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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration Anne R. Bass, Kathleen Stratton, Ogan K. Kumova, and Dara Rosenberg, Editors Committee to Review Relevant Literature Regarding Adverse Events Associated with Vaccines Board on Population Health and Public Health Practice Health and Medicine Division Consensus Study Report PREPUBLICATION COPY—Uncorrected Proofs

NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by a contract between the National Academy of Sciences and Health Resources and Services Administration, which includes funds from the Centers for Disease Control and Prevention. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/27746 This publication is available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2024 by the National Academy of Sciences. National Academies of Sciences, Engineering, and Medicine and National Academies Press and the graphical logos for each are all trademarks of the National Academy of Sciences. All rights reserved. Printed in the United States of America. Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2024. Evidence review of the adverse effects of COVID-19 vaccination and intramuscular vaccine administration. Washington, DC: The National Academies Press. https://doi.org/10.17226/27746. PREPUBLICATION COPY: Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY: Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. Rapid Expert Consultations published by the National Academies of Sciences, Engineering, and Medicine are authored by subject-matter experts on narrowly focused topics that can be supported by a body of evidence. The discussions contained in rapid expert consultations are considered those of the authors and do not contain policy recommendations. Rapid expert consultations are reviewed by the institution before release. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY: Uncorrected Proofs

COMMITTEE v COMMITTEE TO REVIEW RELEVANT LITERATURE REGARDING ADVERSE EVENTS ASSOCIATED WITH VACCINES GEORGE J. ISHAM (Chair), Senior Fellow, HealthPartners Institute ANNE R. BASS (Vice Chair), Professor of Clinical Medicine, Department of Medicine, Division of Rheumatology, Hospital for Special Surgery, Weill Cornell Medicine ALICIA CHRISTY, Professor of Obstetrics and Gynecology, Uniformed Services University; Adjunct Professor, Howard University School of Medicine DELISA FAIRWEATHER, Professor of Medicine, Director of Translational Research, Department of Cardiovascular Medicine; Codirector of Research for the Ehlers-Danlos Syndrome Clinic, Department of General Internal Medicine, Mayo Clinic (Jacksonville, FL) JAMES S. FLOYD, Codirector, Cardiovascular Health Research Unit, Associate Professor of Medicine, Adjunct Professor of Epidemiology, University of Washington ERIC J. HEGEDUS, Professor and Chair, Department of Rehabilitation Sciences Tufts University School of Medicine CHANDY C. JOHN, Ryan White Professor of Pediatrics, Professor of Medicine, Microbiology and Immunology, Director, Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine JOHN EDWARD KUHN, Schermerhorn Professor of Orthopaedic Surgery, Chief of Shoulder Surgery, Department of Orthopaedic Surgery, Vanderbilt University Medical Center EVAN MAYO-WILSON, Associate Professor; Department of Epidemiology, University of North Carolina Gillings School of Global Public Health THOMAS LEE ORTEL, Chief, Division of Hematology, Department of Medicine Professor of Medicine and Pathology, Duke University School of Medicine NICHOLAS S. REED, Assistant Professor, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health; Assistant Professor, Department of Otolaryngology, Division of Otology/Audiology, Johns Hopkins University School of Medicine ANDY STERGACHIS, Professor and Associate Dean of Pharmacy, School of Pharmacy; Professor of Global Health, School of Public Health, University of Washington MICHEL TOLEDANO, Assistant Professor of Neurology, Department of Neurology, Mayo Clinic (Rochester, MN) ROBERT B. WALLACE, Irene Ensmenger Stecher Professor Emeritus of Epidemiology and Internal Medicine, University of Iowa OUSSENY ZERBO, Research Scientist II, Vaccine Study Center, Division of Research Kaiser Permanente Northern California National Academy of Medicine Fellow INMACULADA HERNANDEZ, Professor, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California PREPUBLICATION COPY: Uncorrected Proofs

vi VACCINE EVIDENCE REVIEW Health and Medicine Division Staff KATHLEEN STRATTON, Study Director OGAN K. KUMOVA, Program Officer (since February 2023) DARA ROSENBERG, Associate Program Officer NERISSA HART, Senior Program Assistant (through May 2023) OLIVIA LOIBNER, Senior Program Assistant (since June 2023) MISRAK DABI, Finance Business Partner REBECCA MORGAN, Senior Research Librarian ANNE-MARIE HOUPPERT, Senior Research Librarian ROSE MARIE MARTINEZ, Director, Board on Population Health and Public Health Practice PREPUBLICATION COPY: Uncorrected Proofs

