimulation of PBMC in vitro. Serum antibody, effector, and memory B-cell responses were greater in TIV recipients than LAIV recipients. Prior year TIV recipients had significantly higher baseline HAI titers, but lower HAI response after vaccination with either TIV or LAIV, and lower IgA ASC response after vaccination with TIV than prior year LAIV or no vaccination recipients. Lower levels of baseline HAI titer were associated with a greater fold-increase of HAI titer and ASC number after vaccination, which also differed by type of vaccine. Our findings suggest that the type of vaccine received in the prior year affects the serum antibody and the B-cell responses to subsequent vaccination. In particular, prior year TIV vaccination is associated with sustained higher HAI titer one year later but lower antibody response to new LAIV or TIV vaccination, and a lower effector B-cell response to new TIV but not LAIV vaccination.
View details for DOI 10.1371/journal.pone.0002975
View details for Web of Science ID 000264420900002
View details for PubMedID 18714352
- The promise and challenge of adolescent immunization AMERICAN JOURNAL OF PREVENTIVE MEDICINE 2008; 35 (2): 152-157
- Mandates for adolescent immunizations - Recommendations from the National Vaccine Advisory Committee AMERICAN JOURNAL OF PREVENTIVE MEDICINE 2008; 35 (2): 145-151
Immunogenicity, safety and consistency of new trivalent inactivated influenza vaccine
2008; 26 (32): 4057-4061
To augment the available influenza vaccine supply, a phase III study was conducted to evaluate the immunogenicity, safety, and consistency of a new trivalent inactivated influenza vaccine manufactured by CSL Limited. Healthy adults (ages 18-64) were randomized to receive either a single dose of TIV from multi-dose vials with thimerosal, TIV from pre-filled syringes without thimerosal, or placebo. Of the TIV recipients, 97.8% achieved a post-vaccination titer > or =40 against H1N1, 99.9% against H3N2 component, and 94.2% against influenza B. Few local or systemic adverse events were noted after vaccination with either TIV presentation. TIV was well tolerated and immunogenic.
View details for DOI 10.1016/j.vaccine.2008.05.024
View details for Web of Science ID 000258610900014
View details for PubMedID 18602726
Baseline Levels of Influenza-Specific CD4 Memory T-Cells Affect T-Cell Responses to Influenza Vaccines
2008; 3 (7)
Factors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens.During the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-gamma(+) cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-gamma(+) CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56(dim) NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56(dim) NK and DC.These results demonstrate that assessment of baseline biomarkers may predict immunologic outcome of influenza vaccination and may reveal some of the mechanisms responsible for variable immune responses following vaccination and natural infection.
View details for DOI 10.1371/journal.pone.0002574
View details for Web of Science ID 000263288200039
View details for PubMedID 18596908
Phenotypic changes in influenza-specific CD8(+) T cells after immunization of children and adults with influenza vaccines
26th Annual Meeting of the American-Society-for-Virology
UNIV CHICAGO PRESS. 2008: 803–11
The effect of trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV) on the phenotypes of circulating influenza-specific CD8+ T cells was analyzed by interferon (IFN)-gamma flow cytometry and tetramer staining. In adults, the expression of the T cell differentiation marker CD27 on virus-specific CD8+ T cells decreased after LAIV but increased after TIV. In children, expression of the cytotoxicity molecule perforin in influenza-specific CD8+ T cells increased after TIV but not after LAIV. Among children aged 6 months to 4 years who had not been vaccinated previously and who received 2 doses of TIV, CD27 expression decreased after each dose, whereas perforin expression increased after the second dose. These findings indicate that the phenotypic changes of influenza-specific CD8+ T cells differ depending on the type of vaccine and the age of the vaccinee. These differences are potentially affected by the different routes of vaccination and pathways of antigen presentation for TIV and LAIV.
View details for DOI 10.1086/528804
View details for Web of Science ID 000253773900005
View details for PubMedID 18279048
Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults
JOURNAL OF INFECTIOUS DISEASES
2008; 197 (5): 667-675
Influenza A H5N1 viruses pose a significant threat to human health.We conducted a multicenter, randomized, double-blind study in 394 healthy adults. Subjects were randomly assigned to receive 2 intramuscular doses of either saline placebo; influenza A/Vietnam/1203/2004(H5N1) vaccine alone at 45, 30, or 15 microg per dose; vaccine at 15 or 7.5 microg per dose with MF59; or vaccine at 30, 15, or 7.5 microg per dose with aluminum hydroxide. Subjects were followed up for safety and blood samples were obtained to determine antibody responses.The vaccine formulations were well tolerated but local adverse effects were common; the incidence of these effects increased in a dose-dependent manner and was increased by the addition of adjuvants. The addition of MF59 increased the antibody response, whereas the addition of aluminum hydroxide did not. The highest antibody responses were seen in the group that received 15 microg of vaccine per dose with MF59, in which 63% of subjects achieved the predetermined endpoint (hemagglutination-inhibition titer > or =40) 28 days after the second dose, compared with 29% in the group that received the highest dose (45 microg per dose) of vaccine alone.A 2-dose regimen of subvirion influenza A (H5N1) vaccine was well tolerated. The antibody responses to 15 microg of A/H5 vaccine with MF59 were higher than the responses to 45 microg of vaccine alone.ClincalTrials.gov identifier: http://www.clinicaltrials.gov/ct2/show/NCT00280033?term= NCT00280033&rank=1 NCT00280033 .
