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This PDF is available at http://nap.nationalacademies.org/27746
Evidence Review of the Adverse Effects
of COVID-19 Vaccination and
Intramuscular Vaccine Administration
(2024)
336 pages | 8.5 x 11 | PAPERBACK
ISBN 978-0-309-71832-5 | DOI 10.17226/27746
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; National Academies of Sciences, Engineering, and
Medicine
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.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
Consensus Study Report
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
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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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.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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Consensus Study Reports published by the National Academies of Sciences, Engineering,
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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COMMITTEE v
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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
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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vi VACCINE EVIDENCE REVIEW
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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
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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REVIEWERS vii
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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
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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.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
ACKNOWLEDGEMENTS ix
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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.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
CONTENTS xi
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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
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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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 317
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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BOXES, FIGURES, AND TABLES xiii
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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
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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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
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BOXES, FIGURES, AND TABLES xv
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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
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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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
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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PREFACE xvii
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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.
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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
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ACRONYMS AND ABBREVIATIONS xix
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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
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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
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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
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Summary
Vaccines are a major public health success story, preventing or mitigating the effects of a
myriad of infectious diseases. However, the threat of litigation over safety concerns related to the
whole cell pertussis vaccines in particular led manufacturers to slow vaccine research and
development and leave the market. In 1986, Congress addressed this looming crisis for public
health by passing the National Childhood Vaccine Injury Act (P.L. 99-660) to improve federal
coordination of vaccine efforts around research and development and address the concerns of
those who asserted that they or their children were injured by vaccines. The Vaccine Injury
Compensation Program (VICP), housed in the Health Resources and Services Administration
(HRSA) in the Department of Health and Human Services and jointly administered by the
Department of Justice, serves as a key policy solution developed by Congress. The program
includes vaccines recommended for routine use in children or pregnant women, and anyone who
receives those vaccines is eligible to apply for compensation. The VICP has long depended on
the reports from the National Academies of Sciences, Engineering, and Medicine (the National
Academies) as an important scientific contribution to its compensation decisions.
HRSA also administers the Countermeasures Injury Compensation Program (CICP) for
those harmed by medical countermeasures, which include vaccines, medications, devices, or
other preventions, diagnostics, or treatments for a public health emergency or security
threat. Established by the Public Readiness and Emergency Preparedness Act of 2005 (P.L. 148,
Division C), CICP differs significantly from VICP (HRSA, 2023a).
On January 31, 2020, the Secretary of Health and Human Services declared a Public
Health Emergency related to SARS-CoV-2 under Section 319 of the Public Health Service Act.
The public health emergency expired on May 11, 2023. The public health emergency was
declared because SARS-CoV-2 and the disease caused by SARS-CoV-2, COVID-19, were the
greatest public health crisis to date of the 21st century. As of February 2024, it had led to an
estimated 7 million deaths worldwide, including 1.2 million deaths in the United States (WHO,
2024). COVID-19 was a major cause of death and illness in both adults and children. In 2021,
COVID-19 was the third most common cause of death in adults in the United States (CDC,
2021), and from 2020–2022, COVID-19 was among the top 10 causes of death in children in the
United States (Flaxman et al., 2023).
Part of the public health emergency was the announcement of “Operation Warp Speed,” a
rapid response by the federal government to speed vaccine development (for detailed
information, see GAO, 2021). Four vaccines were developed and used in the United States, all
under Emergency Use Authorization (EUA) (see FDA, 2023), with some now fully approved by
the Food and Drug Administration (FDA). However, as of June 1, 2023, FDA revoked the EUA
from Ad26.CoV2.S for safety concerns (FDA, 2023). EUA allowed vaccines to be used before
all phase 3 trials were completed.1 COVID-19 vaccines, introduced in 2020, are highly effective
in adults and children (CDC, 2023) and were key to control of the pandemic. COVID-19
1 The sentence was updated after the report was shared with the sponsor to clarify the EUA process.
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vaccines are estimated to have prevented 14.4 million deaths worldwide in the first year of
vaccination alone (Watson et al., 2022). Although in this report the committee is tasked with
evaluating the causal association with select serious harm, a comparative study analyzing the
prevalence and types of side effects following COVID-19 vaccination showed that the most
common side effects across different vaccines were flu-like syndrome and local reactions at the
injection site, which aligns with the side effect profiles of many vaccines.