REVIEWERS vii Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, 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 thank the following individuals for their review of this report: DOUGLAS B. CINES, Director, Coagulation Laboratory; Director, Office of Faculty Development, Pathology and Laboratory Medicine; Professor of Pathology and Laboratory Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine BETTY DIAMOND, Director, Director, Institute of Molecular Medicine, The Feinstein Institute for Medical Research North Shore-LIJHealth System, Northwell Health KATHRYN EDWARDS, Professor of Pediatrics; Sarah H. Sell and Cornelius Vanderbilt Chair, Vanderbilt Vaccine Research Program; Vanderbilt University Medical Center MARIE GRIFFIN, Professor Emerita, Vanderbilt University School of Medicine AKIKO IWASAKI, Howard Hughes Medical Institute Investigator; Director, Center for Infection and Immunity; Sterling Professor of Immunobiology and Molecular, Cellular, and Developmental Biology, Yale University EMILY JUNGHEIM, Chief of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynecology, Northwestern University TIANJING LI, Associate Professor, University of Colorado Anschutz Medical Campus JENNIFER S. LIN, Distinguished Investigator, Kaiser Permanente Center for Health Research CLAUDIA LUCCHINETTI, Dean, Dell Medical School; Senior Vice President for Medical Affairs, University of Texas at Austin H. CODY MEISSNER, Professor of Pediatrics and Medicine, Geisel School of Medicine at Dartmouth; Senior Vaccine and Biologics Development Analyst, Biomedical Advanced Research and Development Authority; Administration for Strategic Preparedness and Response, U.S. Department of Health and Human Services PREPUBLICATION COPY: Uncorrected Proofs

viii VACCINE EVIDENCE REVIEW BRIAN OLSHANSKY, Emeritus Professor of Internal Medicine - Cardiovascular Medicine, Carver College of Medicine, University of Iowa, University of Iowa Hospital and Clinics JAMES SEGARS, Director, Division of Reproductive Sciences and Women’s Health Research, Johns Hopkins University School of Medicine UMASUTHAN SRIKUMARAN, Assistant Professor, Orthopaedic Surgery, Johns Hopkins University GRETA C. STAMPER, Audiology Division Chair, Audiology Externship Program Director, Consultant in Otorhinolaryngology, Mayo Clinic Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of this report was overseen by coordinator DAVID SAVITZ, Professor of Epidemiology, Brown University, and monitor WALTER FRONTERA, Professor of Physical Medicine, Rehabilitation, and Sports Medicine, University of Puerto Rico School of Medicine. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. PREPUBLICATION COPY: Uncorrected Proofs

ACKNOWLEDGEMENTS ix Acknowledgments The Committee to Review Relevant Literature Regarding Adverse Events Associated with Vaccines and the committee staff would like to thank many individuals for their contributions throughout all phases of the study: Misrak Dabi (Finance Business Partner), Crysti Park (Program Coordinator), Lori Brenig (Editorial Projects Coordinator), Taryn Young (Report Review Associate), Leslie Sim (Senior Report Review Officer), Benjamin Hubbert (Communications Specialist), Amber McLaughlin (Director of Communications), Tasha Bigelow (copy editor), Rebecca Morgan (Senior Research Librarian), and Anne Marie Houppert (Senior Research Librarian). The committee acknowledges and thanks the members of the public who provided valuable insight to the committee via email correspondence and in public comments. PREPUBLICATION COPY: Uncorrected Proofs

