IMMUNIZATION SAFETY REVIEW

HEPATITIS B VACCINE AND DEMYELINATING NEUROLOGICAL DISORDERS

Kathleen Stratton, Donna A.Almario, and Marie C.McCormick, Editors

Immunization Safety Review Committee

Board on Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu



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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders IMMUNIZATION SAFETY REVIEW HEPATITIS B VACCINE AND DEMYELINATING NEUROLOGICAL DISORDERS Kathleen Stratton, Donna A.Almario, and Marie C.McCormick, Editors Immunization Safety Review Committee Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. Support for this project was provided by the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health as part of a National Institutes of Health Task Order No. 74. The views presented in this report are those of the Institute of Medicine Immunization Safety Review Committee and are not necessarily those of the funding agencies. International Standard Book Number 0-309-08469-5 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624– 6242 or (202) 334–3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. For more information regarding this report and other reports to be issued by this committee, visit the IOM project web page at www.iom.edu/imsafety. Copyright 2002 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders “Knowing is not enough; we must apply. Willing is not enough; TVS must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Shaping the Future for Health

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M.Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm.A.Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V.Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M.Alberts and Dr. Wm.A.Wulf are chair and vice chair, respectively, of the National Research Council www.national-academies.org

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders IMMUNIZATION SAFETY REVIEW COMMITTEE MARIE C.McCORMICK, M.D., Sc.D., (Chair), Professor and Chair, Department of Maternal and Child Health, Harvard School of Public Health RONALD BAYER, Ph.D., Professor, Division of Sociomedical Sciences, School of Public Health, Columbia University ALFRED BERG, M.D., M.P.H., Professor and Chair, Department of Family Medicine, University of Washington School of Medicine ROSEMARY CASEY, M.D., Associate Professor of Pediatrics, Jefferson Medical College and Director, Lankenau Faculty Pediatrics, Wynnewood, Pennsylvania JOSHUA COHEN, Ph.D., Senior Research Associate, Harvard Center for Risk Analysis, Harvard School of Public Health CONSTANTINE GATSONIS, Ph.D., Professor of Medical Science and Applied Math, and Director, Center for Statistical Sciences, Brown University STEVEN GOODMAN, M.D., M.H.S., Ph.D., Associate Professor, Department of Oncology, Division of Biostatistics, Johns Hopkins School of Medicine ELLEN HORAK, M.S.N., Education and Nurse Consultant, Public Management Center, University of Kansas MICHAEL KABACK, M.D., Professor, Pediatrics and Reproductive Medicine, University of California, San Diego GERALD MEDOFF, M.D., Professor, Department of Internal Medicine, Washington University School of Medicine, St. Louis REBECCA PARKIN, Ph.D., Associate Research Professor, Department of Occupational and Environmental Health, School of Public Health and Health Services, George Washington University BENNETT SHAYWITZ, M.D., Professor of Pediatrics and Neurology, Co-Director, Yale Center for the Study of Learning and Attention The following individuals are members of the Immunization Safety Review Committee but were unable to attend the meeting on the topic of this report: BETSY FOXMAN, Ph.D., Professor, Department of Epidemiology, School of Public Health, University of Michigan CHRISTOPHER B.WILSON, M.D., Professor and Chair, Department of Immunology, University of Washington Health Promotion and Disease Prevention Board Liaison RICHARD B.JOHNSTON, Jr., M.D., Professor of Pediatrics, Associate Dean for Research Development, University of Colorado School of Medicine and National Jewish Medical and Research Center

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Study Staff KATHLEEN STRATTON, Ph.D., Study Director DONNA A.ALMARIO, M.P.H., Research Associate KYSA CHRISTIE, Research Assistant KATRINA J.LAWRENCE, M.S., Senior Project Assistant ROSE MARIE MARTINEZ, Sc.D., Director, Board on Health Promotion and Disease Prevention Contract Writer JANE S.DURCH, M.A., Freelance Writer and Editor, Arlington, Virginia Contract Editor STEVEN J.MARCUS, Ph.D., Freelance Editor, Brookline, Massachusetts