STATEMENT OF TASK
HRSA requested that the National Academies convene a committee to review the
evidence regarding specific potential harms (see Box S-1 for the Statement of Task) related to
the COVID-19 vaccines used in the United States. See Table S-1 for a list of the vaccines and
naming conventions used in this report. The list of harms includes those for which, when the
project began, HRSA had claims for compensation. The committee added postural orthostatic
tachycardia syndrome (POTS) to its review after presentations at its second public meeting.
HRSA also requested that the committee review the evidence regarding any vaccine, not
specifically COVID-19 vaccines, and shoulder injuries, to help VICP better understand whether
vaccination can cause very specific types of shoulder injuries or a more general syndrome that it
designated as Shoulder Injuries Related to Vaccine Administration (Grimes, 2023). Claims
regarding shoulder injuries after routinely administered vaccines are handled by VICP; COVID-
19 vaccines are currently the purview of CICP (HRSA, 2023b).
For the committee’s work, it was irrelevant whether a vaccine is covered under VICP or
CICP; the committee did not consider VICP or CICP processes when reviewing the evidence.
BOX S-1
Statement of Task
The National Academies of Sciences, Engineering, and Medicine will convene an ad hoc
committee to review the epidemiological, clinical, and biological evidence regarding the
relationship between
• COVID-19 vaccines and specific adverse events i.e., Guillain-Barré Syndrome (GBS), chronic
inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Bell’s palsy, hearing
loss, tinnitus, chronic headaches, infertility, sudden death, myocarditis/pericarditis, thrombosis
with thrombocytopenia syndrome (TTS), immune thrombocytopenic purpura (ITP),
thromboembolic events (e.g., cerebrovascular accident (CVA), myocardial infarction (MI),
pulmonary embolism, deep vein thrombosis (DVT)), capillary leak syndrome, and
• intramuscular administration of vaccines and shoulder injuries.
The committee will make conclusions about the causal association between vaccines and
specific adverse events.
The National Academies convened an ad hoc committee comprising 15 members with
expertise in epidemiology, causal inference, cardiology, rheumatology, gynecology, audiology,
neurology, infectious disease, pediatrics, internal medicine, hematology, orthopedics, and
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immunology. The committee held two sessions open to the public. On January 30, 2023, it heard
from representatives of HRSA and CDC on how they intend to use its report and why they asked
for the review. On March 30, 2023, the committee held an open session during which members
of the public registered to provide 2-minute statements concerning its task.
Although the committee reviewed the literature thoroughly, it did not conduct what is
commonly referred to as a “systematic review,” the formal steps of which were described by
IOM in 2011 (IOM, 2011). The processes and time frame for a systematic review were
considered incompatible with this work and, more importantly, the goals were different from
those of most systematic reviews and clinical guidelines. The committee was not tasked with
estimating the magnitude or strength of associations between vaccinations and outcomes. To
fulfill its narrower goals, the committee did incorporate important attributes of good systematic
reviews, such as searching multiple databases, using structured search terms, prespecifying a
final date of searching, and using multiple reviewers to screen out irrelevant abstracts identified
in the search. The committee does not address the benefits of vaccines, which have been
established for COVID-19 vaccines and all vaccines covered by VICP. This review addresses
evidence only about specific potential harms and vaccines available in the United States. The
committee does not make conclusions regarding specific patient cases (such as reported in
published case reports) or whether VICP or CICP should award compensation in individual cases
or in general.
Vaccines and other medical products can cause both benefits and harms. Harms are
sometimes described, including by previous IOM committees, using terms such as “adverse
event,” “adverse effect,” “side effect,” or “safety.” Such terms might not convey the importance
of unwanted medical events. Moreover, readers might be confused by the use of different terms
with overlapping meanings or the same terms to mean different things in different contexts
(Qureshi et al., 2022). For example, “adverse events” are defined in regulatory research as
unwanted events not necessarily related to an intervention (e.g., a vaccine, a drug). By
comparison, “adverse effects” are both unwanted and related to an intervention. On the other
hand, “side effects” might be desirable or unwanted, and they are related to an intervention.
Following best practices (Junqueira et al., 2023; Zorzela et al., 2016), this report uses plain
language to describe the opposite of benefits as “harms.” To emphasize that an individual might
or might not experience specific benefits or harms, this report sometimes describes them as
“potential.” Identifying a “harm” does not mean that it occurs frequently; harms associated with
vaccines are rare. For example, vaccine-associated paralytic polio is an established harm of the
oral polio vaccine (OPV), but it is estimated to occur at a rate of 1 in 2.7 million first doses of
OPV (WHO, 2023).