x VACCINE EVIDENCE REVIEW PREPUBLICATION COPY: Uncorrected Proofs

CONTENTS xi Contents Preface xvii Acronyms and Abbreviations xix Summary 1 1 Introduction 13 2 Immunologic Response to COVID-19 Vaccines 27 3 Neurologic Conditions and COVID-19 Vaccines 53 GUILLAIN-BARRÉ SYNDROME ....................................................................................... 53 CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY .................... 72 BELL’S PALSY ..................................................................................................................... 76 TRANSVERSE MYELITIS ................................................................................................... 86 CHRONIC HEADACHE........................................................................................................ 92 POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME.......................................... 95 4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines 113 SENSORINEURAL HEARING LOSS ................................................................................ 113 TINNITUS ............................................................................................................................ 122 5 Thrombosis with Thrombocytopenia Syndrome, Immune Thrombocytopenic Purpura, Capillary Leak Syndrome, and COVID-19 Vaccines 133 THROMBOSIS WITH THROMBOCYTOPENIA SYNDROME ...................................... 133 IMMUNE THROMBOCYTOPENIC PURPURA ............................................................... 141 CAPILLARY LEAK SYNDROME ..................................................................................... 149 6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism 157 MYOCARDIAL INFARCTION .......................................................................................... 164 ISCHEMIC STROKE ........................................................................................................... 170 HEMORRHAGIC STROKE ................................................................................................ 175 PREPUBLICATION COPY: Uncorrected Proofs

xii VACCINE EVIDENCE REVIEW DEEP VEIN THROMBOSIS, PULMONARY EMBOLISM, AND VENOUS THROMBOEMBOLISM ..................................................................................................... 181 7 Myocarditis, Pericarditis, and COVID-19 Vaccines 199 8 Sudden Death and COVID-19 Vaccines 239 9 Female Infertility and COVID-19 Vaccines 245 10 Shoulder Injuries and Vaccines 257 SUBACROMIAL/SUBDELTOID BURSITIS .................................................................... 259 ACUTE ROTATOR CUFF OR ACUTE BICEPS TENDINOPATHY ............................... 264 CHRONIC ROTATOR CUFF DISEASE ............................................................................ 268 ADHESIVE CAPSULITIS ................................................................................................... 269 SEPTIC ARTHRITIS ........................................................................................................... 273 BONE INJURY .................................................................................................................... 275 AXILLARY OR RADIAL NERVE INJURY ...................................................................... 279 PARSONAGE-TURNER SYNDROME .............................................................................. 282 COMPLEX REGIONAL PAIN SYNDROME (CRPS) ....................................................... 288 11 Crosscutting Remarks 299 Appendix A Committee Member and Staff Biographies 311 Appendix B 319 PREPUBLICATION COPY: Uncorrected Proofs

BOXES, FIGURES, AND TABLES xiii Boxes, Figures, and Tables BOXES S-1 Statement of Task, 2 S-2 Categories of Causation, 4 1-1 Statement of Task, 15 3-1 Conclusions for Guillain-Barré Syndrome, 53 3-2 Conclusions for Chronic Inflammatory Demyelinating Polyneuropathy, 72 3-3 Conclusions for Bell’s Palsy, 76 3-4 Conclusions for Transverse Myelitis, 86 3-5 Conclusions for Chronic Headache, 92 3-6 Conclusions for Postural Orthostatic Tachycardia Syndrome, 95 4-1 Conclusions for Sensorineural Hearing Loss, 113 4-2 Conclusions for Tinnitus, 122 5-1 Conclusions for Thrombosis with Thrombocytopenia Syndrome, 133 5-2 Conclusions for Immune Thrombocytopenic Purpura, 141 5-3 Conclusions for Capillary Leak Syndrome, 149 6-1 Conclusions for Myocardial Infarction, 164 6-2 Conclusions for Ischemic Stroke, 170 6-3 Conclusions for Hemorrhagic Stroke, 175 6-4 Conclusions for Deep Vein Thrombosis, Pulmonary Embolism, and Venous Thromboembolism, 181 7-1 Conclusions for Myocarditis and Pericarditis, 199 8-1 Conclusions for Sudden Death, 239 9-1 Conclusions for Female Infertility, 245 10-1 Conclusions for Shoulder Injuries, 258 11-1 Conclusions Regarding BNT162b2, 300 11-2 Conclusions Regarding mRNA-1273, 301 11-3 Conclusions Regarding Ad26.COV2.S, 301 PREPUBLICATION COPY: Uncorrected Proofs

