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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Post-marketing Monitoring of Vaccine Safety

Principal Investigator: Robert Ball, MD
Office / Division: OBE / DE


Public Health Issue: Risks can be associated with biologic products, such as adverse events from vaccines. Risks can emerge during pre-market phases, post-market, or during an event that necessitates its use. Since many rare adverse events are seen only after the vaccine is licensed and used in large populations, attention needs to be paid to collecting and analyzing adverse events following in the vaccine post-marketing era.

Regulatory Contribution: In collaboration with the CDC, CBER/FDA have established the Vaccine Adverse Event Reporting System (VAERS), where reports of vaccine adverse events are collected, studied and analyzed.

Research Approach: 1. Arthritis After Lyme Vaccine: A Case-Control Study of HLA Type and T-cell Reactivity to Recombinant Outer Surface Protein A and human Leukocyte Function-Associated Antigen-1. The goal of this VAERS-based case-control study is to explore a possible association between development of arthritis following Lyme vaccination and the presence of Treatment Resistant Lyme Arthritis (TRLA)-associated Human Leukocyte Antigen (HLA)-DRB1 alleles and T-lymphocyte reactivity to the OspA protein and to human leukocyte function-associated antigen-1 (hLFA-1). A small percentage of patients with Lyme disease infection, caused by the tickborne spirochete Borrelia burgdorferi, develop TRLA. TRLA has been associated with the presence of certain Class II (HLA) DRB1 alleles, including HLA-DRB1 0401. One proposed mechanism of TRLA is an autoimmune response to a human protein, hLFA-1, due to molecular mimicry between an epitope of the Bb Outer surface protein-A (OspA165-173) and an hLFA-1 epitope (hLFA1 L332-340). The TRLA HLA DRB1 alleles are proposed to be responsible for presenting these antigens to T-cells that play a role in TRLA. Regulatory contribution: The Lyme disease vaccine licensed in 1998 contains recombinant OspA (rOspA). Consequently, individuals who have the TRLA associated HLA-DRB1 alleles could, in theory, be at risk of developing an autoimmune arthritis, similar to TRLA, following Lyme vaccination. We propose a VAERS-based case-control study to explore whether an association might possibly exist between arthritis following Lyme vaccination and the presence of the TRLA associated HLA-DRB1 alleles, and T-lymphocyte reactivity to both of the OspA and hLFA-1 epitopes.

2. Evaluating the impact of the American Academy of Pediatrics and Public Health Service 1999 joint recommendation to temporarily delay newborn Hepatitis B vaccination due to thimerosal content using United Health Group's linked administrative database. This study is designed to evaluate the impact of the 1999 American Academy of Pediatrics (AAP) and Public Health Service (PHS) recommendation to temporarily delay the newborn hepatitis B vaccination for infants born to Hepatitis B surface antigen negative mothers due to thimerosal content on neonatal hepatitis B transmission as well as immunization timing and compliance for hepatitis B vaccine and other recommended pediatric vaccines. This study will explore the consequences of regulatory decisions made for safety. In the first year of the study we used the administrative claims data from seven UHG-affiliated health plans to identify cohorts of infants born before (7/1/98-6/30/99), during (7/1/99-9/30/99), or after (10/1/99-9/30/00) the vaccine delay. The medical claims of these eligible children were screened for a period of up to two years following their date of birth for ICD-9 diagnosis or CPT-4 procedure codes indicating hepatitis B. In the second year of the study, we propose to review the medical records of identified infants to validate a diagnosis of hepatitis B and collect additional clinical information not available through administrative data, including results of hepatitis B testing and immunization history.

3. The Division of Epidemiology in CBER is conducting a follow-up study of reports of autism following vaccination to the Vaccine Adverse Event Reporting System (VAERS). Some members of the public have expressed concerns about autism and vaccination, and the FDA is charged with monitoring the safety of vaccines. The first part of the study concerns the medical aspects of autism following vaccination using a questionnaire and medical record review. The goals of this study are to: (1) gather information about the clinical features of the cases; (2) look for patterns that might provide clues into the etiology of autism; and (3) look into whether there is a possible connection of the cases of autism, especially the regressive subtype, with vaccination. The second part of the study concerns parental risk perception. The questionnaire addresses such issues as parental concerns about vaccination, how parents came to believe their child's autism was related to vaccination, where parents obtain information about vaccines, and what factors (e.g. race, socioeconomic status, education) might influence risk perception.

