Adverse Events Associated with CHILDHOOD VACCINES

Evidence Bearing on Causality

Kathleen R. Stratton, Cynthia J. Howe, and Richard B. Johnston, Jr., Editors

Vaccine Safety Committee

Division of Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.
1994



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Adverse Events Associated with CHILDHOOD VACCINES Evidence Bearing on Causality Kathleen R. Stratton, Cynthia J. Howe, and Richard B. Johnston, Jr., Editors Vaccine Safety Committee Division of Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C. 1994

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 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. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this the Institute acts under the Academy’s 1863 congressional charter responsibility to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is President of the Institute of Medicine. The project was supported by funds coordinated through the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (contract no. NO1-AI-15130). Library of Congress Cataloging-in-Publication Data Adverse events associated with childhood vaccines : evidence bearing on causality / Kathleen R. Stratton, Cynthia J. Howe, and Richard B. Johnston, Jr., editors ; Division of Health Promotion and Disease Prevention, Institute of Medicine. p. cm. “The project was supported by funds coordinated through the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (contract no. NO-AI-15130)”—T.p. verso. Includes bibliographical references and index. ISBN 0-309-04895-8 1. Vaccination of children—Complications. 2. Vaccines—Health aspects. 3. Vaccines—Toxicology. I. Stratton, Kathleen R. II. Howe, Cynthia J. III. Johnston, Richard B., 1935- . IV. Institute of Medicine (U.S.). Division of Health Promotion and Disease Prevention. V. National Institute of Allergy and Infectious Diseases (U.S.). [DNLM: 1. Vaccines—adverse effects. 2. Immunization—in infancy & childhood. WS 135 A244 1993] RJ240.A38 1993 615'.372'083—dc20 DNLM/DLC 93-32099 for Library of Congress CIP Copyright 1994 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 Staatlichemuseen in Berlin.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality VACCINE SAFETY COMMITTEE RICHARD B. JOHNSTON, JR. (Chair), Senior Vice President for Program and Medical Director, The March of Dimes Birth Defects Foundation, White Plains, New York; Adjunct Professor of Pediatric Yale University School of Medicine, New Haven, Connecticut E. RUSSELL ALEXANDER, Professor of Epidemiology, School of Public Health and Community Medicine of the University of Washington; Chief of Epidemiology, Seattle-King County Health Department, Seattle, Washington ALAN M. ARON, Professor of Neurology and Director of Child Neurology, Mount Sinai School of Medicine, New York, New York ARTHUR K. ASBURY,* Van Meter Professor of Neurology and Vice Dean for Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania CHARLES C. J. CARPENTER,* Professor of Medicine, Brown University; Physician-in-Chief, The Miriam Hospital, Providence, Rhode Island K. LYNN CATES, Associate Professor of Pediatrics, Case Western Reserve University School of Medicine; Chief, Pediatric Infectious Diseases, Rainbow Babies and Childrens Hospital, Cleveland, Ohio KAY DICKERSIN, Assistant Professor, Department of Epidemiology an Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland RICHARD T. JOHNSON,* Professor and Director, Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland MICHAEL KATZ,* Carpentier Professor of Pediatrics, Emeritus, Columbia University; Vice President for Research, The March of Dimes Birth Defects Foundation, White Plains, New York MICHAEL S. KRAMER, Professor, Departments of Pediatrics and of Epidemiology and Biostatistics, McGill University Faculty of Medicine, Montreal, Quebec, Canada KENNETH MCINTOSH, Professor, Department of Pediatrics, Harvard University Medical School; Chief, Division of Infectious Diseases, Children's Hospital, Boston, Massachusetts CATHERINE J. ROSE, Pediatrician, San Jose, California PENELOPE G. SHACKELFORD, Professor of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality PAUL D. STOLLEY,* Professor and Chairman, Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland Project Staff Michael A. Stoto, Director, Division of Health Promotion and Disease Prevention Kathleen R. Stratton, Project Director Cynthia J. Howe, Program Officer Dorothy R. Majewski, Project Assistant Michael K. Hayes, Project Editor Tamar Lasky, Consultant Hanaa Elhefni, Consultant *   Member, Institute of Medicine.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Preface Few would question the profound importance of vaccines to public health. Not only have deaths from the most common childhood infections been almost eliminated, but so have the devastating morbidities of diseases like measles, paralytic polio, and congenital rubella. This revolution has occurred within the life spans of middle-aged Americans, and it has led to major savings in medical costs and gains in work productivity, as well as to reductions in death and suffering. In the United States this success has been achieved through increased public awareness, continued support of basic and applied research, the capacity of the pharmaceutical industry, and the dedication of the public and private health care workers responsible for administration of the vaccines. In the 1980s, however, a few concerned citizens in this country began to raise questions about the risks of vaccination. In fact, although the benefits to society were obvious, the risks to individual infants and children had not been well defined. Some parents considered not having their children immunized, and manufacturers threatened to shut down vaccine production because of an increasing number of lawsuits. In response, the U.S. Congress passed the National Childhood Vaccine Injury Act in 1986 and the Vaccine Compensation Amendments in 1987. This legislation established a federal compensation process for persons judged to be injured by a vaccine. In addition, Section 312 of the Act mandated that the Institute of Medicine should conduct a scientific review of the possible adverse consequences of pertussis and rubella vaccines. The re-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality sults of that review were published in 1991. Section 313 of the Act mandated that a second Institute of Medicine committee review possible adverse events associated with the other vaccines commonly given in childhood. This report comprises the deliberations and conclusions of that committee, the Vaccine Safety Committee. The principal purpose of the committee's work was to describe as precisely as possible, on the basis of all available evidence, the relationships between the vaccines under review and specific adverse events. This led the committee to ask with each vaccine-adverse event pair, "Can administration of the vaccine cause the adverse event?" All available sources of information were analyzed, from epidemiologic studies to unpublished case reports. Final decisions on causality were made by consensus after group discussion of all of the available evidence. In pursuing its conclusions, the committee adopted a neutral stance and maintained that stance consistently through each step in the process, assuming neither the presence nor the absence of a causal relation between the vaccines and the adverse events until the evidence indicated otherwise. In reaching a conclusion that the evidence favored rejection of a causal relation, the committee used only epidemiologic studies (controlled observational studies and controlled clinical trials). In reaching conclusions favoring acceptance of a causal relation, however, the committee most commonly relied on case series and individual case reports. This required that the nature and timing of the adverse event were appropriate for causality and that there were no likely alternative explanations for the event. Biologic plausibility was weighed in the overall balance of the determination but was not in itself considered sufficient evidence to accept or reject a causal relation. As this report describes in detail, it was possible with some of the vaccine-adverse event pairs to reach a conclusion one way or the other—either that the evidence favored rejection (category 3) or that the evidence weighed more or less heavily for acceptance (categories 4 and 5) of a causal relation (see Chapter 2 for explanations of the five categories). With the majority of vaccine-adverse event pairs the evidence was considered inadequate to accept or reject causality. In some instances, the relation has not been well studied and the data are scarce; in others, the data are abundant but the evidence, on the whole, was not conclusive. Category 2 does not distinguish between these two situations, since the conclusion is the same. It could be argued in these cases that since the body of available evidence did not support causality, a causal relation does not exist. It could also be argued that in the absence of evidence favoring rejection of causality, it is possible that the vaccine could cause the adverse event. Both of these interpretations are possible. The committee regrets that this uncertainty may not make it easier to resolve litigation centered on individual instances