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders REVIEWERS This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Arthur K.Asbury, M.D., University of Pennsylvania Ann Bostrom, Ph.D., Georgia Institute of Technology Linda Cowan, Ph.D., University of Oklahoma Bradley N.Doebbeling, M.D., M.Sc., University of Iowa Healthcare Stephen L.Hauser, M.D., University of California, San Francisco Christopher Karp, M.D., Children’s Hospital Research Foundation Edgar K.Marcuse, M.D., M.P.H., Children’s Hospital & Regional Medical Center John Menkes, M.D., Cedars Sinai Medical Center, University of California, Los Angeles Peter H.Meyers, J.D., The George Washington University Helen Ranney, M.D., Alliance Pharmaceutical Corporation Richard Rheingans, Ph.D., Emory University Harvey Sadow, Ph.D., Former Chairman, President and CEO of Boehringer Ingelheim Pharmaceuticals and Boehringer Ingelheim Corportaion Brian Ward, M.D., Montreal General Hospital Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Robert Lawrence, M.D., Johns Hopkins University and Ronald Estabrook, Ph.D., University of Texas Southwestern. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Foreword Vaccines are among the greatest public health accomplishments of the past century. In recent years, however, a number of concerns have been raised about the safety of, and need for, certain immunizations. Indeed, immunization safety is a contentious area of public health policy, with discourse around it having become increasingly polarized and exceedingly difficult. The numerous controversies and allegations surrounding immunization safety signify an erosion of public trust in those responsible for vaccine research, development, licensure, schedules, and policy making. Because vaccines are so widely used—and because state laws require that children be vaccinated to enter daycare and school, in part to protect others—immunization safety concerns should be vigorously pursued in order to restore this trust. It is in this context that the Institute of Medicine (IOM) was approached more than a year ago by the Centers for Disease Control and Prevention and the National Institutes of Health to convene an independent committee that could provide timely and objective assistance to the Department of Health and Human Services in reviewing emerging immunization safety concerns. The IOM was chartered by the National Academy of Sciences in 1970 to serve as an adviser to the federal government on issues affecting the public’s health, as well as to act independently in identifying important issues of medical care, research, and education. The IOM thus brings to this mission three decades of experience in conducting independent analyses of significant public health policy issues. In particular, as described in more detail in this report, the IOM has a long history of involvement in vaccine safety. The IOM published its first

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders major vaccine safety report in 1977, followed by a subsequent report in 1988; both focused on the safety of polio vaccines. Two subsequent major reports, published in 1991 and 1994, examined the adverse events of childhood vaccines. Since then, the IOM has conducted several smaller studies and workshops focused on various vaccine safety topics. These studies were all well received by both the public and policy makers, and previous IOM committees on vaccine safety issues have been viewed as objective and credible. Given the sensitive nature of the present immunization safety review study, the IOM felt it was especially critical to establish strict criteria for committee membership. These criteria prevented participation by anyone with financial ties to vaccine manufacturers or their parent companies, previous service on major vaccine advisory committees, or prior expert testimony or publications on issues of vaccine safety. The rationale for imposing these stringent criteria was twofold. First, given growing public concern about vaccine safety and the public scrutiny surrounding this committee’s work, it was important to establish standards that would preclude any real or perceived conflict of interest or bias on the part of the committee members. While the committee members all share a belief in the benefits of vaccines to the public health, none of them has any vested interest in any of the vaccine safety issues that will come before them. Second, the IOM wanted to ensure consistency in the committee membership and avoid having members recuse themselves from the deliberations because they had participated in the development or evaluation of a vaccine under study. Thus, the IOM has convened a distinguished panel of 15 members who possess significant breadth and depth of expertise in a number of fields, including pediatrics, neurology, immunology, internal medicine, infectious diseases, genetics, epidemiology, biostatistics, risk perception and communication, decision analysis, public health, nursing, and ethics. The committee members were chosen because they are leading authorities in their respective fields, are well respected by their colleagues, and have no conflicts of interest. This committee brought a fresh perspective to these critically important issues and approached its charge with impartiality and scientific rigor. The IOM does not propose the use of the criteria it has laid out above in selecting members for federal vaccine advisory committees. The IOM committee was convened for a very different purpose from the usual federal vaccine advisory committees and, as such, required different standards. As with all reports from the IOM, the committee’s work was reviewed by an independent panel of experts. The purpose of the review process is to enhance the clarity, cogency, and accuracy of the final report and to ensure that the authors and the IOM are creditably represented by the report published in their names. The report review process is overseen by the National Research Council’s (NRC) Report Review Committee (RRC), comprised of approximately 30 members of the National Academy of Sciences, National Academy of Engineer-

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders ing, and IOM. The IOM, in conjunction with the RRC, appoints a panel of reviewers with a diverse set of perspectives on key issues considered in the report. Unlike the selection criteria for committee membership (discussed above), many reviewers will have strong opinions and biases about the report topic. The composition of the review panel is not disclosed to the committee until after the report is approved for release. While the committee must consider and evaluate all comments from reviewers, it is not obligated to change its report in response to the reviewers’ comments. The committee must, however, justify its responses to the reviewers’ comments to the satisfaction of the RRC’s review monitor and the IOM’s review coordinator. A report may not be released to the sponsors or the public, nor may its findings be disclosed, until after the review process has been satisfactorily completed and all authors have approved the revised draft. This report represents the unanimous conclusions and recommendations of that dedicated committee whose members deliberated a critical health issue. The report’s conclusions and recommendations should be of value to all concerned about these important matters. Kenneth I.Shine President, Institute of Medicine (until June 30th 2002)

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Acknowledgments The committee would like to acknowledge the many speakers and attendees at its open meeting held on March 11, 2002, in Washington, DC. The discussions were informative and helpful. The committee would also like to thank those people who submitted information to the committee through the mail or e-mail. Finally, the committee would like to thank the IOM staff for their dedication to this project. Without their commitment, attention to detail, creativity, sensitivity, and hard work, this project would be unworkable.

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Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders Contents     Executive Summary   1     Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders   17     The Charge to the Committee   17     The Study Process   19     The Framework for Scientific Assessment   20     Under Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders   27     Scientific Assessment   38     Significance Assessment   69     Recommendations for Public Health Response   80     Summary   82     References   85 Appendix A       91 Appendix B       100 Appendix C       103

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