View details for DOI 10.1086/527489
View details for Web of Science ID 000253773400009
View details for PubMedID 18260764
Risk factors for developing apnea after immunization in the neonatal intensive care unit
2008; 121 (3): 463-469
Among hospitalized NICU infants, preimmunization apnea is a well-recognized predictor of postimmunization apnea. However, predictors for postimmunization apnea among NICU infants without preimmunization apnea have not been investigated.Using a large NICU database in the Northern California Kaiser Permanente Medical Care Program, we abstracted NICU charts of infants who were hospitalized for > or = 53 days and who were also immunized, capturing preimmunization (24 hours before immunization) and postimmunization (48 hours after immunization) events. We assessed factors associated with postimmunization apnea by using multivariate logistic regression.Of 16,146 infants admitted to the NICU, 557 received > or = 1 vaccine and 497 met the criteria for study entry. All infants with preimmunization apnea (n = 27) and all except 3 infants with postimmunization apnea (n = 65) had gestational ages of < 31 weeks. Multivariate analyses revealed preimmunization apnea as the most important predictor of postimmunization apnea, although higher 12-hour Score for Neonatal Acute Physiology II and age of < 67 days (mean cohort age) were also associated. Multivariate analysis exclusively among infants without preimmunization apnea similarly found elevated Score for Neonatal Acute Physiology II, age of < 67 days, and weight of < 2000 g to be associated with postimmunization apnea. Forty-nine infants without preimmunization apnea and with > or = 1 apnea predictor were discharged within 48 hours after immunization; 2 were subsequently readmitted because of apnea.For infants in the NICU without apnea during the 24 hours immediately before immunization, younger age, smaller size, and more severe illness at birth are important predictors of postimmunization apnea.
View details for DOI 10.1542/peds.2007-1462
View details for Web of Science ID 000253780100002
View details for PubMedID 18310193
A role for genetics in the immune response to the varicella vaccine
PEDIATRIC INFECTIOUS DISEASE JOURNAL
2007; 26 (4): 300-305
A wide range in antibody titers has been found after immunization with the varicella vaccine, although the basis for these differences has not been described.To evaluate the contribution of a genetic component in the immune response to the varicella vaccine, concordance for six-week postimmunization antibody titers was evaluated among 248 biologic siblings who participated in varicella vaccine clinical trials by comparing all pairs of siblings (151 pairs) to all possible unrelated, nonsibling pairs created from within this same cohort (30,477 pairs).Postimmunization antibody titers after 1 varicella vaccine dose were within the range observed historically among healthy vaccinees, with 85.4% of subjects having antibody responses greater than the approximate correlate of protection of 5 gpELISA units. Postimmunization antibody titers within sibling pairs clustered together more than or less than 10 gpELISA units when compared with within nonsibling pairs (P < 0.0001). Postimmunization titers within sibling pairs were also quantitatively closer together than were those within unrelated, nonsibling pairs (P = 0.022). The age-adjusted intraclass correlation coefficient indicated that the heritability of the varicella vaccine immune response is 45% (95% confidence interval of 15-75%).Similarities in siblings' response to varicella vaccine are supportive of the hypothesis that genetic factors play a role in the antibody response to the varicella vaccine.
View details for DOI 10.1097/01.inf.0000257454.74513.07
View details for Web of Science ID 000245287200005
View details for PubMedID 17414391
Humoral and cellular immune responses in children given annual immunization with trivalent inactivated influenza vaccine
PEDIATRIC INFECTIOUS DISEASE JOURNAL
2007; 26 (2): 107-115
There have been no prior reports of the frequency of circulating influenza-specific, interferon gamma-producing memory CD4+ and CD8+ T-cells in healthy children who have received multiple influenza immunizations.We evaluated 21 previously immunized children, ages 3 to 9 years, before and 1 month after administration of trivalent inactivated influenza vaccine. Frequencies of influenza-specific CD4+ and CD8+ T-cells stimulated with trivalent inactivated influenza vaccine or A/Panama (H3N2) virus were determined by flow cytometry, and antibody responses to vaccine strains and a drifted H3N2 strain were measured by hemagglutination inhibition assay and neutralizing antibody assays.Mean change in CD4+ and in CD8+ T-cell frequencies after immunization was 0.01% (P > 0.39) with postimmunization CD4+ frequencies higher than CD8+ frequencies. Children with more previous vaccinations had a higher baseline frequency of CD4+ T-cells (P = 0.0002) but a smaller increase or even a decline from baseline after immunization (P = 0.003). An association between age and change in frequency was not detected. Baseline geometric mean titers (GMTs) and seroprotection rates were significantly higher in older children against A/Panama (neutralizing baseline GMT, P = 0.0488) and A/New Caledonia (hemagglutination inhibition baseline GMT and seroprotection, P < 0.0297). Baseline GMTs against B/Hong Kong were not associated with age or quantity of prior vaccinations.These findings suggest that children may plateau in CD4+ T-cell responses to influenza antigens with repeated exposures and that the number of exposures may play a large role in building a memory CD4+ T-cell response to influenza A, perhaps independently from age.
