Evidence and Causality
Committee to Review Adverse Effects of Vaccines
Board on Population Health and Public Health Practice
Kathleen Stratton, Andrew Ford, Erin Rusch, and Ellen Wright Clayton,
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
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.
This study was supported by Contract No. HHSH230200446009I, Task Order 13 between the National Academy of Sciences and the Health Resources and Services Administration of the U.S. Department of Health and Human Services. The Centers for Disease Control and Prevention and the National Vaccine Program Office also provided support through that contract. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
Library of Congress Cataloging-in-Publication Data
Institute of Medicine (U.S.). Committee to Review Adverse Effects of Vaccines.
Adverse effects of vaccines : evidence and causality / Committee to Review Adverse Effects of Vaccines, Board on Population Health and Public Health Practice ; Kathleen Stratton … [et al.], editors.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-309-21435-3 (hardcover) — ISBN 978-0-309-21436-0 (PDF)
I. Stratton, Kathleen R. II. Title.
[DNLM: 1. Vaccines—adverse effects. 2. Bacterial Infections—prevention & control. 3. Causality. 4. Virus Diseases—prevention & control. QW 805]
Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; Internet, http://www.nap.edu.
For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu.
Copyright 2012 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.
Suggested citation: IOM (Institute of Medicine). 2012. Adverse effects of vaccines: Evidence and causality. Washington, DC: The National Academies Press.
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
Advising the Nation. Improving Health.
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. Ralph J. Cicerone 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. Charles M. Vest 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. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.
COMMITTEE TO REVIEW ADVERSE EFFECTS OF VACCINES
Ellen Wright Clayton (Chair), Craig-Weaver Professor of Pediatrics; Director, Center for Biomedical Ethics and Society; Professor of Law; Vanderbilt University
Inmaculada B. Aban, Associate Professor, Department of Biostatistics, University of Alabama, Birmingham
Douglas J. Barrett, Professor, Departments of Pediatrics, Molecular Genetics & Microbiology, Pathology, Immunology, & Laboratory Medicine, University of Florida College of Medicine
Martina Bebin, Associate Professor of Neurology and Pediatrics, University of Alabama at Birmingham
Kirsten Bibbins-Domingo, Associate Professor and Attending Physician, University of California, San Francisco
Graham A. Colditz,1 Associate Director for Prevention and Control, Alvin J. Siteman Cancer Center, and Niess-Gain Professor in the School of Medicine, Department of Surgery, Washington University School of Medicine
Martha Constantine-Paton, Investigator, McGovern Institute for Brain Research; Professor of Biology, Department of Biology, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology
Deborah J. del Junco, Senior Epidemiologist and Associate Professor of Biostatistics, Epidemiology, and Research Design, University of Texas Health Science Center at Houston
Betty A. Diamond, Head, Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, North Shore-LIJ Health System
S. Claiborne Johnston, Associate Vice Chancellor of Research; Director, Clinical and Translational Science, Institute Professor of Neurology and Epidemiology; Director, Neurovascular Disease and Stroke Center; University of California, San Francisco
Anthony L. Komaroff, Steven P. Simcox, Patrick A. Clifford, and James H. Higby Professor of Medicine; Senior Physician, Brigham and Women’s Hospital; Harvard Medical School
B. Paige Lawrence, Associate Professor of Environmental Medicine; Associate Professor of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry
M. Louise Markert, Associate Professor of Pediatrics and Immunology, Division of Pediatric Allergy and Immunology, Department of Pediatrics, Duke University Medical Center