Mission Relevance and Outcomes: These studies are oriented at evaluating the risk of various possible vaccine adverse events, e.g., personalized risk for vaccine adverse events, understanding the consequences of regulatory decisions made during the post-marketing period for safety, the generation of hypotheses that could be evaluated in subsequent controlled epidemiological studies, and to help improve the government's ability to communicate the risks and benefits of vaccination to the public.


Public Health Nurs 2006 Jul-Aug;23(4):339-46
Correlates of public health workforce acceptance of smallpox immunization in Virginia.
Bryant-Genevier M, Sommer S, McMahon A, Ball R, Braun MM

Vaccine 2006 Apr 24;24(17):3632-5
Passive surveillance for generalized vaccinia in the United States using the Vaccine Adverse Event Reporting System (VAERS).
Bryant-Genevier M, O'Connell K, Ball R, Braun MM, McMahon A

JAMA 2005 Dec 7;294(21):2720-2725
Adverse Events Reported Following Live, Cold-Adapted, Intranasal Influenza Vaccine.
Izurieta HS, Haber P, Wise RP, Iskander J, Pratt D, Mink C, Chang S, Braun MM, Ball R

J Pediatr 2005 Nov;147(5):640-644
Transient Bulging Fontanelle after Vaccination: Case Report and Review of the Vaccine Adverse Event Reporting System.
Freedman SB, Reed J, Burwen DR, Wise RP, Weiss A, Ball R

Arch Pediatr Adolesc Med 2005 Nov;159(11):1083
Fatal syncope-related fall after immunization.
Woo EJ, Ball R, Braun MM

Pharmacoepidemiol Drug Saf 2005 Sep;14(9):601-9
Comparing data mining methods on the VAERS database.
Banks D, Woo EJ, Burwen DR, Perucci P, Braun MM, Ball R

Pediatrics 2005 Feb;115(2):453-60
Adverse events after inactivated influenza vaccination among children less than 2 years of age: analysis of reports from the vaccine adverse event reporting system, 1990-2003.
McMahon AW, Iskander J, Haber P, Chang S, Woo EJ, Braun MM, Ball R

Stat Med 2005 Feb 28;24(4):551-62
Using simulation to assess the sensitivity and specificity of a signal detection tool for multidimensional public health surveillance data.
Rolka H, Bracy D, Russell C, Fram D, Ball R

J Rheumatol 2004 Nov;31(11):2181-8
Polyarteritis Nodosa Reports to the Vaccine Adverse Event Reporting System (VAERS): Implications for Assessment of Suspected Vaccine-Provoked Vasculitis.
Begier EM, Langford CA, Sneller MC, Wise RP, Ball R

JAMA 2004 Oct 13;292(14):1702-10
Postlicensure safety surveillance for 7-valent pneumococcal conjugate vaccine.
Wise RP, Iskander J, Pratt RD, Campbell S, Ball R, Pless RP, Braun MM

Am J Public Health 94 (6): 990-995 JUN 2004
Vaccine risk perception among reporters of autism after vaccination: Vaccine adverse event reporting system 1990-2001.
Woo EJ, Ball R, Bostrom A, Shadomy SV, Ball LK, Evans G, Braun M

Pediatr Infect Dis J 2004 Apr;23(4):287-294
Understanding vaccine safety information from the Vaccine Adverse Event Reporting System.
Varricchio F, Iskander J, Destefano F, Ball R, Pless R, Braun MM, Chen RT

Clin Infect Dis 2004 Mar 15;38(6):771-9
Postmarketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002.
Begier EM, Burwen DR, Haber P, Ball R, Vaccine Adverse Event Reporting System Working Group


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