View details for DOI 10.1097/01.inf.0000253251.03785.9b
View details for Web of Science ID 000243985700002
View details for PubMedID 17259871
Comparison of the influenza virus-specific effector and memory C-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines
JOURNAL OF VIROLOGY
2007; 81 (1): 215-228
Cellular immune responses to influenza virus infection and influenza virus vaccination have not been rigorously characterized. We quantified the effector and memory B-cell responses in children and adults after administration of either live attenuated (LAIV) or inactivated (TIV) influenza virus vaccines and compared these to antibody responses. Peripheral blood mononuclear cells were collected at days 0, 7 to 12, and 27 to 42 after immunization of younger children (6 months to 4 years old), older children (5 to 9 years old), and adults. Influenza virus-specific effector immunoglobulin A (IgA) and IgG circulating antibody-secreting cells (ASC) and stimulated memory B cells were detected using an enzyme-linked immunospot assay. Circulating influenza virus-specific IgG and IgA ASC were detected 7 to 12 days after TIV and after LAIV immunization. Seventy-nine percent or more of adults and older children had demonstrable IgG ASC responses, while IgA ASC responses were detected in 29 to 53% of the subjects. The IgG ASC response rate to LAIV immunization in adults was significantly higher than the response rate measured by standard serum antibody assays (26.3% and 15.8% by neutralization and hemagglutination inhibition assays, respectively). IgG ASC and serum antibody responses were relatively low in the younger children compared to older children and adults. TIV, but not LAIV, significantly increased the percentage of circulating influenza virus-specific memory B cells detected at 27 to 42 days after immunization in children and adults. In conclusion, although both influenza vaccines are effective, we found significant differences in the B-cell and antibody responses elicited after LAIV or TIV immunization in adults and older children and between young children and older age groups.
View details for DOI 10.1128/JVI.01957-06
View details for Web of Science ID 000242958600020
View details for PubMedID 17050593
Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines
JOURNAL OF VIROLOGY
2006; 80 (23): 11756-11766
The patterns of cellular immune responses induced by live attenuated influenza vaccine (LAIV) versus those of the trivalent inactivated influenza vaccine (TIV) have not been studied extensively, especially in children. The goals of this study were to evaluate the effects of TIV and LAIV immunization on cellular immunity to live influenza A virus in children and adults and to explore factors associated with variations in responses to influenza vaccines among individuals. A gamma interferon (IFN-gamma) flow cytometry assay was used to measure IFN-gamma-producing (IFN-gamma+) NK and T cells in peripheral blood mononuclear cell cultures stimulated with a live influenza A virus strain before and after LAIV or TIV immunization of children and adults. The mean percentages of influenza A virus-specific IFN-gamma+ CD4 and CD8 T cells increased significantly after LAIV, but not TIV, immunization in children aged 5 to 9 years. No increases in the mean levels of influenza A virus-reactive IFN-gamma+ T cells and NK cells were observed in adults given LAIV or TIV. TIV induced a significant increase in influenza A virus-reactive T cells in 6-month- to 4-year-old children; LAIV was not evaluated in this age group. The postvaccination changes (n-fold) in the percentages of influenza A virus-reactive IFN-gamma+ T and NK cells in adults were highly variable and correlated inversely with the prevaccination percentages, in particular with that of the CD56(dim) NK cell subset. In conclusion, our findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.
View details for DOI 10.1128/JVI.01460-06
View details for Web of Science ID 000242222200032
View details for PubMedID 16971435
Variability and gender differences in memory T cell immunity to varicella-zoster virus in healthy adults
2006; 24 (33-34): 5913-5918
Latent varicella zoster virus (VZV) can reactivate and cause zoster, the prevention of which relies upon cellular immunity to VZV. To assess temporal variation of VZV cell-mediated immunity in healthy naturally immune adults, we evaluated VZV-specific responder cell frequencies (RCF) longitudinally over 1 year in each of 25 adults. VZV-specific CD4+ T cells were detected (p < 0.003) and showed minimal variability in RCF. Additional analysis of VZV T cell RCF revealed differences between genders, with only males (p < 0.005) having detectable VZV-specific memory CD4+ T cell responses by this method. Taken together, results suggest that further studies regarding immunization of younger adults and females with the modified, high-potency live attenuated VZV vaccine may be warranted.
View details for DOI 10.1016/j.vaccine.2006.04.060
View details for Web of Science ID 000239982300001
View details for PubMedID 16759768
T cell-dependent production of IFN-gamma by NK cells in response to influenza A virus
JOURNAL OF CLINICAL INVESTIGATION
2004; 114 (12): 1812-1819
The role of human NK cells in viral infections is poorly understood. We used a cytokine flow-cytometry assay to simultaneously investigate the IFN-gamma response of NK and T lymphocytes to influenza A virus (fluA). When PBMCs from fluA-immune adult donors were incubated with fluA, IFN-gamma was produced by both CD56(dim) and CD56(bright) subsets of NK cells, as well as by fluA-specific T cells. Purified NK cells did not produce IFN-gamma in response to fluA, while depletion of T lymphocytes reduced to background levels the fluA-induced IFN-gamma production by NK cells, which indicates that T cells are required for the IFN-gamma response of NK cells. The fluA-induced IFN-gamma production of NK cells was suppressed by anti-IL-2 Ab, while recombinant IL-2 replaced the helper function of T cells for IFN-gamma production by NK cells. This indicates that IL-2 produced by fluA-specific T cells is involved in the T cell-dependent IFN-gamma response of NK cells to fluA. Taken together, these results suggest that at an early stage of recurrent viral infection, NK-mediated innate immunity to the virus is enhanced by preexisting virus-specific T cells.