1 Committee member resigned August 2010.
Ruby H. N. Nguyen,2 Assistant Professor, Division of Epidemiology and Community Health, University of Minnesota School of Public Health
Marc C. Patterson, Chair, Division of Child and Adolescent Neurology; Professor of Neurology, Pediatrics, and Medical Genetics; Director, Child Neurology Training Program, Mayo Clinic
Hugh A. Sampson, Professor of Pediatrics and Immunology; Dean for Translational Biomedical Sciences; Director of the Jaffe Food Allergy Institute, Mount Sinai School of Medicine
Pauline A. Thomas, Associate Professor, Department of Preventive Medicine and Community Health, New Jersey Medical School; and Associate Professor, School of Public Health, University of Medicine and Dentistry of New Jersey
Leslie P. Weiner, Richard Angus Grant, Sr. Chair in Neurology; Professor of Neurology and Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California
Kathleen Stratton, Study Director
Andrew Ford, Program Officer
Erin Rusch, Research Associate
Trevonne Walford, Research Assistant (from August 2009)
William McLeod, Senior Research Librarian
Hope Hare, Administrative Assistant
Amy Pryzbocki, Financial Associate
Rose Marie Martinez, Director, Board on Population Health and Public Health Practice
2 Committee member resigned March 2010.
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 National Research Council’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:
Steven Black, Cincinnati Children’s Hospital
Patricia K. Crumrine, University of Pittsburgh School of Medicine
Anne A. Gershon, Columbia University College of Physicians & Surgeons
Marie R. Griffin, Vanderbilt University Medical Center
Neal Halsey, Johns Hopkins Bloomberg School of Public Health
Diane Harper, University of Missouri-Kansas City School of Medicine
Sean Hennessy, University of Pennsylvania School of Medicine
Gerald T. Nepom, University of Washington
Richard Platt, Harvard Medical School
Stanley A. Plotkin, University of Pennsylvania
Sam Shekar, Northrop Grumman
Donald Silberberg, University of Pennsylvania Medical Center
John J. Treanor, University of Rochester School of Medicine and Dentistry
Chris Wilson, The Bill & Melinda Gates Foundation
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 Charles C. J. Carpenter, The Miriam Hospital, and Floyd E. Bloom, The Scripps Research Institute. 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.
Vaccines are widely recognized as one of the greatest public health successes of the last century, significantly reducing morbidity and mortality from a variety of bacteria and viruses. Diseases that were once the cause of many outbreaks, common causes of loss of health and life, are now rarely seen, because they have been prevented by vaccines. However, vaccines can in rare cases themselves cause illness. A rare potential for harm can loom large when people no longer experience or fear the targeted disease. In this regard, the public opinion of vaccines can be a victim of their success. The Institute of Medicine (IOM) was charged by Congress when it enacted the National Childhood Vaccine Injury Act in 1986 with reviewing the literature regarding the adverse events associated with vaccines covered by the program, a charge which the IOM has addressed 11 times in the past 25 years. Following in this tradition, the task of this committee was to assess dispassionately the scientific evidence about whether eight different vaccines cause adverse events (AE), a total of 158 vaccine-AE pairs, the largest study undertaken to date, and the first comprehensive review since 1994.
The committee had a herculean task, requiring long and thoughtful discussions of our approach to analyzing the studies culled from more than 12,000 peer-reviewed articles in order to reach our conclusions, which are spelled out in the chapters that follow. In the process, we learned some lessons that may be of value for future efforts to evaluate vaccine safety. One is that some issues simply cannot be resolved with currently available epidemiologic data, excellent as some of the collections and studies are. Particularly for rare events, we look to the day when electronic medical records truly are universal and when society reaches a broad-based con-
sensus about how these records may be used to detect very rare adverse events from vaccines as well as other drugs and medical interventions. Even then, challenges will remain. Some adverse events caused by vaccines are also caused by the natural infection. These effects often cannot be detected by epidemiologic methods, which typically cannot distinguish between the adverse events that are caused by the vaccine itself and the decrease in adverse events due to the decreased rate of natural infection. In addition, even very large epidemiologic studies may not detect or rule out rare events. Subgroup analysis or more focused epidemiologic studies, informed by as yet incomplete knowledge of the biologic mechanisms of vaccine-induced injury, may be required.