The committee used different types of evidence to draw conclusions concerning possible
associations between vaccination and potential harms. Some study types were not available or
were considered uninformative for certain outcomes. Conclusions about causality were informed
by the totality of the evidence without applying arbitrary rules or thresholds regarding the
number or types of studies required to draw conclusions. For each outcome, the committee
discussed the totality of the evidence and used consensus methods to draw conclusions about
causality. Iterative discussions about the evidence were particularly important given the
committee’s decision not to use a formal grading system for each published article or for the
causality conclusions. The committee used expert judgment based on clinical and research
expertise and analysis, paying careful attention to ensure that all outcomes under study were
evaluated similarly to ensure a consistent approach to the causal conclusions was maintained.
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The committee adopted the wording for the categories of causal conclusions used by the
IOM vaccine safety committees (IOM, 1991, 1994, 2012), and approached the evaluation of
evidence from a position of neutrality, presuming neither causation nor lack of causation. The
conclusion categories are necessarily asymmetrical: although evidence can establish a causal
relationship, the committee determined that it was unlikely that it could establish the absence of
one for any harm. Similar to other evidence-review efforts, the committee incorporated the
potential role of future research in determining the appropriate conclusion, as described below.
See Box S-2 for a description of the categories.
CONCLUSIONS
Given that this review occurred shortly after vaccines were available, the information in
this report is a snapshot in time. New vaccines will be developed, and more research conducted.
For example, the evidence does not address the real-world use of the COVID-19 vaccines in
which many individuals received a “mix and match” sequence of them. Many people vaccinated
for COVID-19 received other vaccines (e.g., influenza) simultaneously. Most of the evidence
regarding COVID-19 vaccines was from the primary series; because children were among the
last groups to be vaccinated, less evidence exists about them. The committee was not charged to
evaluate the benefits of vaccines. All conclusions must be assessed in the context of the
established harms of the infections against which a vaccine is directed and the well-documented
benefits of vaccines in preventing those harms.
The committee makes 85 conclusions in eight chapters about the causal relationship
between vaccines and possible harms. Although the committee lacked evidence to establish,
accept, or reject a causal relationship for many possible harms, it identified sufficient evidence
for 20 conclusions. It is not surprising that evidence is insufficient for the majority; many of the
conditions had relatively few studies in the literature from which to draw conclusions. As Box S-
2 indicates, the committee incorporated the notion that further research might lead to a different
conclusion for all but conclusions establishing causation. See Tables S-1 and S-2 for all
committee conclusions.
BOX S-2
Categories of Causation
● Evidence establishes a causal relationship—The totality of the evidence suggests that
vaccination can cause this harm. Further research is unlikely to lead to a different
conclusion.
● Evidence favors acceptance of a causal relationship—The totality of the evidence
suggests that vaccination might cause this harm, but meaningful uncertainty remains.
Studies that better minimize bias and confounding, and studies that estimate effects
more precisely, could lead to a different conclusion.
● Evidence is inadequate to accept or reject a causal relationship—The available evidence
is too limited (e.g., few studies in humans, biased, imprecise) or inconsistent to draw
meaningful conclusions in support of or against causality. Future research could lead to
a different conclusion. This conclusion also applies to situations in which no studies were
identified.
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● Evidence favors rejection of a causal relationship—The totality of the evidence suggests
that vaccination does not cause this harm, but meaningful uncertainty remains. The
committee acknowledges that individual causal effects are difficult to ascertain and the
limitations of applying population average effects to draw conclusions about the causes
of specific events in individual people. For example, it is possible that both vaccination
and disease cause certain harms. Thus, (1) an event could be more common in an
unvaccinated than a vaccinated population and (2) some of the events in the vaccinated
population could be caused by vaccination. Research demonstrating a clear mechanism
of action, or research demonstrating increased risk among vaccinated people compared
with unvaccinated people, could lead to a different conclusion.
Conclusions by Vaccine
Most of the evidence the committee reviewed addressed BNT162b2.2 This is not
surprising, as it was the first available in the United States and many other countries; mRNA-
1273 3 followed quickly, and many studies addressed it as well. Conversely, NVX-CoV2373 was
the last vaccine available in the United States, and the committee identified no published studies
relevant for review. The U.S. FDA revoked the authorization for Ad26.COV2.S,4 and the small
number of studies reflected that short availability.