View details for DOI 10.1172/JCI200422797
View details for Web of Science ID 000225695800016
View details for PubMedID 15599406
Selective developmental defects of cord blood antigen-presenting cell subsets
2004; 65 (11): 1356-1369
Defective antigen-presenting cell (APC) function has been hypothesized to contribute to increased infection susceptibility in newborns. We used multiparameter flow cytometry to characterize APC subsets in adult peripheral blood (APB) and cord blood (CB). APB had a higher proportion of CD11c+ dendritic cells (DC), whereas CB mainly contained CD123+ DC. APB was enriched in CD16+CD11c+ DC subset, whereas CD34+CD11c-CD123lo cells were prominent in CB. Lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production was dampened in myeloid DC and monocytes from CB, whereas IL-1alpha production was not different. The reduction in TNF-alpha response did not appear to result from reduced surface detection of LPS, because CD14, toll-like receptor (TLR)-4 and TLR-2 levels were not reduced in CB APC compared with APB cells. Also, there was no correlation between TLR-2 or TLR-4 levels and TNF-alpha production in myeloid DC and monocytes. CB monocytes had lower surface HLA-DR immediately ex vivo. Both APB and CB monocytes upregulated HLA-DR after incubation, but an additional LPS-induced increase in HLA-DR was suggested only in APB monocytes. APB monocytes also showed a greater LPS-induced increase in CD40 expression. Together, our data show significant, selective differences in circulating APC between neonates and adults.
View details for DOI 10.1016/j.humimm.2004.09.011
View details for Web of Science ID 000225728800010
View details for PubMedID 15556686
Intestinal Imaging of children with acute rotavirus gastroenteritis
JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION
2004; 39 (3): 270-274
To examine the morphology and motility of the distal small bowel of infants with rotavirus gastroenteritis using non-invasive/non-ionizing imaging technology.Prospective, non-randomized observational study of five infants with symptomatic rotavirus infection. Infants were imaged by real-time magnetic resonance imaging (MRI) and ultrasound within 5 days of onset of gastroenteritis symptoms. Imaging studies were repeated in the convalescent period 5 to 9 weeks later.Three of five infants had a significant increase in the ileal wall thickness visualized by ultrasound during acute rotavirus infection compared with convalescence. The number and size of mesenteric lymph nodes visualized by ultrasound appeared similar in the acute and convalescent phases, as did peristaltic activity assessed by MRI.Abdominal ultrasound can detect changes in ileal wall thickness in infants with rotavirus infection. These changes may reflect ileal inflammation elicited by viral infection. Such studies may prove useful in evaluating morphologic response to attenuated rotavirus vaccines.
View details for Web of Science ID 000223570600009
View details for PubMedID 15319628
Antiviral CD8 T cells in the control of primary human cytomegalovirus infection in early childhood
40th Annual Meeting of the Infectious-Diseases-Society-of-America
UNIV CHICAGO PRESS. 2004: 1619–27
Human cytomegalovirus (CMV) establishes persistent infection, with control of replication thought to be mediated by CMV-specific CD8 T cells. Primary CMV infection commonly affects young children and causes prolonged viral shedding in saliva and urine. We investigated whether this virus-host interaction pattern reflects a developmental deficiency of antiviral CD8 T cell-mediated immunity during childhood. CMV-specific CD8 T cell responses in asymptomatic children with active infection were not different from adults with recent or long-term infection in frequency and functional analyses. High urine CMV concentrations were detected, despite these CMV-specific CD8 T cell responses. We conclude that delayed resolution of primary CMV infection in young children is not caused by a deficient CMV-specific CD8 T cell response. Because these healthy children continue to have local CMV replication, we suggest that CD8 T cells may function primarily to prevent symptomatic, disseminated disease.
View details for Web of Science ID 000220951300010
View details for PubMedID 15116298
Persistent and selective deficiency of CD4(+) T cell immunity to cytomegalovirus in immunocompetent young children
JOURNAL OF IMMUNOLOGY
2004; 172 (5): 3260-3267
Healthy young children who acquire CMV have prolonged viral shedding into the urine and saliva, but whether this is attributable to limitations in viral-specific immune responses has not been explored. In this study, we found that otherwise immunocompetent young children after recent primary CMV infection accumulated markedly fewer CMV-specific CD4(+) T cells that produced IFN-gamma than did adults. These differences in CD4(+) T cell function persisted for more than 1 year after viral acquisition, and did not apply to CMV-specific IFN-gamma production by CD8(+) T cells. The IFN-gamma-producing CD4(+) T cells of children or adults that were reactive with CMV Ags were mainly the CCR7(low) cell subset of memory (CD45R0(high)CD45RA(low)) cells. The decreased IFN-gamma response to CMV in children was selective, because their CCR7(low) memory CD4(+) T cells and those of adults produced similar levels of this cytokine after stimulation with staphylococcal enterotoxin B superantigen. CD4(+) T cells from children also had reduced CMV-specific IL-2 and CD154 (CD40 ligand) expression, suggesting an early blockade in the differentiation of viral-specific CD4(+) T cells. Following CMV acquisition, children, but not adults, persistently shed virus in urine, and this was observable for at least 29 mo postinfection. Thus, CD4(+) T cell-mediated immunity to CMV in humans is generated in an age-dependent manner, and may have a substantial role in controlling renal viral replication and urinary shedding.
View details for Web of Science ID 000189186000069
View details for PubMedID 14978134
- Pediatric uses of valacyclovir, penciclovir and famciclovir PEDIATRIC INFECTIOUS DISEASE JOURNAL 2001; 20 (11): 1079-1081
Antiviral agents effective against herpesviruses.
