Bio

Clinical Focus


  • Infectious Diseases, Pediatric
  • Pediatric Infectious Disease
  • Influenza, Human
  • Vaccine Safety
  • Vaccine Clinical Trials

Academic Appointments


Administrative Appointments


  • Medical Director, Stanford-LPCH Vaccine Program (1999 - Present)
  • Member, Department of Pediatrics Research Advisory Committee (2009 - Present)
  • Member, Department of Pediatrics Administrative Advisory Committee (2008 - 2009)
  • IRB Reviewer, Stanford Administrative Panel on Human Subjects in Medical Research, Panel 3 (2002 - Present)
  • Member, Stanford GCRC Advisory Committee (2006 - Present)

Honors & Awards


  • 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 Study to Determine the Human Infectious Doses Causing 50% Infection with the GII.4 Norovirus Filtrate, CIN 1 (2013 - 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)
  • 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 Study Drug: ACC-001 (vanutide cridificar) a joint development project for an Alzheimer’s disease vaccine between Pfizer and Janssen (2011 - Present)
  • Member, HIV Vaccine Trial Network Safety Monitoring Board (Chair 2014-present) (2009 - Present)
  • Member, NIH DMID SMC Evaluation of a Challenge Pool of Norwalk Virus Inocula in Human Subjects (2008 - Present)
  • Member, NVAC H1N1 Subgroup (2009 - 2010)
  • 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)
  • Member and SMC 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 (2004 - 2007)
  • Member, Bentley School Board of Trustees (2001 - 2004)

Professional Education


  • 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)

Research & Scholarship

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 largestt 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 is 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 newer 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 are conducting 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 3 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.

Our group also is funded as part of the Vaccine Treatment and Evaluation Units by NIH through our collaborators at Vanderbilt University. We have 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 is ongoing 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 collaborate with Dr. Greg Enns on a 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.

Clinical Trials


  • Adenovirus Vaccine for Malaria Not Recruiting

    Malaria is caused by a parasite carried by a mosquito. Currently, there is no vaccine licensed to prevent malaria. The purpose of this study is to find the most effective and safest dose of an experimental vaccine for the treatment of malaria. Participants will include 72 healthy adults, ages18 to 45, enrolled at Vanderbilt University Medical Center and Stanford University. Volunteers will receive 3 doses of either the malaria vaccine or placebo (contains no vaccine) by injection into a muscle at 0, 1 and 6 months. Investigators will evaluate how the body responds to increasing dosage strengths of the vaccine. Study procedures include physical exam, multiple blood draws, and completion of a memory aid (diary). Each participant will be actively involved in the study for about 12 months. Then, an annual phone call will be made to check for any serious illness events for a period of 5 years.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stanford-LPCH Vaccine Program, (650) 498 - 7284.

    View full details

  • Seasonal Influenza HA DNA With Trivalent Inactivated Vaccine (TIV) Administered ID or IM in Healthy Adults 18-70 Years Recruiting

    This is a Phase Ib study in healthy adults (18-70 years) to evaluate the safety, tolerability, and immunogenicity of same season and sequential season vaccination schedules consisting of the 2012/2013 seasonal influenza DNA vaccine (HA DNA) and licensed trivalent influenza vaccine (TIV) administered intradermally (ID) or intramuscularly (IM). The hypothesis is that evaluation of these investigational schedules will inform development of novel influenza vaccine strategies that may offer improved and cross-protective immunity against antigenically diverse influenza strains.

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  • Comparison of Immune Responses to Influenza Vaccine In Adults of Different Ages Not Recruiting

    The immune system is central to human health and its impairment can have serious consequences. One of the hallmarks of aging is the progressive loss of immune function exposing older people to increased risk from infectious diseases that would not normally be more than an inconvenience. This project will use state-of-the-art technology developed by the Stanford Human Immune Monitoring Center to survey older individuals for signs of immune system aging and to gather information about the factors associated with the decline of immune function.

    Stanford is currently not accepting patients for this trial.