xiv VACCINE EVIDENCE REVIEW 11-4 Conclusions Regarding NVX-CoV2373, 302 11-5 Conclusions Regarding Shoulder Injuries, 303 11-6 Conclusions for Which the Evidence Establishes a Causal Relationship, 304 11-7 Conclusions for Which the Evidence Favors Acceptance of a Causal Relationship, 304 11-8 Conclusions for Which the Evidence Favors Rejection of a Causal Relationship, 305 FIGURES 2-1 COVID-19 vaccines contributing to this report and their mechanism of action, 31 2-2 Immune responses to intramuscular administration of SARS-CoV-2 mRNA vaccines, 32 3-1 Overview of the pathogenesis and therapeutic targets of the two major Guillain-Barré syndrome subtypes, 55 3-2 Postulated mechanisms of orthostatic intolerance and tachycardia in POTS, 98 10-1 Illustration of intramuscular injection techniques, 260 TABLES S-1 Causal Conclusions Regarding COVID-19 Vaccines, 7 S-2 Conclusions Regarding Shoulder Injuries After to Any Vaccinations, 9 1-1 COVID-19 Vaccines Used in the United States, 16 1-2 COVID-19 Vaccine U.S. Food and Drug Administration Emergency Use Authorization Dates, Adults and Children, 19 2-1 Immune Responses to U.S. COVID-19 Vaccines, 37 2-2 Vaccine-Mediated Reactions and Their Mechanisms, 41 2-3 Most Commonly Used Adjuvants in Vaccines, 44 3-1 Epidemiological Studies in the Guillain-Barré Syndrome Evidence Review, 57 3-2 Pharmacovigilance Studies in the Guillain-Barré Syndrome Evidence Review, 66 3-3 Epidemiological Study in the Chronic Inflammatory Demyelinating Polyneuropathy, 74 3-4 Epidemiological Studies in the Bell’s Palsy Evidence Review, 78 3-5 Epidemiological Studies in the Transverse Myelitis Evidence Review, 88 3-6 Epidemiological Study in the Postural Orthostatic Tachycardia Syndrome Evidence Review, 98 4-1 Epidemiological Studies in the Sensorineural Hearing Loss Evidence Review, 117 4-2 Epidemiological Studies in the Tinnitus Evidence Review, 125 5-1 Epidemiological Studies in the Thrombosis with Thrombocytopenia Evidence Review, 137 PREPUBLICATION COPY: Uncorrected Proofs