The causality conclusions for the two messenger ribonucleic acid (mRNA) vaccines
(BNT162b2 and mRNA-1273) were almost identical; the committee found convincing evidence
that established a causal relationship with myocarditis. In contrast, the committee concluded that
the evidence favored rejection of a causal relationship between both mRNA vaccines and
thrombosis with thrombocytopenia syndrome (TTS), infertility, Guillain-Barré syndrome (GBS),
Bell’s palsy (BP), and myocardial infarction (MI). The committee identified numerous studies
supporting the conclusions about GBS, BP, and MI. The evidence for TTS and infertility was
more limited but still suggestive of no effect. The committee also concluded that the evidence
favored rejection of a causal relationship between BNT162b2 and ischemic stroke, but the
evidence was inadequate to accept or reject a causal relationship between mRNA-1273 and
ischemic stroke, as the data were more limited.
Despite the limited use of Ad26.COV2.S in the United States and therefore the limited
number of published studies, the committee identified sufficient evidence to conclude that it
favored acceptance of a causal relationship with two specific harms, TTS and GBS. The
evidence base for these two conclusions were very different. The conclusion about TTS relied on
strong mechanistic evidence of binding of vaccine-generated anti-PF4 antibody to platelets in
people who developed TTS who had been given ChAdOx1-S, which is a similar platform to
Ad26.CoV2.S. Although the mechanistic findings for ChAdOx1-S were stronger, the similar
findings with Ad26.COV2.S combined with pharmacovigilance data led the committee to
conclude that the evidence favors acceptance of a causal relationship. The conclusion for GBS
was based on strong epidemiological studies and pharmacovigilance data. Tables S-1 and S-2
contain the causality conclusions for each potential harm.
2 Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®.
3 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®.
4 Refers to the COVID-19 vaccine manufactured by Janssen.
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Conclusions by Causal Category
The committee made six conclusions that the evidence establishes a causal relationship
with vaccination. The evidence for these conclusions fell into two broad categories. The
conclusions regarding myocarditis and the mRNA platform–based vaccines, BNT162b2 and
mRNA-1273, relied upon extensive data from many sources and well-supported mechanistic
evidence. In patients with vaccine-associated myocarditis, elevated levels of spike protein were
detected in their blood and on myocardial tissue. Studies in animal models and ex vivo human
samples show a connection between myocarditis and the activation of specific immune
pathways, such as TLR4/inflammasome/IL-1β, triggered by mRNA COVID-19 vaccines. The
conclusions regarding certain shoulder injuries after intramuscular injection (independent of type
of vaccine) relied heavily on numerous well-documented case reports and a good mechanistic
understanding that injection directly into certain areas of the shoulder could lead to injury of the
bursa, tendon, bone, or nerve.
The committee also made two conclusions that the evidence favors acceptance of a
causal relationship between Ad26.COV2.S and GBS and TTS. The evidence for these two
conclusions varied quite a bit, with mechanistic data and pharmacovigilance providing the
support for TTS and epidemiological studies for GBS.
The committee made conclusions favoring rejection of causality for 12 possible harms.
For both GBS and TTS, the committee concluded that the evidence favored rejection with both
mRNA platform vaccines but convincingly supported a causal relationship with Ad26.COV2.S.
This supports the understanding that the platform distinctly influenced the adverse response. The
committee also favored rejection of a causal relationship for the mRNA vaccines and several
other outcomes: female infertility, BP, MI, and ischemic stroke (BNT162b2 only). The evidence
varied widely for these conclusions. The committee also concluded that the evidence favors
rejection of a causal relationship between vaccine injection and chronic rotator cuff disease.
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TABLE S-1 Causal Conclusions Regarding COVID-19 Vaccines
Chapter Potential Harm
Causality Conclusions
BNT162b2
(Pfizer-BioNTech)
mRNA-1273
(Moderna)
Ad26.COV2.S
(Janssen)
NVX-CoV2373
(Novavax)
3
Guillain-Barré
syndrome
Favors rejection
of a causal
relationship
Favors rejection
of a causal
relationship
Favors acceptance
of a causal
relationship
I
Chronic
inflammatory
demyelinating
polyneuropathy
I I I I
Bell’s palsy
Favors rejection
of a causal
relationship
Favors rejection
of a causal
relationship
I I
Transverse myelitis I I I I
Chronic headache I I I I
Postural orthostatic
tachycardia
syndrome
I I I I
4
Sensorineural
hearing loss I I I I
Tinnitus I I I I
5
Thrombosis with
thrombocytopenia
syndrome
Favors rejection
of a causal
relationship
Favors rejection
of a causal
relationship
Favors acceptance
of a causal
relationship
I
Immune
thrombocytopenic
purpura
I I I I
Capillary leak
syndrome I I I I
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TABLE S-1 Continued
Chapter Potential Harm
Causality Conclusions
BNT162b2
(Pfizer-BioNTech)
mRNA-1273
(Moderna)
Ad26.COV2.S
(Janssen)
NVX-CoV2373
(Novavax)
6
Myocardial
infarction
Favors rejection
of a causal
relationship
Favors rejection
of a causal
relationship
I I
Ischemic stroke
Favors rejection
of a causal
relationship
I I I
Hemorrhagic
stroke I I I I
Deep vein
thrombosis,
pulmonary
embolism, venous
thromboembolism
I I I I
7
Myocarditis Establishes
a causal relationship
Establishes
a causal relationship I I
Pericarditis
without
myocarditis
I I I I
8 Sudden death I I I I
9 Female infertility
Favors rejection
of a causal
relationship
Favors rejection
of a causal
relationship
I I
*NOTE: “I” indicates that the evidence was inadequate to accept or reject a causal relationship.