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  • T Cell Responses to Varicella Zoster Virus (VZV) Not Recruiting

    With increasing age, immune responses to vaccination begin to decline. A decrease in vaccination success rates is already evident in the 6th and 7th decade of life. With the changing demographics of the US population, this decline in immune function is a major health concern. The study of the immune responses to the naturally-acquired chicken pox virus and to the shingles vaccine will provide an important opportunity to learn more about the aging immune system and may lead to an improvement in vaccination strategies and identification of ways to improve vaccine responses in older individuals

    Stanford is currently not accepting patients for this trial.

    View full details

  • Responses to Influenza Vaccine in Patients With Mitochondrial Disorders (MELAS) Not Recruiting

    This pilot clinical study, funded by the National Institutes of Health, will evaluate the safety and metabolic responses to a licensed inactivated seasonal influenza vaccine (TIV). This single arm study will consist of two cohorts: MELAS syndrome volunteers (a specific identified disorder of mitochondrial dysfunction: mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) between 13-60 years for OR adult control volunteers between 18-65 years of age. Both cohorts will receive the same treatment: a single vaccination with an FDA-licensed intramuscular seasonal trivalent inactivated influenza vaccine (TIV).

    Stanford is currently not accepting patients for this trial. For more information, please contact Greg Enns, MD, (650) 498-5798.

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  • Sanofi H1N1 Influenza Vaccine Administered at Different Dose Levels With and Without AS03 Adjuvant in Healthy Adult and Elderly Populations Not Recruiting

    The purpose of this study is to see how the body reacts to different strengths of the H1N1 flu shot when it is given with or without an "adjuvant." An adjuvant is a substance that may cause the body to produce more antibodies when it is given with a vaccine. This study will also compare how age affects the body's response to the H1N1 flu shot. In this study, 3 strengths of the H1N1 flu shot will be tested combined with an adjuvant. In addition, 2 strengths of the H1N1 flu shot will be tested without adjuvant. Two H1N1 flu shots of the same strength, with or without adjuvant, will be given about 3 weeks apart. Participants will include up to 800 healthy adults, approximately 500 individuals ages 18-64 and 250 individuals greater than or equal to age 65. Study procedures include: physical exam, blood samples, completing a memory aid to record vaccine side effects, medications and daily oral temperature. Participants will be involved in study related procedures for up to 13 months.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stanford-LPCH Vaccine Program, (650) 498 - 7284.

    View full details

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • Live Vaccine Use and Safety in DiGeorge Syndrome. Pediatrics Hofstetter, A. M., Jakob, K., Klein, N. P., Dekker, C. L., Edwards, K. M., Halsey, N. A., Baxter, R., Williams, S. E., Graham, P. L., LaRussa, P. 2014; 133 (4): e946-54

    Abstract

    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 Wang, C., Liu, Y., Xu, L. T., Jackson, K. J., Roskin, K. M., Pham, T. D., Laserson, J., Marshall, E. L., Seo, K., Lee, J., Furman, D., Koller, D., Dekker, C. L., Davis, M. M., Fire, A. Z., Boyd, S. D. 2014; 192 (2): 603-611

    Abstract

    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 Furman, D., Hejblum, B. P., Simon, N., Jojic, V., Dekker, C. L., Thiébaut, R., Tibshirani, R. J., Davis, M. M. 2014; 111 (2): 869-874

    Abstract

    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

  • Distinct cross-reactive B-cell responses to live attenuated and inactivated influenza vaccines. The Journal of infectious diseases Sasaki, S., Holmes, T. H., Albrecht, R. A., García-Sastre, A., Dekker, C. L., He, X. S., Greenberg, H. B. 2014

    Abstract

    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

  • Immediate hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines: Reports to VAERS VACCINE Halsey, N. A., Griffioen, M., Dreskin, S. C., Dekker, C. L., Wood, R., Sharma, D., Jones, J. F., LaRussa, P. S., Garner, J., Berger, M., Proveaux, T., Vellozzi, C., Broder, K., Setse, R., Pahud, B., Hrncir, D., Choi, H., Sparks, R., Williams, S. E., Engler, R. J., Gidudu, J., Baxter, R., Klein, N., Edwards, K., Cano, M., Kelso, J. M. 2013; 31 (51): 6107-6112

    Abstract

    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 Creech, C. B., Dekker, C. L., Ho, D., Phillips, S., Mackey, S., Murray-Krezan, C., Grazia Pau, M., Hendriks, J., Brown, V., Dally, L. G., Versteege, I., Edwards, K. M. 2013; 9 (12): 2548-2557

    Abstract

    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 Horowitz, A., Strauss-Albee, D. M., Leipold, M., Kubo, J., Nemat-Gorgani, N., Dogan, O. C., Dekker, C. L., Mackey, S., Maecker, H., Swan, G. E., Davis, M. M., Norman, P. J., Guethlein, L. A., Desai, M., Parham, P., Blish, C. A. 2013; 5 (208): 208ra145-?