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality of putative causality. However, the stringency of our charge precluded statements beyond what the evidence allowed. Concern about this unfortunate condition of uncertainty has led the committee to urge that more definitive research be done on possible adverse events during the development of new vaccines or vaccine combinations and to urge that efforts to sharpen current postmarketing surveillance systems be accelerated. This report represents the product of long hard work by committee members and Institute of Medicine staff. The Acknowledgments section lists a large number of other people who contributed to the effort in an important way, including parents who had the courage to remind us that public health measures affect the lives of individual human beings. In addition, the committee has recognized that it owes a special debt to its predecessor, the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines. That committee developed a logical system, on the basis of the available evidence, of classifying—and thereby communicating—the nature of the causal relations between vaccines and adverse events. The committee has also recognized that the quality of this report could not have been achieved without the work of the extraordinary staff assigned to us by the Institute of Medicine—Kathleen Stratton, Cynthia Howe, Michael Stoto, and Dorothy Majewski. In particular, Kathleen Stratton, the Project Director, with intelligence, infinite kindness, and untiring persistence, kept the committee to its proper task; and we are deeply grateful. Whatever its commissioned intent, in the end, the work of the Vaccine Safety Committee will have succeeded if this report contributes to present worldwide efforts to protect children from preventable infections using vaccines that incur the lowest possible risk. Richard B. Johnston, Jr. Chairman