Current clinical topics in infectious diseases
2001; 21: 271-301
View details for PubMedID 11572155
Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection - Two randomized controlled trials
37th Interscience Conference on Antimicrobial Agents and Chemotherapy
AMER MEDICAL ASSOC. 1999: 331–40
In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic.To evaluate the efficacy of a vaccine for prevention of HSV-2 infection.Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 microg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization.We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of HSV-2-infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine.Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group.Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P =.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P>.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2-specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes.Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.
View details for Web of Science ID 000081596800028
View details for PubMedID 10432030
Immunotherapy of recurrent genital herpes with recombinant herpes simplex virus type 2 glycoproteins D and B: Results of a placebo-controlled vaccine trial
JOURNAL OF INFECTIOUS DISEASES
1997; 176 (5): 1129-1134
To determine the safety, immunogenicity, and efficacy of a recombinant herpes simplex virus type 2 glycoprotein D and B vaccine in the treatment of recurrent genital herpes, a randomized, placebo-controlled trial was held at two referral centers. Healthy patients with 4-14 recurrences per year received injections of both glycoproteins in MF59 adjuvant or of MF59 alone at 0, 2, 12, and 14 months. For 18 study months, the rate and number of recurrences, the duration and severity of the first confirmed recurrence, vaccine immunogenicity, and rates of local and systemic reactions were determined. The monthly rate of recurrences was not significantly improved, but the duration and severity of the first study outbreak was reduced significantly by vaccination. Glycoprotein-specific and neutralizing antibodies were boosted by vaccination for the duration of the study. This vaccine is safe and immunogenic and ameliorated an observed first postvaccination genital recurrence, but it does not reduce recurrence frequency.
View details for Web of Science ID A1997YD80900001
View details for PubMedID 9359709
Safety and immunogenicity of Chiron/Biocine(R) recombinant acellular pertussis-diphtheria-tetanus vaccine in infants and toddlers
PEDIATRIC INFECTIOUS DISEASE JOURNAL
1997; 16 (1): 53-58
To evaluate the safety and immunogenicity of the recombinant acellular pertussis-diphtheria-tetanus (aPDT) vaccine (C-aPDT, Chiron/Biocine).This is a randomized blinded trial evaluating the safety and immunogenicity of the recombinant aPDT vaccine (C-aPDT, Chiron/Biocine) in 2000 infant recipients compared with 498 controls who received whole cell diphtheria-pertussis-tetanus (wDPT; Connaught) vaccine at 2, 4 and 6 months of age. In addition the safety and immunogenicity of the same C-aPDT vaccine were evaluated as a booster dose in a subset of the same population when given at 15 to 18 months of age and compared with licensed Lederle aPDT vaccine.The C-aPDT vaccine was associated with very few local or systemic reactions when compared with wDPT. In toddlers the local and systemic side effects observed were similar after either acellular vaccine. When the immunogenicity of the C-aPDT vaccine was compared with the wDPT (Connaught) in infancy, the vaccines were equivalent for anti-diphtheria response, the wDPT developed higher anti-tetanus response and the C-aPDT vaccine was significantly more immunogenic for all other antigens tested. In toddlers the C-aPDT acellular vaccine exhibited equal or improved immunogenicity for antigens tested as compared with Lederle aPDT except for a higher anti-filamentous hemagglutinin response with the Lederle aPDT vaccine.The Chiron/Biocine aPDT vaccine offers an improved safety profile as well as improved immunogenicity when compared with a licensed wDPT product.
View details for Web of Science ID A1997WC70100011
View details for PubMedID 9002102
Safety and immunogenicity of Env 2-3, a human immunodeficiency virus type 1 candidate vaccine, in combination with a novel adjuvant, MTP-PE/MF59
AIDS RESEARCH AND HUMAN RETROVIRUSES
1996; 12 (8): 683-693
We investigated the safety and immunogenicity of a candidate HIV-1 vaccine, Env 2-3 (Chiron Biocine Co.), in combination with an adjuvant emulsion, MF59, with or without an additional immune modulator, MTP-PE 78 healthy HIV-1-seronegative adults. Sixteen subjects participated in a dose escalation study of MTP-PE in MF59 without Env 2-3, given at 0 and 1 months; 48 subjects participated in a study of a fixed dose of 30 micrograms of Env 2-3 in MF59 with increasing doses of MTP-PE (0, 5, 10, 25, 50, and 100 micrograms), and 14 subjects participated in a study of 100 micrograms of Env 2-3 in MF59 without MTP-PE. Subjects were assigned to study groups under a randomized, double-blind allocation. Subjects received immunization at 0, 1, and 6 months, and had the option of receiving a fourth dose at 12-18 months. Env 2-3 in MTP-PE/MF59 was associated with significant reactogenicity, in that severe, although self-limited systemic and/or local reactions occurred in 15 of 30 vaccinees. In contrast, Env 2-3 in MF59 without MTP-PE was relatively well tolerated, and severe local and/or systemic reactions occurred in only 2 of 18 subjects. Env 2-3 stimulated serum antibodies to HIV-1 envelope protein (gp120) as detected by Western blot in 39 of 43 subjects and to HIV-1 virus lysate by EIA in 28 of 43 subjects after three injections. The majority of subjects also developed EIA antibodies to recombinant gp120 (SF-2), gp120 (LAI), and V3 peptide (SF-2). Neutralizing antibodies to the homologous SF-2 strain developed in 30 of 43 and 27 of 34 subjects, and fusion inhibition antibodies in 25 of 43 and 15 of 36 subjects after three and four injections, respectively. Lymphoproliferative responses to the immunogen, Env 2-3 were observed in over 80% of the vaccinees examined, and CD4+ cytotoxic T cell activity directed against HIV-1 was noted transiently in 2 of 20 vaccinees. Addition of MTP-PE to Env 2-3 or increasing the dose of Env 2-3 from 30 to 100 micrograms did not augment immunogenicity. Env 2-3 in MF59 was well tolerated and immunogenic in HIV-1-seronegative individuals. The addition of MTP-PE significantly increased reactogenicity, but had little, if any, effect on immunogenicity.