    Abstract

    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 Vollmers, C., Sit, R. V., Weinstein, J. A., Dekker, C. L., Quake, S. R. 2013; 110 (33): 13463-13468

    Abstract

    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 Williams, S. E., Edwards, K. M., Baxter, R. P., LaRussa, P. S., Halsey, N. A., Dekker, C. L., Vellozzi, C., Marchant, C. D., Donofrio, P. D., Reimschisel, T. E., Berger, M., Gidudu, J. F., Klein, N. P. 2013; 162 (6): 1276-?

    View details for DOI 10.1016/j.jpeds.2013.01.028

    View details for Web of Science ID 000319502700038

    View details for PubMedID 23452584

  • Lineage Structure of the Human Antibody Repertoire in Response to Influenza Vaccination SCIENCE TRANSLATIONAL MEDICINE Jiang, N., He, J., Weinstein, J. A., Penland, L., Sasaki, S., He, X., Dekker, C. L., Zheng, N., Huang, M., Sullivan, M., Wilson, P. C., Greenberg, H. B., Davis, M. M., Fisher, D. S., Quake, S. R. 2013; 5 (171)

    Abstract

    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 Web of Science ID 000314810000008

    View details for PubMedID 23390249

  • Clinical Assessment of Serious Adverse Events in Children Receiving 2009 H1N1 Vaccination PEDIATRIC INFECTIOUS DISEASE JOURNAL Pahud, B. A., Williams, S. E., Dekker, C. L., Halsey, N., LaRussa, P., Baxter, R. P., Klein, N. P., Marchant, C. D., Sparks, R. C., Jakob, K., Aukes, L., Swope, S., Barnett, E., Lewis, P., Berger, M., Dreskin, S. C., Donofrio, P. D., Sejvar, J. J., Slade, B. A., Gidudu, J., Vellozzi, C., Edwards, K. M. 2013; 32 (2): 163-168

    Abstract

    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 He, X., Sasaki, S., Baer, J., Khurana, S., Golding, H., Treanor, J. J., Topham, D. J., Sangster, M. Y., Jin, H., Dekker, C. L., Subbarao, K., Greenberg, H. B. 2013; 207 (2): 288-296

    Abstract

    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. PloS one Price, J. V., Jarrell, J. A., Furman, D., Kattah, N. H., Newell, E., Dekker, C. L., Davis, M. M., Utz, P. J. 2013; 8 (5)

    Abstract

    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 Furman, D., Jojic, V., Kidd, B., Shen-Orr, S., Price, J., Jarrell, J., Tse, T., Huang, H., Lund, P., Maecker, H. T., Utz, P. J., Dekker, C. L., Koller, D., Davis, M. M. 2013; 9: 659-?

    Abstract

    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 VACCINE Rowhani-Rahbar, A., Klein, N. P., Dekker, C. L., Edwards, K. M., Marchant, C. D., Vellozzi, C., Fireman, B., Sejvar, J. J., Halsey, N. A., Baxter, R. 2012; 31 (1): 271-277

    Abstract

    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

  • 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 Jackson, L. A., Chen, W. H., Stapleton, J. T., Dekker, C. L., Wald, A., Brady, R. C., Edupuganti, S., Winokur, P., Mulligan, M. J., Keyserling, H. L., Kotloff, K. L., Rouphael, N., Noah, D. L., Hill, H., Wolff, M. C. 2012; 206 (6): 811-820

    Abstract

    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 VACCINE Halsey, N. A., Edwards, K. M., Dekker, C. L., Klein, N. P., Baxter, R., LaRussa, P., Marchant, C., Slade, B., Vellozzi, C. 2012; 30 (39): 5791-5798