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TABLE S-2 Conclusions Regarding Shoulder Injuries After Any Vaccination
Specific Shoulder Injury (Chapter 10) Causality Conclusion
Subacromial/subdeltoid bursitis caused by direct
injection into the bursa
Establishes a causal relationship
Acute rotator cuff or acute biceps tendinopathy
caused by direct injection into or adjacent to the
tendon
Establishes a causal relationship
Chronic rotator cuff disease Favors rejection of a causal relationship
Adhesive capsulitis I
Septic arthritis I
Bone injury caused by direct injection into or
adjacent to the bone
Establishes a causal relationship
Axillary or radial nerve injury caused by direct
injection into or adjacent to the nerve
Establishes a causal relationship
Parsonage-Turner syndrome I
Complex regional pain syndrome I
NOTE: “I” indicates that the evidence was inadequate to accept or reject a causal relationship.
Evidence in Children
As described in Chapter 1, vaccine-associated harms may differ in children and adults.
For this reason, the committee conducted an in-depth review of the literature on potential harms
and COVID-19 vaccines specifically in children (individuals younger than 18). At the time of the
review, data on possible harms in children were available only for BNT162b2 and mRNA-1273.
Emergency use authorization of COVID-19 vaccines for children occurred later than for adults,
and decreased uptake in children, particularly those under 11, led to far less data on possible
harms from COVID-19 vaccines in children being available in the literature.
CONCLUDING REMARKS
The COVID-19 pandemic resulted in a voluminous increase in research for many
disciplines on many topics in very little time. Many factors complicated this research. Many
investigators and clinicians were treating patients under very challenging circumstances while
also conducting research. Vaccines were approved or authorized for use at different times for
different populations in different countries. Priority groups among the first vaccines were older
people and those with comorbidities that could have put them at risk for adverse events after
vaccination. The communities being vaccinated had widespread SARS-CoV-2 infection, so that
few studies were able to exclude patients with an infection that occurred simultaneously with
vaccination. Thus, some of the outcomes observed after vaccination might reflect harms from
infection instead. Patterns of non-SARS-CoV-2 infections changed dramatically during the early
days of the pandemic due in part to social distancing and other public health interventions. See
the discussion on GBS in Chapter 3 as an example. This complicates the use of historical
controls in some studies. Many publications report surveillance findings, which do not use
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control populations. Rather, comparisons are made to historical trends, which are not a true
contemporaneous unvaccinated population. Other methodologic limitations across many of the
studies include challenges in confirming vaccine receipt and diagnostic validity. Many studies in
this report were not initiated to support causal inference reviews. Thus, although a particular
paper might have had limited utility to this committee, it likely has relevance and immense
purpose for others.
The committee appreciates the vast amount of work of researchers and clinicians during
the pandemic and the contributions of the participants involved in these studies and hopes that
the information and conclusions in this report are useful to vaccine researchers and the public
health community at large.
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REFERENCES
CDC (Centers for Disease Control and Prevention). 2023. COVID-19 vaccine effectiveness update.
https://covid.cdc.gov/covid-data-tracker/#vaccine-effectiveness (accessed March 8, 2024).
FDA (Food and Drug Administration). 2023. Re: Revocation of EUA 27205 - Janssen COVID-19
vaccine. https://www.fda.gov/media/169003/download?attachment (accessed March 1, 2024).
Grimes, R. 2023. Overview of injury compensation programs—NASEM committee to review relevant
literature regarding adverse events associated with vaccines: Division of Injury Compensation
Programs.
HRSA (Health Resources and Services Administration). 2023a. Comparison of Countermeasures Injury
Compensation Program (CICP) to the National Vaccine Injury Compensation Program (VICP).
https://www.hrsa.gov/cicp/cicp-vicp (accessed December 11, 2023).