BOXES, FIGURES, AND TABLES xv 5-2 Epidemiological Studies in the Immune Thrombocytopenic Purpura Evidence Review, 143 6-1 Epidemiological Studies in the Vascular Conditions Evidence Review, 162 6-2 Epidemiological Studies in the BNT162b2–Myocardial Infarction Evidence Review, 166 6-3 Epidemiological Studies in the mRNA-1273–Myocardial Infarction Evidence Review, 167 6-4 Epidemiological Study in the Ad26.COV2.S–Myocardial Infarction Evidence Review, 168 6-5 Epidemiological Studies in the BNT162b2–Ischemic Stroke Evidence Review, 172 6-6 Epidemiological Study in the mRNA-1273–Ischemic Stroke Evidence Review, 173 6-7 Epidemiological Study in the Ad26.COV2.S–Ischemic Stroke Evidence Review, 174 6-8 Epidemiological Studies in the BNT162b2–Hemorrhagic Stroke Evidence Review, 177 6-9 Epidemiological Study in the mRNA-1273–Hemorrhagic Stroke Evidence Review, 178 6-10 Epidemiological Study in the Ad26.COV2.S–Hemorrhagic Stroke Evidence Review, 179 6-11 Epidemiological Studies in the BNT162b2–Deep Vein Thrombosis Evidence Review, 183 6-12 Epidemiological Studies in the BNT162b2–Pulmonary Embolism Evidence Review, 185 6-13 Epidemiological Studies in the mRNA–1273–Pulmonary Embolism Evidence Review, 186 6-14 Epidemiological Study in the Ad26.COV2.S–Pulmonary Embolism Evidence Review, 187 6-15 Epidemiological Studies in the BNT162b2–Venous Thromboembolism Evidence Review, 188 7-1 Findings from Canada’s Strategy for Patient-Oriented Research, 209 7-2 Selected Epidemiological Studies of Risk of Myocarditis Associated with BNT162b2, 211 7-3 Selected Epidemiological Studies of Risk of Pericarditis Associated with BNT162b2, 214 7-4 Reports to VAERS After mRNA-Based COVID-19 Vaccination That Met the CDC’s Case Definition for Myocarditis Within a 7-Day Risk Interval per Million Doses of Vaccine Administered, 216 7-5 Selected Epidemiological Studies of Risk of Myocarditis Associated with mRNA-1273, 219 7-6 Selected Epidemiological Studies of Risk of Pericarditis Associated with mRNA-1273, 222 8-1 Epidemiological Study in the Sudden Death Evidence Review, 242 9-1 Clinical and Epidemiological Studies in the Female Infertility Evidence Review, 248 PREPUBLICATION COPY: Uncorrected Proofs

xvi VACCINE EVIDENCE REVIEW 10-1 Case Reports Regarding Subacromial/Subdeltoid Bursitis After Vaccination, 261 10-2 Case Reports of Acute Rotator Cuff or Acute Biceps Tendinopathy After Vaccination, 265 10-3 Case Reports of Adhesive Capsulitis After Vaccination, 270 10-4 Case Reports of Septic Arthritis After Vaccination, 273 10-5 Case Reports of Bone Injury After Vaccination, 276 10-6 Case Reports of Axillary or Radial Nerve Injury After Vaccination, 280 10-7 Case Reports of Parsonage-Turner Syndrome After Vaccination, 284 10-8 Budapest Criteria to Diagnose Complex Regional Pain Syndrome, 288 10-9 Case Reports of Complex Regional Pain Syndrome After Vaccination, 289 PREPUBLICATION COPY: Uncorrected Proofs

PREFACE xvii Preface In the 4 years since the first case of COVID-19 was recognized and after a pandemic was declared by the World Health Organization three months later in March 2020, an estimated 3.5 million died from SARS-CoV-2 infection. Millions more became ill, and some have suffered long-term effects (“long COVID”) that are not yet understood fully. Aside from its health impact, the pandemic has caused marked social, economic, and political upheaval. We doubt any have had lives unchanged by COVID-19. The response to the pandemic has been extraordinary. By spring, 2021, only 1 year after the pandemic declaration, vaccines authorized by the U.S. Food and Drug Administration for emergency were being administered across the United States, indeed, around the world. It is estimated that more than 14 million lives were saved in the year after vaccines became available, with one death avoided for every 124 full vaccination courses. Lives were also saved by other public health interventions and often-heroic efforts of health care workers and health care systems. In the 3 years since vaccines against SARS-CoV-2 came into use, the safety and efficacy have been established. Booster vaccinations, and vaccines targeting new SARS-CoV-2 strains have been introduced and are now administered routinely alongside other vaccinations such as for influenza. While local, non-serious side effects, such as malaise or sore arm are seen as with any vaccine, in rare instances, serious adverse events thought to be linked to SARS-CoV-2 vaccination have been noted. The National Academies of Sciences, Engineering, and Medicine have long tackled challenging questions about vaccine safety, beginning with an assessment of the oral polio vaccine in 1977. When Congress enacted the National Childhood Vaccine Injury Act in 1986, it charged the Institute of Medicine (IOM) with reviewing the literature regarding adverse events associated with vaccines covered by the program. The IOM has addressed questions about the safety of routinely administered vaccines 11 times since then. Following in this tradition, the National Academies of Sciences, Engineering, and Medicine (the National Academies) tasked this consensus committee to assess the scientific evidence dispassionately regarding a list of harms potentially associated with vaccination against SARS-CoV-2, as well as an important potential harm associated with the administration of any vaccine, shoulder injury. Thanks to the extraordinary efforts of investigators around the world who rapidly pivoted their research efforts to focus on this new virus (including its treatment and prevention), we now have a large body of evidence to consider. However, despite that large body of evidence, our consensus committee found that in many, if not most, cases, the evidence was insufficient to accept or reject causality for a particular potential harm from a specific COVID-19 vaccine. In other cases, however, the committee considered the evidence to be sufficient to “favor rejection” or to “favor acceptance” of or establish causality. PREPUBLICATION COPY: Uncorrected Proofs