    Abstract

    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 VACCINE Pahud, B. A., Rowhani-Rahbar, A., Glaser, C., Gavali, S., Salibay, C. J., Fireman, B., Dekker, C. L. 2012; 30 (2): 247-253

    Abstract

    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 Klein, N. P., Gidudu, J., Qiang, Y., Pahud, B., Rowhani-Rahbar, A., Baxter, R., Dekker, C. L., Edwards, K. M., Halsey, N. A., LaRussa, P., Marchant, C., Tokars, J. I., DeStefano, F. 2011; 29 (50): 9296-9297
  • Safety and Immunogenicity of LC16m8, an Attenuated Smallpox Vaccine in Vaccinia-Naive Adults JOURNAL OF INFECTIOUS DISEASES Kennedy, J. S., Gurwith, M., Dekker, C. L., Frey, S. E., Edwards, K. M., Kenner, J., Lock, M., Empig, C., Morikawa, S., Saijo, M., Yokote, H., Karem, K., Damon, I., Perlroth, M., Greenberg, R. N. 2011; 204 (9): 1395-1402

    Abstract

    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)-? 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-? 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 VACCINE Williams, S. E., Pahud, B. A., Vellozzi, C., Donofrio, P. D., Dekker, C. L., Halsey, N., Klein, N. P., Baxter, R. P., Marchant, C. D., LaRussa, P. S., Barnett, E. D., Tokars, J. I., McGeeney, B. E., Sparks, R. C., Aukes, L. L., Jakob, K., Coronel, S., Sejvar, J. J., Slade, B. A., Edwards, K. M. 2011; 29 (46): 8302-8308

    Abstract

    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 VACCINE Smith, C. K., McNeal, M. M., Meyer, N. R., Haase, S., Dekker, C. L. 2011; 29 (45): 8141-8146

    Abstract

    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 VACCINE Williams, S. E., Klein, N. P., Halsey, N., Dekker, C. L., Baxter, R. P., Marchant, C. D., LaRussa, P. S., Sparks, R. C., Tokars, J. I., Pahud, B. A., Aukes, L., Jakob, K., Coronel, S., Choi, H., Slade, B. A., Edwards, K. M. 2011; 29 (40): 6920-6927

    Abstract

    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 VACCINE Frenck, R. W., Belshe, R., Brady, R. C., Winokur, P. L., Campbell, J. D., Treanor, J., Hay, C. M., Dekker, C. L., Walter, E. B., Cate, T. R., Edwards, K. M., Hill, H., Wolff, M., Leduc, T., Tornieporth, N. 2011; 29 (34): 5666-5674

    Abstract

    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 ?g HA/strain TIV IM, either 9 ?g or 6 ?g HA/strain of TIV ID given using a new microinjection system (BD Soluvia™ Microinjection System), or 3 ?g 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 ?g and the 6 ?g doses of each strain given ID were non inferior to GMTs generated after standard 15 ?g doses/strain IM. However, for the 3 ?g 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 6?g 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 ?g and 9 ?g) of TIV delivered ID using a novel microinjection system stimulated comparable HAI antibody responses to standard TIV given IM. The reduced 3 ?g dose administered ID by needle and syringe, as well as the 6 ?g ID for subjects aged 50-64 years of age generated poorer immune responses as compared to the 15 ?g 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 Sasaki, S., Sullivan, M., Narvaez, C. F., Holmes, T. H., Furman, D., Zheng, N., Nishtala, M., Wrammert, J., Smith, K., James, J. A., Dekker, C. L., Davis, M. M., Wilson, P. C., Greenberg, H. B., He, X. 2011; 121 (8): 3109-3119

    Abstract

    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 PEDIATRICS Vannice, K. S., Salmon, D. A., Shui, I., Omer, S. B., Kissner, J., Edwards, K. M., Sparks, R., Dekker, C. L., Klein, N. P., Gust, D. A. 2011; 127: S120-S126

