Adverse
Effects of
Vaccines
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,
Editors

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

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



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Adverse Effects of Vaccines 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, Editors

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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 Preven- tion 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] 615.3’72—dc23 2012007052 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.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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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 Acad- emy 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 en- gineers. 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 engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent 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 Insti- tute 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 Sci- ences 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. www.national-academies.org

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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. v

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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 Study Staff 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. vi

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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 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 vii

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viii REVIEWERS 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.

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Preface 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 litera- ture 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- ix

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x PREFACE 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. Associa- tion, 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 Cen- ters 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 im- munodeficiencies. 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 con- vening 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 par- ticular at-risk groups, who can then be examined with more in depth test- ing 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 dif- ficult, but the results are worth it.

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xi PREFACE 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 sci- entifically defensible conclusion about causation, the committee specifically chose not to say which way the evidence “leaned,” reasoning that such indi- cations 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. In- adequate 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 recom- mendations 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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xviii CONTENTS Infantile Spasms, 537 Seizures, 539 Ataxia, 544 Autism, 545 Acute Disseminated Encephalomyelitis, 546 Transverse Myelitis, 547 Optic Neuritis, 549 Multiple Sclerosis Onset in Adults, 550 Multiple Sclerosis Relapse in Adults, 554 Multiple Sclerosis Relapse in Children, 555 Guillain-Barré Syndrome, 557 Chronic Inflammatory Disseminated Polyneuropathy, 558 Opsoclonus Myoclonus Syndrome, 560 Bell’s Palsy, 561 Anaphylaxis, 563 Chronic Urticaria, 565 Serum Sickness, 566 Arthropathy, 567 Type 1 Diabetes, 571 Myocarditis, 579 Fibromyalgia, 581 Sudden Infant Death Syndrome, 581 Immune Thrombocytopenic Purpura, 582 Concluding Section, 584 References, 589 11 MENINGOCOCCAL VACCINE 599 Introduction, 599 Encephalitis and Encephalopathy, 602 Acute Disseminated Encephalomyelitis, 603 Transverse Myelitis, 604 Multiple Sclerosis, 605 Guillain-Barré Syndrome, 606 Chronic Inflammatory Disseminated Polyneuropathy, 607 Anaphylaxis, 608 Chronic Headache, 610 Concluding Section, 610 References, 612 12 INJECTION-RELATED ADVERSE EVENTS 615 Complex Regional Pain Syndrome, 615 Deltoid Bursitis, 618 Syncope, 620

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xix CONTENTS Concluding Section, 624 References, 626 13 CONCLUDING COMMENTS 629 References, 633 APPENDIXES A GLOSSARY 635 B LIST OF ADVERSE EVENTS 649 C LITERATURE SEARCH STRATEGY 655 D CAUSALITY CONCLUSION TABLES 673 E REFERENCES 749 F COMMITTEE BIOSKETCHES 827 G MEETING AGENDAS 835 INDEX 839 FIGURES S-1 Epidemiologic and mechanistic evidence reviewed by the committee, 11 S-2 Strength of evidence that determined the causality conclusions, 16 2-1 Epidemiologic and mechanistic evidence reviewed by the committee, 41 2-2 Strength of evidence that determined the causality conclusions, 51 3-1 Present and past environmental exposures, 83 TABLES S-1 Adverse Events and Causality Conclusions Included in the Vaccine Chapters, 3 S-2 Summary of Causality Conclusions, 19 1-1 Adverse Events Included in the Vaccine Chapters, 31 4-1 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Encephalopathy or Encephalitis, 114 4-2 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Febrile Seizures, 125

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xx CONTENTS 4-3 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Afebrile Seizures, 135 4-4 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Meningitis, 140 4-5 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Autism, 149 4-6 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and MS Onset in Adults, 162 4-7 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Transient Arthralgia in Women, 177 4-8 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Transient Arthralgia in Children, 186 4-9 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Chronic Arthralgia in Women, 192 4-10 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Chronic Arthritis in Women, 197 4-11 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Arthropathy in Men, 203 4-12 Studies Included in the Weight of Epidemiologic Evidence for MMR Vaccine and Type 1 Diabetes, 208 4-13 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Measles, Mumps, and Rubella Vaccine, 218 5-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Varicella Vaccine, 283 6-1 Influenza Vaccines Licensed and Available in the United States, 297 6-2 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Seizures, 305 6-3 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Optic Neuritis, 312 6-4 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and MS Onset in Adults, 317 6-5 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and MS Relapse in Adults, 320 6-6 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and GBS, 328 6-7 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Bell’s Palsy, 338 6-8 Studies Included in the Weight of Epidemiologic Evidence for Inactivated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children and Adults, 351