View details for Web of Science ID A1996UK28600006
View details for PubMedID 8744579
A RECOMBINANT GLYCOPROTEIN VACCINE FOR HERPES-SIMPLEX TYPE-2 - SAFETY AND EFFICACY
ANNALS OF INTERNAL MEDICINE
1995; 122 (12): 889-898
To evaluate the safety and immunogenicity of a recombinant glycoprotein vaccine for herpes simplex virus type 2 (HSV-2), which contains glycoproteins gD2 and gB2 combined with the novel MF59 adjuvant emulsion, in HSV-2-seronegative persons.Integrated summary of two phase I and two phase II studies.University and private outpatient clinics.137 persons seronegative for HSV-2 antibodies as determined by HSV Western blot assay.Open-label vaccine administration with a dose-escalating design (phase I) was followed by randomized vaccine administration (phase II). Vaccine was administered intramuscularly into the deltoid at 0, 1, and 6 months.Neutralizing, HSV-2-binding antibodies and HSV-2-stimulated proliferative responses were measured before and after immunization.Among HSV-seronegative patients, the gD2 and gB2 enzyme-linked immunosorbent assay (ELISA) and HSV-2-neutralizing antibody titers increased to levels equal to or higher than those seen in naturally acquired HSV-2 infection after the full three-dose immunization schedule. Among HSV-1-seropositive patients, one immunization produced increases in gD2 and gB2 ELISA antibody titers and HSV-2-neutralizing antibody titers that were 3 to 5 times greater than those in persons with naturally acquired HSV-2 infection. Among HSV-seronegative patients, frequency analysis assays showed a marked increase in the precursor frequency of gD2- and gB2-specific T cells after vaccination: T-cell responses after two immunizations were equal to the responses of HSV-2-seropositive patients and were sustained at day 180. The vaccine was well tolerated.This subunit vaccine induces both humoral and cellular responses to HSV-2 that are equal to or greater than those of persons with naturally acquired HSV-2 infection. Studies to evaluate this vaccine for the prevention of genital herpes appear warranted.
View details for Web of Science ID A1995RC27000001
View details for PubMedID 7755223
CLINICAL AND IMMUNOLOGICAL RESPONSES TO HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) TYPE 1(SF2) GP120 SUBUNIT VACCINE COMBINED WITH MF59 ADJUVANT WITH OR WITHOUT MURAMYL TRIPEPTIDE DIPALMITOYL PHOSPHATIDYLETHANOLAMINE IN NON-HIV-INFECTED HUMAN VOLUNTEERS
JOURNAL OF INFECTIOUS DISEASES
1994; 170 (5): 1288-1291
A phase 1 study of 42 non-human immunodeficiency virus type 1 (HIV)-infected volunteers was initiated to determine the safety and immunogenicity of an HIV subunit vaccine consisting of recombinant envelope gp120 derived from HIVSF2 (rgp120SF2) combined with a novel adjuvant, MF59, with or without the immunomodulator muramyl tripeptide dipalmitoyl phosphatidylethanolamine (MTP-PE). All injections contained adjuvant MF59, and subjects were grouped according to MTP-PE dose. Injections were given on days 0, 30, 180, and 365. The vaccine was well tolerated with limited local and systemic reactions. These immunizations induced rgp120SF2-specific binding antibodies that persisted > or = 24 weeks. After three immunizations, all subjects receiving the antigen developed neutralizing antibodies to HIVSF2, and serum from 67% of these subjects also cross-neutralized HIVMN. ELISA-reactive antibodies to the HIVSF2 V3 region and strong lymphoproliferative responses to HIVSF2 envelope proteins were detected in all rgp120SF2-immunized subjects.
View details for Web of Science ID A1994PN66800037
View details for PubMedID 7963729
PLACEBO-CONTROLLED TRIAL OF VACCINATION WITH RECOMBINANT GLYCOPROTEIN-D OF HERPES-SIMPLEX VIRUS TYPE-2 FOR IMMUNOTHERAPY OF GENITAL HERPES
1994; 343 (8911): 1460-1463
Immunotherapy of chronic viral diseases with vaccines is an important but unproven concept. We investigated the effect of a vaccine containing recombinant glycoprotein D (gD2) of herpes simplex virus type 2 (HSV-2) on the frequency of symptomatic outbreaks in patients with genital herpes. 98 patients with documented genital herpes who reported 4-14 recurrences per year were enrolled in a double-blind, placebo-controlled trial. Subjects received injections of either 100 micrograms gD2 in alum or alum alone (placebo) at 0 and 2 months, and recurrences were documented for 1 year. The vaccine was well tolerated. gD2 recipients reported fewer recurrences per month than placebo recipients (mean 0.42 [SE 0.05] vs 0.55 [0.05]; p = 0.055), had fewer virologically confirmed recurrences per month (0.18 [0.03] vs 0.28 [0.03]; p = 0.019), and had a lower median number of recurrences for the study year (4 [range 0-17] vs 6 [0-15]; p = 0.039). Neither genital recurrence nor the placebo vaccine had any discernible effect on HSV-2-specific antibody responses, but gD2 vaccine boosted neutralising antibodies to HSV-2 fourfold and gD2-specific titres sevenfold over baseline levels. These results inspire optimism about the potential use of vaccine for the treatment of chronic, recurring viral diseases.