    Abstract

    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 PEDIATRICS Larussa, P. S., Edwards, K. M., Dekker, C. L., Klein, N. P., Halsey, N. A., Marchant, C., Baxter, R., Engler, R. J., Kissner, J., Slade, B. A. 2011; 127: S65-S73

    Abstract

    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 He, X., Sasaki, S., Narvaez, C. F., Zhang, C., Liu, H., Woo, J. C., Kemble, G. W., Dekker, C. L., Davis, M. M., Greenberg, H. B. 2011; 365 (1-2): 67-75

    Abstract

    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 Pahud, B. A., Glaser, C. A., Dekker, C. L., Arvin, A. M., Schmid, D. S. 2011; 203 (3): 316-323

    Abstract

    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

  • Preterm Infants' T Cell Responses to Inactivated Poliovirus Vaccine JOURNAL OF INFECTIOUS DISEASES Klein, N. P., Gans, H. A., Sung, P., Yasukawa, L. L., Johnson, J., Sarafanov, A., Chumakov, K., Hansen, J., Black, S., Dekker, C. L. 2010; 201 (2): 214-222

    Abstract

    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

  • Vaccine effectiveness against laboratory-confirmed influenza in infants: A matched case control study. Human vaccines Cochran, L. W., Black, S., Klein, N. P., Dekker, C. L., Lewis, E., Reingold, A. L. 2010; 6 (9)

    Abstract

    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 PubMedID 20855940

  • Differential maternal responses to a newly developed vaccine information pamphlet VACCINE Klein, N. P., Kissner, J., Aguirre, A., Sparks, R., Campbell, S., Edwards, K. M., Dekker, C. L., Shui, I., Gust, D. A. 2009; 28 (2): 323-328

    Abstract

    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 VACCINE Keitel, W. A., Dekker, C. L., Mink, C., Campbell, J. D., Edwards, K. M., Patel, S. M., Ho, D. Y., Talbot, H. K., Guo, K., Noah, D. L., Hill, H. 2009; 27 (47): 6642-6648

    Abstract

    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 Dekker, C. L., Arvin, A. M. 2009; 360 (12): 1250-1252

    View details for Web of Science ID 000264283400013

    View details for PubMedID 19297578

  • Adolescent Vaccination Recommendations from the National Vaccine Advisory Committee AMERICAN JOURNAL OF PREVENTIVE MEDICINE Freed, G. L. 2009; 36 (3): 278-279

    View details for DOI 10.1016/j.amepre.2008.10.015

    View details for Web of Science ID 000263538300015

    View details for PubMedID 19162432

  • An algorithm for treatment of patients with hypersensitivity reactions after vaccines PEDIATRICS Wood, R. A., Berger, M., Dreskin, S. C., Setse, R., Engler, R. J., Dekker, C. L., Halsey, N. A. 2008; 122 (3): E771-E777

    Abstract

    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 PLOS ONE Sasaki, S., He, X., Holmes, T. H., Dekker, C. L., Kemble, G. W., Arvin, A. M., Greenberg, H. B. 2008; 3 (8)

    Abstract

    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 Freed, G. L., Almquist, J. R., Birkhead, G. S., Dekker, C., Feinberg, M., Fergie, J., Gordon, L. K., Hinman, A. R., Humiston, S. G., Johnson, C., Mein, J. O., Koslap-Petraco, M. B., Lovell, C., Parnell, T., Pavia, A., Riley, L. E., Young, A. E. 2008; 35 (2): 152-157

    View details for DOI 10.1016/j.amepre.2008.03.034

    View details for Web of Science ID 000257893700010

    View details for PubMedID 18617084

  • Mandates for adolescent immunizations - Recommendations from the National Vaccine Advisory Committee AMERICAN JOURNAL OF PREVENTIVE MEDICINE Freed, G. L., Almquist, J. R., Birkhead, G. S., Dekker, C., Feinberg, M., Fergie, J., Gordon, L. K., Hinman, A. R., Humiston, S. G., Johnson, C., Klein, J. O., Koslap-Petraco, M. B., Lovell, C., Parnell, T., Pavia, A., Riley, L. E., Young, A. E. 2008; 35 (2): 145-151