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xxi CONTENTS 6-9 Studies Included in the Weight of Epidemiologic Evidence for Live Attenuated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Children Younger Than 5 Years of Age, 362 6-10 Studies Included in the Weight of Epidemiologic Evidence for Live Attenuated Influenza Vaccine and Asthma Exacerbation or Reactive Airway Disease Episodes in Persons 5 Years of Age or Older, 370 6-11 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Exacerbation of SLE, 376 6-12 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Exacerbation of Vasculitis, 381 6-13 Studies Included in the Weight of Epidemiologic Evidence for Influenza Vaccine and Oculorespiratory Syndrome, 395 6-14 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Influenza Vaccine, 402 7-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Hepatitis A Vaccine, 431 8-1 Studies Included in the Weight of Epidemiologic Evidence for Hepatitis B Vaccine and Optic Neuritis, 445 8-2 Studies Included in the Weight of Epidemiologic Evidence for Hepatitis B Vaccine and MS Onset in Adults, 451 8-3 Studies Included in the Weight of Epidemiologic Evidence for Hepatitis B Vaccine and First Demyelinating Event in Adults, 461 8-4 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Hepatitis B Vaccine, 491 9-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for HPV Vaccine, 521 10-1 Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis– Containing Vaccines Licensed and Available in the United States, 531 10-2 Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis– Containing Vaccines and Seizures, 542 10-3 Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis– Containing Vaccines and MS Onset in Adults, 552

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xxii CONTENTS 10-4 Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis– Containing Vaccines and Arthropathy, 569 10-5 Studies Included in the Weight of Epidemiologic Evidence for Diphtheria Toxoid–, Tetanus Toxoid–, and Acellular Pertussis– Containing Vaccines and Type 1 Diabetes, 575 10-6 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Diphtheria Toxoid (DT)–, Tetanus Toxoid (TT)–, and Acellular Pertussis (aP)–Containing Vaccines, 585 11-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Meningococcal Vaccine, 611 12-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for Injection-Related Adverse Events, 625 B-1 Adverse Events Included in the Vaccine Chapters, 650 D-1 Causality Conclusions Organized by Chapter and Adverse Event, 674 D-2 Causality Conclusions Organized by Adverse Event and Chapter, 689 D-3 Causality Conclusions Organized by Causality Conclusion, Adverse Event, and Chapter, 704 D-4 Causality Conclusions Organized by Epidemiologic Assessment, Adverse Event, and Chapter, 719 D-5 Causality Conclusions Organized by Mechanistic Assessment, Adverse Event, and Chapter, 734

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Acronyms AAP American Academy of Pediatrics AAV ANCA-associated vasculitis 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) AE adverse event AIDS acquired immune deficiency syndrome ALL acute lymphoblastic leukemia ALS amyotrophic lateral sclerosis ALT alanine aminotransferase AMAN acute motor axonal neuropathy ANA anti-nuclear antibodies ANCA antineutrophil cytoplasmic antibody aP acellular pertussis BPV bovine papillomavirus BU Boston University 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 xxiii

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xxiv ACRONYMS CI confidence interval CIDP chronic inflammatory disseminated polyneuropathy CNS central nervous system CRPS complex regional pain syndrome CSF cerebrospinal fluid DMSS Defense Medical Surveillance System DNA deoxyriboneucleic acid 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 EIA enzyme immunoassay ELISA enzyme linked immunosorbent assay ER emergency room EURODIAB ACE European diabetes: aetiology of childhood diabetes on an epidemiological basis Fc Constant region FDA U.S. Food and Drug Administration FEV forced expiratory volume FHA filamentous hemagglutin FOIA Freedom of Information Act FUS/TLS fused in sarcoma/translocated in liposarcoma GBS Guillain-Barré syndrome 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

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xxv ACRONYMS HLA human leukocyte antigen HMO health maintenance organization HPMG HealthPartners Medical Group HPV human papillomavirus HRSA Health Resources and Services Administration HTLV human T-lymphotropic virus HZ herpes zoster ICD International Classification of Diseases IDDM insulin dependent diabetes mellitus Ig immunoglobulin IL interleukin IOM Institute of Medicine IPV inactivated poliovirus vaccine ITP immune thrombocytopenic purpura JIA juvenile idiopathic arthritis KIDSEP French Kids Sclérose en Plaques KP Kaiser Permanente KPMCP Kaiser Permanente Medical Care Program LAIV live attenuated influenza virus LOS lipo-oligosaccharide 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 MPO myeloperoxidase MPSV meningococcal polysaccharide vaccine MR measles-rubella MRI magnetic resonance imaging MS multiple sclerosis NCES National Childhood Encephalopathy Study NCK Northern California Kaiser NCKP Northern California Kaiser Permanente

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xxvi ACRONYMS NCVIA National Childhood Vaccine Injury Act NK natural killer NMO neuromyelitis optica OMS opsoclonus myoclonus syndrome OPV oral polio vaccine ON optic neuritis OR odds ratio ORS oculorespiratory syndrome PAMP pathogen-associated molecular pattern PAN polyarteritis nodosa PCR polymerase chain reaction PDD pervasive developmental disorder PEF peak expiratory flow PFU plaque-forming unit PR3 proteinase 3 PRP polyribosylribitol phosphate PRR pattern recognition receptor RA rheumatoid arthritis RCT randomized controlled trial RNA ribonucleic acid RR relative risk 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 TF tissue factor TIV trivalent inactivated influenza vaccine TT tetanus toxoid

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xxvii ACRONYMS 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

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