xviii VACCINE EVIDENCE REVIEW Limitations inherent in applying population-level average effects to draw conclusions about causes of specific events in individual subjects exist. For this reason, there is asymmetry in the committee’s conclusions, with options to conclude that the evidence “establishes a causal relationship,” “favors acceptance of causal relationship” or “favors rejection of a causal relationship,” but not one to “establish rejection of a causal relationship.” For every potential harm assessed, the committee evaluated the totality of evidence and did not apply what could be seen as arbitrary rules or thresholds regarding the number or types of studies required to draw conclusions. For the evaluation of select postulated vaccine harms, some study types were simply not available or were uninformative. For some cases, there was strong mechanistic as well as epidemiologic evidence supporting a causal relationship (e.g., thrombosis and thrombocytopenia syndrome), while, in others, the evidence was drawn largely from case reports. COVID-19 has, understandably, dominated headlines over the last three years, yet, routine vaccinations, such as, for seasonal influenza, are still given. The list of harms our committee was tasked to review were those for which HRSA had claims for compensation. Perhaps surprisingly, only a minority of these claims related to SARS-CoV-2 vaccination. In fact, over 60% of claims focused on shoulder injury associated with intramuscular vaccine administration. The term “SIRVA” (shoulder injury related to vaccine administration) has been introduced into the literature in recent years and was included in the committee’s statement of task. However, the term “SIRVA” encompasses many disparate shoulder conditions and, due to its lack of precision, the committee decided to dispense with this terminology. Instead, the committee addressed potential causal relationships between vaccine administration and specific shoulder related medical diagnoses (e.g., subacromial bursitis, radial nerve injury). This report does not address benefits of vaccination against SARS-CoV-2 or other pathogens, and readers will hopefully view causality findings in that broader context. Even when evidence of causality was established for some harms, the frequency of these harms was low. However, this report explicitly does not attempt to define point estimates for levels of risk. Many talented, knowledgeable individuals volunteered hours of their time to analyze and report the evidence. Initially strangers, the members of this committee worked through difficult methodological questions together, at times, engaging in spirited debate. In the process, we learned from one another, became a team, and friends. Equally important, members of that team were the committee staff, Dara Rosenberg, Ogan Kumova and Olivia Loibner, led by the incredibly wise and knowledgeable Kathleen Stratton and Rose Marie Martinez. The staff worked tirelessly every step of the way, providing indispensable support and guidance, and contributing greatly to the report itself. This is not the first IOM/National Academies report regarding vaccine safety. Nor will it be the last. We anticipate new vaccines and expect ongoing and future scientific research may challenge the findings reported here. This report necessarily reflects a snapshot in time, albeit a momentous one, and represents our best effort to report the truth. George J. Isham, Chair Anne R. Bass, Vice Chair Committee to Review Relevant Literature Regarding Adverse Events Associated with Vaccines PREPUBLICATION COPY: Uncorrected Proofs