Examining mechanistic evidence to assess causation is also challenging. Many of the case reports the committee reviewed simply cited a temporal relation between vaccine administration and an adverse event. Association, however, does not equal causation. More is required. The proof can be relatively straightforward, as when vaccine-specific virus is recovered from the cerebrospinal fluid of a patient who develops viral meningitis a few weeks after receiving the vaccine. Alleged adverse effects that appear to be immune mediated, as many of them are, are more challenging, in part because the biology is not completely understood. One potentially useful line of inquiry as science advances is to assess whether the vaccine recipient who suffers harm had a preexisting susceptibility to that particular adverse event as such studies may provide insight into the mechanisms by which such events occur. The committee is aware of the work funded by the Centers for Disease Control and Prevention (CDC) to study such individuals and looks forward to their findings. Most individuals, for example, who develop invasive infection from live vaccine viruses have demonstrated immunodeficiencies. Our work was also complicated by the wide variation in the case reports regarding what other tests had been done to rule out other potential causes. To improve the utility of these reports, periodically convening a group of experts to suggest guidelines, based on the best available science, for providing mechanistic evidence that a particular adverse event was caused by a vaccine may be useful. These guidelines could be made available on the Web, and perhaps more important, shared with clinicians who report cases to the Vaccine Adverse Event Reporting System so their reports can be as complete and useful as possible.
The value of dialogue between both epidemiologic and mechanisms approaches cannot be overstated. Epidemiologic studies can identify particular at-risk groups, who can then be examined with more in depth testing to explore predisposing factors. The findings of such studies can then inform more focused epidemiologic research as well as efforts to reduce risks. These conversations between different types of research can be difficult, but the results are worth it.
Although the committee is optimistic that more can and will be known about vaccine safety in the future, the limitations of the currently available peer-reviewed data meant that, more often not, we did not have sufficient scientific information to conclude whether a particular vaccine caused a specific rare adverse event. Where the data were inadequate to reach a scientifically defensible conclusion about causation, the committee specifically chose not to say which way the evidence “leaned,” reasoning that such indications would violate our analytic framework. Some readers doubtless will be disappointed by this level of rigor. The committee particularly counsels readers not to interpret a conclusion of inadequate data to accept or reject causation as evidence either that causation is either present or absent. Inadequate data to accept or reject causation means just that—inadequate. It is also important to recognize what our task was not. We were not charged with assessing the benefits of vaccines, with weighing benefits and costs, or with deciding how, when, and to whom vaccines should be administered. The committee was not charged with making vaccine policy. We did receive calls to stride into this contentious debate, but others, such as the Food and Drug Administration and the CDC, are tasked with formulating recommendations for use that balance the risk of vaccines with the benefits, with studying the safety of the vaccines during pre-release trials, and monitoring them closely once the vaccine is in use in the population.
Our work could not have been accomplished without the concerted efforts of the committee members who did their work carefully with good cheer and open minds. The committee’s talented and intrepid staff, Trevonne Walford, Erin Rusch, and Andrew Ford, led by the wisdom and experience of Kathleen Stratton, could not have been more wonderful to work with or more essential to the committee’s task.
Ellen Wright Clayton, Chair
Committee to Review Adverse Effects of Vaccines