HRSA. 2023b. Countermeasures Injury Compensation Program: Covered countermeasures.
https://www.hrsa.gov/cicp/covered-countermeasures (accessed December 20, 2023).
IOM (Institute of Medicine). 1991. Adverse effects of pertussis and rubella vaccines. Edited by C. P.
Howson, C. J. Howe, and H. V. Fineberg. Washington, DC: National Academy Press.
IOM. 1994. Adverse events associated with childhood vaccines: Evidence bearing on causality. Edited by
K. R. Stratton, C. J. Howe, and R. B. Johnston, Jr. Washington, DC: National Academy Press.
IOM. 2011. Finding what works in health care: Standards for systematic reviews. Edited by J. Eden, L.
Levit, A. Berg, and S. Morton. Washington, DC: The National Academies Press.
Junqueira, D. R., L. Zorzela, S. Golder, Y. Loke, J. J. Gagnier, S. A. Julious, T. Li, E. Mayo-Wilson, B.
Pham, R. Phillips, P. Santaguida, R. W. Scherer, P. C. Gøtzsche, D. Moher, J. P. A. Ioannidis,
and S. Vohra. 2023. Consort harms 2022 statement, explanation, and elaboration: Updated
guideline for the reporting of harms in randomised trials. British Journal of Medicine.
381:e073725. https://doi.org/10.1136/bmj-2022-073725.
Watson, O. J., G. Barnsley, J. Toor, A. B. Hogan, P. Winskill, and A. C. Ghani. 2022. Global impact of
the first year of COVID-19 vaccination: A mathematical modelling study. Lancet Infectious
Diseases 22(9):1293–1302. https://doi.org/10.1016/S1473-3099(22)00320-6.
WHO (World Health Organization). 2023. Polio: Global eradication initiative.
https://cdn.who.int/media/docs/default-source/Documents/gpei-cvdpv-factsheet-march-
2017.pdf?sfvrsn=1ceef4af_0 (accessed December 17, 2023).
Zorzela, L., Y. Loke, J. P. A. Ioannidis, S. Golder, P. Santaguida, D. Altman, D. Moher, S. Vohra, and
PRISMA Harms Group. 2016. PRISMA harms checklist: Improving harms reporting in
systematic reviews. British Journal of Medicine. 352:i157. https://doi.org/10.1136/bmj.i157.
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1
Introduction
Vaccines are a major public health success story, preventing or mitigating the effects of a
myriad of infectious diseases. In 1986, the United States faced a problem with vaccine
development and production. The threat of litigation over safety concerns related to the whole
cell pertussis vaccines in particular led manufacturers to slow research and development and
leave the market. Congress addressed what many considered to be a looming crisis for public
health by passing the National Childhood Vaccine Injury Act (NCVIA) (P.L. 99-660) to improve
federal coordination of vaccine efforts around research and development and address the
concerns of those who asserted that they or their children were injured by vaccines. The Vaccine
Injury Compensation Program (VICP), housed in the Health Resources and Services
Administration (HRSA) in the Department of Health and Human Services and jointly
administered by the Department of Justice, serves as a key policy solution developed by
Congress. The program includes vaccines recommended for routine use in children or pregnant
women, and anyone who receives a covered vaccine is eligible to apply for compensation. The
program is funded by a federal excise tax on covered vaccines; the taxes are held in the Vaccine
Injury Trust Fund (HRSA, 2023a).
VICP has long depended on the reports from the National Academies of Sciences,
Engineering, and Medicine (the National Academies) as an important scientific contribution to
its compensation decisions, beginning with two studies mandated by NCVIA (Sections 312 and
313 of Public Law 99-660). IOM (1991, 1994) focused on assessing the causal relationship of
CDC-recommended childhood vaccines with specific potential harms. That early work was
continued by other National Academies committees reviewing the scientific literature regarding
the potential for vaccines to cause harm (IOM, 2002, 2012). The committees did not recommend
whether or which harms should be compensated but focused on making conclusions about the
causal nature of the vaccines and potential harms after a comprehensive review of biologic,
clinical, and epidemiological literature. Compensation decisions remain determined by the
intricate processes established by VICP (HRSA, 2023b). See HRSA (2023b) for a description of
program administration and the claims process.
HRSA also administers the Countermeasures Injury Compensation Program (CICP) to
provide compensation for those harms by medical countermeasures, which are vaccines,
medications, devices, or other preventions, diagnostics, or treatments for a public health
emergency or security threat. Established by the Public Readiness and Emergency Preparedness
Act of 2005 (P.L. 148, Division C), CICP differs significantly from VICP (HRSA, 2023c).