ACRONYMS AND ABBREVIATIONS xix Acronyms and Abbreviations AAOS American Academy of Orthopedic Surgeons ACE2 angiotensin-converting enzyme 2 ADE acute demyelinating events AIDP acute inflammatory demyelinating polyneuropathy AMAN acute motor axonal neuropathy AMH anti-Müllerian hormone AV adenovirus vector BARDA Biomedical Advanced Research and Development Authority BP Bell’s Palsy bpm beats per minute CAR coxsackie and adenoviral receptor CDC Centers for Disease Control and Prevention CI confidence interval CICP Countermeasure Injury Compensation Program CIDP chronic inflammatory demyelinating polyneuropathy cMRI cardiac magnetic resonance imaging COVID-19 coronavirus disease 2019 CRP C-reactive protein CRPS complex regional pain syndrome CSF cerebrospinal fluid CSI corticosteroid injection DAMP damage-associated molecular pattern DCM dilated cardiomyopathy DNA deoxyribonucleic acid DTaP diphtheria, tetanus, and acellular pertussis vaccine DVT deep vein thrombosis ECG electrocardiogram EHR electronic health record EMG electromyogram EMR electronic medical record ESC European Society of Cardiology EUA emergency use authorization EV extracellular vesicle PREPUBLICATION COPY: Uncorrected Proofs

xx VACCINE EVIDENCE REVIEW FDA Food and Drug Administration FSH follicle-stimulating hormone GBD global burden of disease GBS Guillain-Barré Syndrome HIT heparin-induced thrombocytopenia HLA human leukocyte antigen HPV human papillomavirus HR hazard ratio HRSA Health Resources and Services Administration HSV herpes simplex virus ICD International Classification of Diseases IFN interferon Ig immunoglobin IL interleukin IR incidence rate IRR incidence rate ratio ITP immune thrombocytopenic purpura IV intravenous IVF in vitro fertilization LH luteinizing hormone LNP lipid nanoparticle MI myocardial infarction MRI magnetic resonance imaging mRNA messenger ribonucleic acid MS multiple sclerosis NCS nerve conduction study NF155 neurofascin-155 NIH National Institutes of Health NR not reported NSAID nonsteroidal anti-inflammatory drug O:E observed to expected ratio OPV oral polio vaccine OR odds ratio PE pulmonary embolism POTS postural orthostatic tachycardia syndrome PPV positive predictive value PT physical therapy PTS Parsonage-Turner Syndrome PREPUBLICATION COPY: Uncorrected Proofs

ACRONYMS AND ABBREVIATIONS xxi RCT randomized controlled trial RI relative incidence RNA ribonucleic acid RR relative risk or risk ratio SARS-CoV-2 severe acute respiratory syndrome coronavirus-2 SC self-controlled SCCS self-controlled case series SD source data SHBG sex hormone binding globulin SIR standardized incidence ratio SIRVA shoulder injury related to vaccine administration SPOR Strategy for Patient-Oriented Research SSNHL sudden sensorineural hearing loss SSP supraspinatus SUD sudden unexpected death TM transverse myelitis TNF tumor necrosis factor TTH tension-type headache TTS thrombosis with thrombocytopenia syndrome VAERS Vaccine Adverse Event Reporting System VAS visual analogue scale VICP Vaccine Injury Compensation Program VITT vaccine-induced thrombotic thrombocytopenia VSD Vaccine Safety Datalink VTE venous thromboembolism WHO World Health Organization YLD years lived with disability YLL years of life lost PREPUBLICATION COPY: Uncorrected Proofs

xxii PREPUBLICATION COPY: Uncorrected Proofs

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Vaccines are a public health success story, as they have prevented or lessened the effects of many infectious diseases. To address concerns around potential vaccine injuries, the Health Resources and Services Administration (HRSA) administers the Vaccine Injury Compensation Program (VICP) and the Countermeasures Injury Compensation Program (CICP), which provide compensation to those who assert that they were injured by routine vaccines or medical countermeasures, respectively. The National Academies of Sciences, Engineering, and Medicine have contributed to the scientific basis for VICP compensation decisions for decades.

HRSA asked the National Academies to convene an expert committee to review the epidemiological, clinical, and biological evidence about the relationship between COVID-19 vaccines and specific adverse events, as well as intramuscular administration of vaccines and shoulder injuries. This report outlines the committee findings and conclusions.

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