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|AAP||American Academy of Pediatrics|
|ACIP||Advisory Committee on Immunization Practices|
|ADEM||acute disseminated encephalomyelitis|
|ADI-R||autism diagnostic index—revised|
|ADOS||autism diagnostic observational schedule|
|ADRAC||Adverse Drug Reactions Advisory Committee (Australia)|
|AIDS||acquired immune deficiency syndrome|
|ALL||acute lymphoblastic leukemia|
|ALS||amyotrophic lateral sclerosis|
|AMAN||acute motor axonal neuropathy|
|ANCA||antineutrophil cytoplasmic antibody|
|BVAS||Birmingham Vasculitis Activity Score|
|CAIV||cold-adapted influenza virus or cold-adapted, trivalent intranasal influenza virus vaccine|
|CDC||Centers for Disease Control and Prevention|
|CIDP||chronic inflammatory disseminated polyneuropathy|
|CNS||central nervous system|
|CRPS||complex regional pain syndrome|
|DMSS||Defense Medical Surveillance System|
|DSM||Diagnostic and Statistical Manual of Psychological Disorders|
|DT||diphtheria and tetanus toxoids|
|DTaP||diphtheria toxoid, tetanus toxoid, acellular pertussis|
|DTP||diphtheria toxoid, tetanus toxoid, pertussis|
|DTwP||diphtheria toxoid, tetanus toxoid, whole cell pertussis|
|EAE||experimental allergic encephalomyelitis|
|ELISA||enzyme linked immunosorbent assay|
|EURODIAB ACE||European diabetes: aetiology of childhood diabetes on an epidemiological basis|
|FDA||U.S. Food and Drug Administration|
|FEV||forced expiratory volume|
|FOIA||Freedom of Information Act|
|FUS/TLS||fused in sarcoma/translocated in liposarcoma|
|GHC||Group Health Cooperative|
|GM-CSF||granulocyte/macrophage colony-stimulating factor|
|GPRD||General Practice Research Database|
|HAI||hemagglutination inhibition assay|
|HAV||hepatitis A virus|
|HBIG||hepatitis B immune globulin|
|HBsAg||hepatitis B surface antigen|
|HBV||hepatitis B virus|
|HBVP||hepatitis B virus polymerase|
|HHS||U.S. Department of Health and Human Services|
|HiB||Haemophilus influenzae type B|
|HIV||human immunodeficiency virus|
|HLA||human leukocyte antigen|
|HMO||health maintenance organization|
|HPMG||HealthPartners Medical Group|
|HRSA||Health Resources and Services Administration|
|HTLV||human T-lymphotropic virus|
|ICD||International Classification of Diseases|
|IDDM||insulin dependent diabetes mellitus|
|IOM||Institute of Medicine|
|IPV||inactivated poliovirus vaccine|
|ITP||immune thrombocytopenic purpura|
|JIA||juvenile idiopathic arthritis|
|KIDSEP||French Kids Sclérose en Plaques|
|KPMCP||Kaiser Permanente Medical Care Program|
|LAIV||live attenuated influenza virus|
|MAC||membrane attack complex|
|MBP||myelin basic protein|
|MCC||Measles Control Campaign|
|MCO||medical care organization|
|MHC||major histocompatibility complex|
|MHC||Ministry of Health Mother-Child Health (Israel)|
|MIT||Massachusetts Institute of Technology|
|MMR||measles, mumps, rubella|
|MMRV||measles, mumps, rubella, and varicella|
|MPSV||meningococcal polysaccharide vaccine|
|MRI||magnetic resonance imaging|
|NCES||National Childhood Encephalopathy Study|
|NCK||Northern California Kaiser|
|NCKP||Northern California Kaiser Permanente|
|NCVIA||National Childhood Vaccine Injury Act|
|OMS||opsoclonus myoclonus syndrome|
|OPV||oral polio vaccine|
|PAMP||pathogen-associated molecular pattern|
|PCR||polymerase chain reaction|
|PDD||pervasive developmental disorder|
|PEF||peak expiratory flow|
|PRR||pattern recognition receptor|
|RCT||randomized controlled trial|
|RT-PCR||reverse transcription polymerase chain reaction|
|SAFEVIC||Surveillance of Adverse Events following Vaccination in the Community|
|SAFEVSS||Serious Adverse Events Following Vaccination Surveillance Scheme|
|SIDS||sudden infant death syndrome|
|SIP||sympathetically independent pain|
|SLE||systemic lupus erythematosus|
|SLEDAI||SLE Disease Activity Index|
|SMP||sympathetically maintained pain|
|SSPE||subacute sclerosing panencephalitis|
|SWHP||Scott & White Health Plan|
|TCR||T cell receptor|
|TIV||trivalent inactivated influenza vaccine|
|VAERS||Vaccine Adverse Event Reporting System|
|VAS||visual analogue score|
|VICP||National Vaccine Injury Compensation Program|
|VIS||Vaccine Information Statement|
|VLP||virus like particle|
|VSD||Vaccine Safety Datalink|
|VZV||varicella zoster virus|
|VZVIP||Varicella Zoster Virus Identification Program|
|WAES||Worldwide Adverse Experience System|
|WHO||World Health Organization|