    View details for DOI 10.1016/j.amepre.2008.03.033

    View details for Web of Science ID 000257893700009

    View details for PubMedID 18617083

  • Immunogenicity, safety and consistency of new trivalent inactivated influenza vaccine VACCINE Talbot, H. K., Keitel, W., Cate, T. R., Treanor, J., Campbell, J., Bradye, R. C., Graham, I., Dekker, C. L., Ho, D., Winokur, P., Walter, E., Bennet, J., Formica, N., Hartel, G., Skeljo, M., Edwards, K. M. 2008; 26 (32): 4057-4061

    Abstract

    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 PLOS ONE He, X., Holmes, T. H., Sasaki, S., Jaimes, M. C., Kemble, G. W., Dekker, C. L., Arvin, A. M., Greenberg, H. B. 2008; 3 (7)

    Abstract

    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 JOURNAL OF INFECTIOUS DISEASES He, X., Holmes, T. H., Mahmood, K., Kemble, G. W., Dekker, C. L., Arvin, A. M., Greenberg, H. B. 2008; 197 (6): 803-811

    Abstract

    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 Bernstein, D. I., Edwards, K. M., Dekker, C. L., Belshe, R., Talbot, H. K., Graham, I. L., Noah, D. L., He, F., Hill, H. 2008; 197 (5): 667-675

    Abstract

    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

  • A role for genetics in the immune response to the varicella vaccine PEDIATRIC INFECTIOUS DISEASE JOURNAL Klein, N. P., Fireman, B., Enright, A., Ray, P., Black, S., Dekker, C. L. 2007; 26 (4): 300-305

    Abstract

    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 Zeman, A. M., Holmes, T. H., Stamatis, S., Tu, W., He, X., Bouvier, N., Kemble, G., Greenberg, H. B., Lewis, D. B., Arvin, A. M., Dekker, C. L. 2007; 26 (2): 107-115

    Abstract

    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 Sasaki, S., Jaimes, M. C., Holmes, T. H., Dekker, C. L., Mahmood, K., Kemble, G. W., Arvin, A. M., Greenberg, H. B. 2007; 81 (1): 215-228

    Abstract

    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 He, X., Holmes, T. H., Zhang, C., Mahmood, K., Kemble, G. W., Lewis, D. B., Dekker, C. L., Greenberg, H. B., Arvin, A. M. 2006; 80 (23): 11756-11766

    Abstract

    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 VACCINE Klein, N. P., Holmes, T. H., Sharp, M. A., Heineman, T. C., Schleiss, M. R., Bernstein, D. I., Kemble, G., Arvin, A. M., Dekker, C. L. 2006; 24 (33-34): 5913-5918

    Abstract

    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 He, X. S., Draghi, M., Mahmood, K., Holmes, T. H., Kemble, G. W., Dekker, C. L., Arvin, A. M., Parham, P., Greenberg, H. B. 2004; 114 (12): 1812-1819

    Abstract

    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 HUMAN IMMUNOLOGY Drohan, L., Harding, J. J., Holm, B., Cordoba-Tongson, E., Dekker, C. L., Holmes, T., Maecker, H., Mellins, E. D. 2004; 65 (11): 1356-1369

    Abstract

    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 Bass, D., Cordoba, T., Dekker, T., Schuind, A., Cassady, J. 2004; 39 (3): 270-274

    Abstract

    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 JOURNAL OF INFECTIOUS DISEASES Chen, S. F., Tu, W. W., Sharp, M. A., Tongson, E. C., He, X. S., Greenberg, H. B., Holmes, T. H., Wang, Z. T., Kemble, G., Manganello, A. M., Adler, S. P., Dekker, C. L., Levvis, D. B., Arvin, A. M. 2004; 189 (9): 1619-1627

    Abstract

    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 Tu, W. W., Chen, S., Sharp, M., Dekker, C., Manganello, A. M., Tongson, E. C., Maecker, H. T., Holmes, T. H., Wang, Z. T., Kemble, G., Adler, S., Arvin, A., Lewis, D. B. 2004; 172 (5): 3260-3267

    Abstract

    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 Dekker, C. L., Prober, C. G. 2001; 20 (11): 1079-1081