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Acknowledgments The committee would like to thank the following individuals who provided us with information or assistance: Kenneth J. Bart, National Vaccine Program; W. J. Bellini, Centers for Disease Control and Prevention; Bruce Berget, University of Chicago; Else Borst-Eilers, Health Council of The Netherlands; Philip A. Brunell, Cedars-Sinai Medical Center; John Brydon, Demler Armstrong & Rowland, Long Beach, California; Christine Buhk, Sturgeon Bay, Wisconsin; Hilary Butler, Tuakau, Auckland, New Zealand; Kim Chapman, Colorado Springs, Colorado; Robert T. Chen, Centers for Disease Control and Prevention; James D. Cherry, UCLA Medical Center; Kathleen Crozier, Infectious Disease News; Colette Cogliandro, Chesapeake, Virginia; Shannon Dixon, Honolulu, Hawaii; Andrew W. Dodd, Torrance, California; Philippe Duclos, Health and Welfare Canada; Paul Dyken, University of Southern Alabama; Hanaa Elhefni, University of Maryland, Baltimore; Jan Erickson, National Vaccine Information Center; Elaine C. Esber, U.S. Food and Drug Administration; Juhani Eskola, National Public Health Institute, Finland: Geoffrey Evans, Division of Vaccine Injury Compensation; Gerald M. Fenichel, Vanderbilt University/Advisory Commission on Childhood Vaccines; Jesse Ferguson, Milwaukee, Wisconsin; Reinhard Fescharek, Behringwerke AG; Harvey V. Fineberg, Harvard School of Public Health; Barbara Loe Fisher, Dissatisfied Parents Together; Bonnie Plumeri Franz, Ogdensburg, New York; James Froeschle, Connaught Laboratories; Robert Fujinami, University of Utah; Vincent A. Fulginiti, Tulane University/National Vaccine Advisory Committee; Susan Garzonio, Brodhead, Wiscon-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality sin; Mark Geier, medical/legal consultant, Silver Spring, Maryland; Cynthia Goldenberg, Laguna Niguel, California; Stephen R. Gordon, Vaccine Adverse Events Reporting System, Ogden BioServices Corporation; Dan M. Granoff, St. Louis Children's Hospital; Marjorie Grant, Determined Parents to Stop Hurting Our Tots; Diane Griffin, Johns Hopkins University; Stephen Hadler, Centers for Disease Control and Prevention; Caroline B. Hall, University of Rochester/American Academy of Pediatrics; Neal A. Halsey, The Johns Hopkins University; Carolyn Hardegree, U.S. Food and Drug Administration; Joanne Hatem, National Vaccine Information Center; Sandra Holmes, Centers for Disease Control and Prevention; Michael Hugo, Schlichtman, Conway, Crowley, and Hugo, Boston, Massachusetts; Terry and Kurt Johnson, Mission Viejo, California; Samuel Katz, Duke University Medical Center/ Advisory Committee on Immunization Practices; Marcel Kinsbourne, Winchester, Massachusetts; Gloria Koslofsky, Norwood, New York; Saul Krugman, New York University Medical Center; Leonard P. Kurland, Mayo Clinic; Walter Kyle, attorney, Franconia, New Hampshire; John LaMontagne, National Institute of Allergy and Infectious Diseases; Kathleen Lane, Spring City, Pennsylvania; Tamar Lasky, University of Maryland, Baltimore; Rosalyn Leiderman, National Library of Medicine; Donald Lindberg, National Library of Medicine; Noel Maclaren, University of Florida; Ruth Macrides, Naples, Florida; Frank Mahoney, Centers for Disease Control and Prevention; Susan Maloney, Rowley, Massachusetts; Andrea Martin, Woodland, California; Dale McFarlin, National Institute of Neurologic Diseases and Stroke; Ann Millan, National Vaccine Information Center; Sandy Mintz, Parents Concerned about the Safety of Vaccines, Anchorage, Alaska; J. Anthony Morris, The Bell of Atri, Inc.; Edward A. Mortimer, Jr., Case Western Reserve University School of Medicine; Robert Moxley, Gage and Moxley, Cheyenne, Wyoming; John Mullen, Centers for Disease Control and Prevention; David Nalin, Merck Research Laboratories; Neal Nathanson, University of Pennsylvania; Elena O. Nightingale, Carnegie Corporation of New York; Abner Notkins, National Institute of Dental Research; Walter A. Orenstein, Centers for Disease Control and Prevention; Mary Pearce, Philadelphia, Pennsylvania; Georges Peter, Rhode Island Hospital/American Academy of Pediatrics; Stanley A. Plotkin, Pasteur Mérieux Connaught Company; John Pollard, University of Sydney Department of Medicine, Sydney, Australia; Arthur L. Prensky, Washington University School of Medicine; Regina Rabinovich, National Institute of Allergy and Infectious Diseases; Vincent Racaniello, Columbia University; Suresh Rastogi, U.S. Food and Drug Administration; Frederick C. Robbins, Case Western Reserve University; Eugene Robin, Stanford University School of Medicine; Amy Scott, U.S. Food and Drug Administration; Martin Smith, Advisory Commission on Childhood Vaccines; William Stevens, U.S. Food and Drug Administration; Peter M. Strebel, Centers for Disease Control and Prevention; Roland Sutter,