On January 31, 2020, the Secretary of Health and Human Services declared a Public
Health Emergency related to SARS-CoV-2 under Section 319 of the Public Health Service Act.
The public health emergency expired on May 11, 2023.
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The public health emergency was declared because SARS-CoV-2 and the disease caused
by SARS-CoV-2, COVID-19, were the greatest public health crisis to date of the 21st century.
As of February 2024, it had led to an estimated 7 million deaths worldwide, including 1.2 million
deaths in the United States (WHO, 2024). COVID-19 was a major cause of death and illness in
both adults and children. Long COVID is a particular concern. In 2021, COVID-19 was the third
most common cause of death in adults in the United States (CDC, 2021), and from 2020-2022,
COVID-19 was among the top 10 causes of death in children in the United States (Flaxman et
al., 2023).
Part of the public health emergency was the announcement of “Operation Warp Speed,” a
rapid response by the federal government to speed vaccine development (for detailed
information, see GAO, 2021). Four vaccines were developed and used in the United States, all
under Emergency Use Authorization (EUA) (see FDA, 2023), with some now fully approved by
the Food and Drug Administration (FDA). However, as of June 1, 2023, FDA revoked the EUA
from Ad26.CoV2.S for safety concerns (FDA, 2023b). EUA allowed vaccines to be used before
all phase 3 trials were completed.1 COVID-19 vaccines, introduced in 2020, are highly effective
in adults and children (CDC, 2023), and were key to control of the pandemic. COVID-19
vaccines are estimated to have prevented 14.4 million deaths worldwide in the first year of
vaccination alone (Watson et al, 2022). Although in this report, the committee is tasked with
evaluating the causal association with select serious harms, a comparative study analyzing the
prevalence and types of side effects following COVID-19 vaccination showed that the most
common side effects across different vaccines were flu-like syndrome and local reactions at the
injection site, which aligns with the side effect profiles of many vaccines (Yadegarynia et al.,
2023).
STATEMENT OF TASK
HRSA requested that the National Academies convene a committee to review the
evidence regarding specific potential harms (see Box 1-1) and the COVID-19 vaccines used in
the United States. See Table 1-1 for a list of those vaccines and the naming conventions used in
this report. The list of harms to be addressed requested by HRSA are those for which, when the
project began, HRSA had claims for compensation. The committee added postural orthostatic
tachycardia syndrome (POTS) to its review after presentations at a public meeting.
1 The sentence was updated after the report was shared with the sponsor to clarify the EUA process.
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BOX 1-1
Statement of Task
The National Academies of Sciences, Engineering, and Medicine will convene an ad hoc
committee to review the epidemiological, clinical, and biological evidence regarding the
relationship between
• COVID-19 vaccines and specific adverse events i.e., Guillain-Barré Syndrome (GBS), chronic
inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Bell’s palsy, hearing
loss, tinnitus, chronic headaches, infertility, sudden death, myocarditis/pericarditis, thrombosis
with thrombocytopenia syndrome (TTS), immune thrombocytopenic purpura (ITP),
thromboembolic events (e.g., cerebrovascular accident (CVA), myocardial infarction (MI),
pulmonary embolism, deep vein thrombosis (DVT)), capillary leak syndrome, and
• intramuscular administration of vaccines and shoulder injuries.
The committee will make conclusions about the causal association between vaccines and
specific adverse events.
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TABLE 1-1 COVID-19 Vaccines Used in the United States
Non-
Commercial
Name
Commercial
Name Manufacturer Platform Type
Adjuvant or
Functional
Adjuvant
U.S. EUA
Date
U.S. Full
Approval
Date
Approved
for Use in
BNT162b2 Comirnaty® Pfizer and
BioNTech mRNA Self#- LNP
and mRNA
December 11,
2020
August 23,
2021
Adults and
children aged
6+ months
mRNA-1273 Spikevax® Moderna mRNA Self# - LNP
and mRNA
December 18,
2020
January
31, 2022
Adults and
children aged
6+ months
Ad26.COV2.S* NA Janssen AV Self#- AV February 27,
2021 - Adults (18+)
NVX-CoV2373 NA Novavax Protein Subunit Matrix-M® July 13,
2022 - Adults (18+)
NOTE: *This vaccine is the same type of platform as ChAdOx1, manufactured by AstraZeneca, but uses a different adenovirus vector. ChAdOx1
is not used in the United States. # mRNA and previously used AV vaccines in the United States do not contain discrete adjuvants. The LNP and
AV function as adjuvants to activate the innate immune system. AV: adenovirus vector; EUA: emergency use authorization; mRNA: messenger
ribonucleic acid; LNP: lipid nanoparticle.