View details for Web of Science ID A1994NQ41500008
View details for PubMedID 7911177
PILOT EVALUATION OF INFLUENZA-VIRUS VACCINE (IVV) COMBINED WITH ADJUVANT
1993; 11 (9): 909-913
The safety of licensed influenza virus vaccine (IVV) combined with a novel adjuvant containing muramyl tripeptide (MTP) conjugated to phosphatidylethanolamine (PE) was evaluated in a randomized pilot study. Ten healthy 23-30-year-old men were given a single intramuscular dose of IVV combined with saline (n = 5) or with 100 micrograms of MTP-PE in the MF59 adjuvant emulsion (MF59-100) (n = 5). Evaluations were performed on days 0, 1, 2, 4, 7 and 28 after inoculation. IVV alone was well tolerated. All volunteers immunized with IVV/MF59-100 experienced moderate to severe local and systemic reactions which interfered with usual activities. Discomfort at the injection site was first noted at 2-6 h; induration (5/5), erythema (3/5), and regional adenopathy (3/5) persisted for up to 4 days. Systemic symptoms including chills (5/5), fever (3/5), nausea (3/5) and/or dizziness (2/5) developed within 12 h of inoculation and resolved by 48 h. Elevated white blood cell count (days 1 and 2), erythrocyte sedimentation rate and serum fibrinogen were transiently observed. Although peak serum neutralizing antibody titres versus influenza A/H3N2 and influenza B antigens were higher in the group given IVV with MF59-100, these unexpected reactions indicate that this dose of adjuvant is unsuitable for use in combination with this IVV.
View details for Web of Science ID A1993LM70700003
View details for PubMedID 8212835
UNRECOGNIZED PERTUSSIS INFECTION IN ADOLESCENTS
AMERICAN JOURNAL OF DISEASES OF CHILDREN
1993; 147 (5): 575-577
Little information is available regarding the level of immunity to Bordetella pertussis among adolescents. We measured serum antibodies in 156 healthy adolescents to the following pertussis antigens: pertussis toxin, filamentous hemagglutinin, and 69-kd outer membrane protein. In an attempt to identify intercurrent pertussis infections, we also obtained a total of 43 repeated samples during the following 5 years. Using a 50% or greater rise in IgG enzyme-linked immunosorbent assay titers to define seroconversion, we found an annual incidence of 6.1%; by alternative definitions of seropositivity, the predicted annual incidence of infection ranged from 1.2% to 8.2%. These data suggest that infection with B pertussis is common in the adolescent population.
View details for Web of Science ID A1993LB22200030
View details for PubMedID 8488807
INDUCTION AND ENHANCEMENT OF IMMUNE-RESPONSES TO HERPES-SIMPLEX VIRUS TYPE-2 IN HUMANS BY USE OF A RECOMBINATN GLYCOPROTEIN-D VACCINE
JOURNAL OF INFECTIOUS DISEASES
1993; 167 (5): 1045-1052
View details for Web of Science ID A1993KZ49900008
COMPARISON OF ACELLULAR AND WHOLE-CELL PERTUSSIS-COMPONENT DIPHTHERIA-TETANUS-PERTUSSIS VACCINES IN INFANTS
JOURNAL OF PEDIATRICS
1991; 119 (2): 194-204
View details for Web of Science ID A1991FZ69200006
PROTECTIVE EFFICACY OF THE TAKEDA ACELLULAR PERTUSSIS-VACCINE COMBINED WITH DIPHTHERIA AND TETANUS TOXOIDS FOLLOWING HOUSEHOLD EXPOSURE OF JAPANESE CHILDREN
AMERICAN JOURNAL OF DISEASES OF CHILDREN
1990; 144 (8): 899-904
The clinical efficacy of an acellular pertussis vaccine containing lymphocytosis-promoting factor, filamentous hemagglutinin, agglutinogens, and the 69-kd outer membrane protein, combined with diphtheria and tetanus toxoids and adsorbed onto an aluminum salt, was assessed in a household contact study. The occurrence of pertussis 7 to 30 days following home exposure among 62 previously vaccinated children was compared with that among 62 unvaccinated children similarly exposed. Classic whooping cough was diagnosed in 43 unimmunized children, and 1 vaccinated child experienced a 5-week illness that was probably pertussis (efficacy, 98%; 95% confidence interval, 84% to 99%). A few children in each group incurred respiratory illnesses that may have represented mild, atypical pertussis; including these as probable pertussis, vaccine efficacy was 81% (95% confidence interval, 64% to 90%). It is concluded that prior immunization with this four-component pertussis vaccine combined with diphtheria and tetanus toxoids is highly efficacious in preventing pertussis.