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Centers for Disease Control and Prevention; Dirk Teuwen, SmithKline Beecham; Klaus V. Toyka, Neurologische Universitatsklinik und Poliklinik im Kopfklinikum, University of Wurzburg; Claudette Varanko, Demler, Armstrong & Rowland, Long Beach, California; Burton A. Waisbren, Milwaukee, Wisconsin; Joel Ward, UCLA Center for Vaccine Research; Steven G. Wassilak, Centers for Disease Control and Prevention; Curtis Webb, Webb, Burton, Carlson, Ledersen & Webb, Twin Falls, Idaho; Robert Weibel, Division of Vaccine Injury Compensation; Susan Weinberg, Baltimore, Maryland; R. P. Wise, U.S. Food and Drug Administration; Peter F. Wright, Vanderbilt University Hospital; Arthur Zahalsky, Southern Illinois University, Edwardsville, Illinois; and Elizabeth Zell, Centers for Disease Control and Prevention. The committee also appreciates the cooperation of the following organizations or institutions: Advisory Commission on Childhood Vaccines; Bell of Atri, Inc.; Centers for Disease Control and Prevention; Determined Parents to Stop Hurting Our Tots; Dissatisfied Parents Together; National Institute of Allergy and Infectious Diseases; National Library of Medicine; National Vaccine Information Center; National Vaccine Program Office; Parents Concerned About the Safety of Vaccines; U.S. Food and Drug Administration; Vaccine Adverse Event Reporting System. The committee would also like to thank the Institute of Medicine (IOM) staff members whose work supported its deliberations, principally Kathleen R. Stratton, Study Director; Cynthia J. Howe, Program Officer; Dorothy R. Majewski, Project Assistant; and Michael A. Stoto, Director, Division of Health Promotion and Disease Prevention. Others within the IOM and the National Academy of Sciences who were instrumental in seeing the project to completion were Kenneth I. Shine, President of the IOM; Enriqueta C. Bond, Executive Officer; Gary B. Ellis, Former Director, Division of Health Promotion and Disease Prevention; Christopher P. Howson, Deputy Director, Division of International Health; Linda DePugh, Administrative Assistant; Jennifer Holliday, Project Assistant; Jana Katz, intern; Marcia Lewis, Administrative Assistant; Scott Jones and Robert Albritton, computer analysts; Claudia Carl, Michael Edington, and Betsy Turvene, Reports and Information Office; Sally Stanfield, Estelle Miller, and Francesca Moghari, National Academy Press; and Susan Turner-Lowe, Office of News and Public Information. We greatly appreciate the editorial assistance of Michael Hayes. Finally, special thanks are due for the expert assistance of research librarian Laura Baird and library assistants Yauthary Keo, Eileen Moynihan, and Rhashida Beynum.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Contents 1 EXECUTIVE SUMMARY   1 2 CAUSALITY AND EVIDENCE   19     Causality   19     Sources of Evidence for Causality   27     Summarizing the Evidence for Causality   31 3 NEUROLOGIC DISORDERS   34     Demyelinating Disease   34     Non-Demyelinating Disease   48 4 IMMUNOLOGIC REACTIONS   59     Anaphylaxis   59     Interaction of Antibody with Normal Tissue Antigens   61     Arthus Reaction   61     Delayed-Type Hypersensitivity   62     Effect of Vaccines on the Immune System   62 5 DIPTHERIA AND TETANUS TOXOIDS   67     Background and History   67     Biologic Events Following Immunization   70     Encephalopathy   72     Residual Seizure Disorder   78