    View details for Web of Science ID 000172186600012

    View details for PubMedID 11734715

  • Antiviral agents effective against herpesviruses. Current clinical topics in infectious diseases Dekker, C. L., Prober, C. G. 2001; 21: 271-301

    View details for PubMedID 11572155

  • 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 Straus, S. E., Wald, A., KOST, R. G., McKenzie, R., Langenberg, A. G., Hohman, P., LEKSTROM, J., Cox, E., Nakamura, M., Sekulovich, R., Izu, A., Dekker, C., Corey, L. 1997; 176 (5): 1129-1134

    Abstract

    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 Black, S. B., Shinefield, H. R., Bergen, R., Hart, C., KREMERS, R., LAVETTER, A., LEMESURIER, J., Morozumi, P. A., Ray, P., Lewis, E. M., Fireman, B., Schwalbe, J., Hallam, P., Shandling, M., Dekker, C., Granoff, D. M., Izu, A., Podda, A. 1997; 16 (1): 53-58

    Abstract

    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 Keefer, M. C., Graham, B. S., McElrath, M. J., Matthews, T. J., Stablein, D. M., Corey, L., Wright, P. F., LAWRENCE, D., Fast, P. E., Weinhold, K., Hsieh, R. H., Chernoff, D., Dekker, C., Dolin, R. 1996; 12 (8): 683-693

    Abstract

    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 Langenberg, A. G., BURKE, R. L., ADAIR, S. F., SEKULOVICH, O., TIGGES, M., Dekker, C. L., Corey, L. 1995; 122 (12): 889-898

    Abstract

    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 Kahn, J. O., Sinangil, F., Baenziger, J., Murcar, N., Wynne, D., Coleman, R. L., Steimer, K. S., Dekker, C. L., Chernoff, D. 1994; 170 (5): 1288-1291

    Abstract

    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

  • PILOT EVALUATION OF INFLUENZA-VIRUS VACCINE (IVV) COMBINED WITH ADJUVANT VACCINE Keitel, W., Couch, R., Bond, N., Adair, S., Vannest, G., Dekker, C. 1993; 11 (9): 909-913

    Abstract

    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 Cromer, B. A., Goydos, J., Hackell, J., Mezzatesta, J., Dekker, C., Mortimer, E. A. 1993; 147 (5): 575-577

    Abstract

    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

  • 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 Mortimer, E. A., Kimura, M., Cherry, J. D., KUNOSAKAI, H., Stout, M. G., Dekker, C. L., Hayashi, R., Miyamoto, Y., Scott, J. V., Aoyama, T., Isomura, S., Iwata, T., KAMIYA, H., Kato, T., NOYA, J., Suzuki, E., Takeuchi, Y., Yamaoka, H. 1990; 144 (8): 899-904

    Abstract

    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 Blumberg, D. A., Mink, C. M., Cherry, J. D., Reisinger, K. S., Blatter, M. M., Congeni, B. L., Dekker, C. L., Stout, M. G., Mezzatesta, J. R., Scott, J. V. 1990; 117 (1): 46-51

    Abstract

    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 MORGAN, C. A., Blumberg, D. A., Cherry, J. D., Reisinger, K. S., Blatter, M. M., Blumer, J. L., Dekker, C. L., Stout, M. G., Christenson, P. D. 1990; 144 (1): 41-45

    Abstract

    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 Dekker, C., ELLIS, M. N., McLaren, C., Hunter, G., Rogers, J., Barry, D. W. 1983; 12: 137-152

    Abstract

    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 McLaren, C., Corey, L., DEKKET, C., Barry, D. W. 1983; 148 (5): 868-875

    Abstract

    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 Peiffer, R. L., DEKKER, C. D., Siegel, F. L. 1983; 24 (8): 1070-1078

    Abstract

    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

Conference Proceedings


  • Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection - Two randomized controlled trials Corey, L., Langenberg, A. G., Ashley, R., Sekulovich, R. E., Izu, A. E., Douglas, J. M., Handsfield, H. H., Warren, T., Marr, L., Tyring, S., DiCarlo, R., Adimora, A. A., Leone, P., Dekker, C. L., BURKE, R. L., Leong, W. P., Straus, S. E. AMER MEDICAL ASSOC. 1999: 331-340

    Abstract

    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

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