View details for Web of Science ID A1990DT47400029
View details for PubMedID 2378338
Comparison of an acellular pertussis-component diphtheria-tetanus-pertussis (DTP) vaccine with a whole-cell pertussis-component DTP vaccine in 17- to 24-month-old children, with measurement of 69-kilodalton outer membrane protein antibody.
journal of pediatrics
1990; 117 (1): 46-51
Healthy 17- to 24-month-old children, previously immunized with three doses of whole-cell diphtheria-tetanus-pertussis (DTP) vaccine, were enrolled in a multi-center double-blind, randomized study comparing a DTP vaccine with an acellular pertussis-component (APDT) and a conventional whole-cell pertussis-component DTP vaccine. Thirty-eight children received APDT vaccine, and 37 children received DTP vaccine. APDT vaccine recipients had significantly less local pain and warmth than DTP vaccine recipients. Antibody responses to lymphocytosis-promoting factor were similar in the two groups. The APDT vaccine recipients had a higher IgG antibody response to filamentous hemagglutinin than the DTP vaccinees had. Equivalent agglutinin responses were seen in the two groups. The APDT vaccine recipients had a significantly better antibody re-enzyme-linked immunosorbent assay, than DTP vaccinees had 1 month and 1 year after immunization. This APDT vaccine was immunogenic and caused fewer local reactions than conventional DTP vaccine when administered as a fourth dose to 17- to 24-month-old children.
View details for PubMedID 2196360
COMPARISON OF ACELLULAR AND WHOLE-CELL PERTUSSIS-COMPONENT DTP VACCINES - A MULTICENTER DOUBLE-BLIND-STUDY IN 4-YEAR-OLD TO 6-YEAR-OLD CHILDREN
AMERICAN JOURNAL OF DISEASES OF CHILDREN
1990; 144 (1): 41-45
An acellular pertussis-component combined diphtheria and tetanus toxoids, and pertussis (APDT) vaccine adsorbed was compared with a licensed whole-cell pertussis-component combined diphtheria and tetanus toxoids, and pertussis (DTP) vaccine adsorbed for reactogenicity and immunogenicity when given as the fifth DTP immunization to eighty-two 4- to 6-year-old children. The reaction rates with both vaccines were low; APDT vaccine recipients had significantly less pain and warmth at the injection site than did DTP vaccine recipients. Antibody responses to pertussis antigens (lymphocytosis-promoting factor, filamentous hemagglutinin, and agglutinogens) and to diphtheria and tetanus toxoids were all brisk. The APDT vaccine recipients had a more marked response in antibodies to filamentous hemagglutinin and a less marked response in agglutinins than whole-cell vaccine recipients. On the day after immunization, both APDT and DTP vaccine recipients had an increase in mean leukocyte and neutrophil counts. This APDT vaccine is immunogenic and less reactogenic than a DTP vaccine with a whole-cell pertussis component when administered as a booster to 4- to 6-year-old children.
View details for Web of Science ID A1990CG25700027
View details for PubMedID 2403747
VIRUS-RESISTANCE IN CLINICAL-PRACTICE
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
1983; 12: 137-152
The sensitivity to acyclovir of more than 800 herpes simplex virus (HSV) isolates from over 300 patients were tested by the dye-uptake method. While a broad spectrum of sensitivity was found, approximately 90% of the isolates were inhibited by less than 1 mg/l of acyclovir. Therapy usually did not significantly alter the sensitivity of HSV isolates except in a few severely immunocompromised patients in whom resistant viruses produced asymptomatic or indolent infections. The sensitivity of viruses isolated during subsequent recurrences was similar to that of the originally infecting virus, regardless of therapy. The requirement of convenient and standardized methods of virus sensitivity testing is emphasized so that additional data can be accumulated to allow more precise correlations between in-vitro virus sensitivity and clinical response to acyclovir therapy.
View details for Web of Science ID A1983RL30900018
View details for PubMedID 6313593
INVITRO SENSITIVITY TO ACYCLOVIR IN GENITAL HERPES-SIMPLEX VIRUSES FROM ACYCLOVIR-TREATED PATIENTS
JOURNAL OF INFECTIOUS DISEASES
1983; 148 (5): 868-875
Genital isolates of herpes simplex virus (HSV) from patients given acyclovir or placebo were tested in vitro for sensitivity to acyclovir. Isolates obtained before therapy were sensitive to acyclovir concentrations of 0.01-19 micrograms/ml, with 86 of 97 isolates inhibited by less than 1 microgram/ml. Before therapy, six patients had isolates of HSV type 2 with ID50 values (concentrations of drug reducing viral cytopathic effect by 50%) of greater than 3 micrograms/ml. Plaque purification revealed mixed populations of virus; some clones were associated with high and some with low rates of acyclovir phosphorylation. Sensitivity to acyclovir decreased in isolates obtained after therapy from four of 25 patients given acyclovir and three of 30 patients given placebo. The occurrence of this change with similar frequency in the two groups suggests that factors other than the use of acyclovir influence the in vitro sensitivity of clinical HSV isolates to this agent. In one patient in whom an acyclovir-resistant, thymidine kinase-negative strain of HSV type 2 emerged during therapy, infection subsequently recurred. The isolate responsible for the recurrence was sensitive to acyclovir and had a high level of acyclovir-phosphorylating activity.
View details for Web of Science ID A1983RR57200012
View details for PubMedID 6313820
OCULAR LESIONS IN MICE FOLLOWING INTRACEREBRAL INJECTION OF HERPES-SIMPLEX VIRUS TYPE-1
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
1983; 24 (8): 1070-1078
A clinical isolate of type I Herpes virus was injected intracerebrally in 4-week-old Balb/C mice. Bilateral ocular disease was observed initially clinically as a leukocoria and an anterior uveitis on the 7th to 11th postinjection days. By day 21 an organized vascularized retrolental membrane had formed with resolution of active inflammation and secondary cataract formation. Light microscopy revealed the process to involve a necrotizing retinitis with associated optic nerve demyelination. Electron microscopy and tissue culture demonstrated the virus in involved tissues.
View details for Web of Science ID A1983RE81000009
View details for PubMedID 6307915