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality     Demyelinating Diseases of the Central Nervous System   83     Guillain-Barré Syndrome   86     Neuropathy   90     Arthritis   94     Erythema Multiforme   98     Anaphylaxis   100     Death   109 6 MEASLES AND MUMPS VACCINES   118     Background and History   118     Biologic Events Following Immunization   121     Encephalopathy and Encephalitis   122     Aseptic Meningitis   130     Subacute Sclerosing Panencephalitis   135     Residual Seizure Disorder   142     Sensorineural Deafness   146     Optic Neuritis   147     Transverse Myelitis   149     Guillain-Barré Syndrome   151     Insulin-Dependent Diabetes Mellitus   153     Sterility Due to Orchitis   160     Thrombocytopenia   163     Anaphylaxis   170     Death   176 7 POLIO VACCINES   187     Background and History   187     Biologic Events Following Immunization   189     Poliomyelitis   189     Transverse Myelitis   196     Guillain-Barré Syndrome   200     Anaphylaxis and Thrombocytopenia   204     Death   205 8 HEPATITIS B VACCINES   211     Background and History   211     Biologic Events Following Immunization   213     Guillain-Barré Syndrome   216     Other Demyelinating Diseases   219     Arthritis   222     Anaphylaxis   228     Death   231

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality 9 HAEMOPHILUS INFLUENZAE TYPE B VACCINES   236     Background and History   236     Biologic Events Following Immunization   239     Transverse Myelitis   241     Guillain-Barré Syndrome   243     Thrombocytopenia   247     Early Susceptibility to H. influenzae type b   250     Anaphylaxis   261     Death   263 10 DEATH   274     Examples   275     Reports of Death Identified from VAERS   278     Vaccine-Specific Data Concerning Death After Immunization   287 11 NEED FOR RESEARCH AND SURVEILLANCE   305     Diphtheria and Tetanus Toxoids   305     Measles and Mumps Vaccines   306     Polio Vaccines   306     Hepatitis B Vaccines   306     Guillain-Barré Syndrome   306     Death   307     Simultaneous Administration of More Than One Vaccine   307     Risk-Modifying Factors   307     General Surveillance and Epidemiologic Studies   307 APPENDIXES     A   Executive Summary from Adverse Effects of Pertussis and Rubella Vaccines   309 B   Strategies for Gathering Information   318 C   Glossary   335 D   Committee and Staff Biographies   342 BIBLIOGRAPHY   348 INDEX   451

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Adverse Events Associated with Childhood Vaccines Evidence Bearing on Causality

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