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HRSA also requested that the committee review the evidence regarding any vaccine, not
specifically COVID-19 vaccines, and shoulder injuries. Claims for compensation for shoulder
injuries after vaccination comprise over 63 percent of claims submitted to VICP in fiscal years
2021 and 2022 (Grimes, 2023). The scientific review was requested to help VICP better
understand whether vaccination can cause very specific types of shoulder injuries or a more
general syndrome that it designated as Shoulder Injuries Related to Vaccine Administration
(SIRVA) (HRSA, 2023d). Claims regarding shoulder injuries after routinely administered
vaccines are handled by VICP and COVID-19 vaccines by CICP. For the committee’s work, it is
irrelevant whether a vaccine is covered under VICP or CICP; National Academies committees
do not consider VICP or CICP processes when reviewing the evidence.
The committee comprised 15 members with expertise in epidemiology, causal inference,
cardiology, rheumatology, gynecology, audiology, neurology, infectious disease, pediatrics,
internal medicine, hematology, orthopedics, pharmacoepidemiology, and immunology. Their
biosketches can be found in Appendix A. The committee held two sessions open to the public.
On January 30, 2023, it heard from representatives of HRSA and CDC on how they intend to use
the report and why they asked for the review. On March 30, 2023, the committee held an open
session during which members of the public registered to provide 3-minute statements
concerning its task. Written material submitted to the committee is in a Public Access File.2
The committee attempted to identify and analyze published literature about the vaccines
and potential harms. Although it reviewed the literature thoroughly, it did not conduct what is
commonly referred to as a “systematic review,” formal steps of which were described by IOM
(2011). The processes and time frame for a systematic review were considered incompatible with
this work and, more importantly, the goals of this work were different from those of most
systematic reviews and clinical guidelines. The committee was not tasked with estimating the
magnitude or strength of associations between vaccinations and outcomes, and the evidence was
not expected to be conducive to meta-analysis in any case. To fulfill its narrower goals, the
committee did incorporate important attributes of good systematic reviews. A more detailed
description of the process by which the committee identified and analyzed the literature follows.
The committee does not address the benefits of vaccines. This review addresses evidence
only about specific potential harms and vaccines available in the United States. The committee
does not make conclusions regarding specific patient cases (such as in published case reports) or
whether VICP or CICP should award compensation in individual cases or in general. The
committee does aim to present evidence in a way useful to VICP, CICP, claimants and their legal
representatives, clinicians, and the public.
Vaccines and other medical products can cause both benefits and harms. Harms are
sometimes described using terms such as “adverse event,” “adverse effect,” “side effect,” or
“safety.” Such terms might not convey the importance of unwanted medical events. Moreover,
readers might be confused by the use of different terms with overlapping meanings or the same
terms to mean different things in different contexts (Qureshi et al., 2022). For example, “adverse
events” are defined in regulatory research as unwanted events not necessarily related to an
intervention (e.g., a vaccine, a drug). By comparison, “adverse effects” are both unwanted and
related to an intervention. On the other hand, “side effects” might be desirable or unwanted, and
they are related to an intervention. Following best practices (Junqueira et al., 2023; Zorzela et al.,
2 A list of Public Access File materials can be requested on the study’s National Academies Projects and
Activities Repository page: www.nationalacademies.org/our-work/review-of-relevant-literature-regarding-adverse-
events-associated-with-vaccines.
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18 VACCINE EVIDENCE REVIEW
2016), this report describes the opposite of benefits as “harms.” To emphasize that an individual
patient might or might not experience specific benefits or harms, this report sometimes describes
them as “potential.” Identifying a “harm” does not mean that it occurs frequently; harms
associated with vaccines are rare. For example, vaccine-associated paralytic polio is an
established harm of the oral polio vaccine (OPV), but it is estimated to occur at a rate of 1 in 2.7
million first doses of OPV (WHO, 2023).
Literature Search
The committee provided the National Academies research librarian with a comprehensive
list of search terms for each potential harm. The librarian conducted separate literature searches
for epidemiological and mechanistic literature based on the search terms using Embase, Medline,
PubMed, Scopus, and Cochrane Central Register of Controlled Trials (Ovid).
Epidemiological Evidence
Three comprehensive epidemiological literature searches were conducted. Each search
included terms specific to each potential harm in at least one search field (i.e., title, abstract,
keywords) The list of search terms is available through the project Public Access File.3
The first search was for literature published January 1, 2020–February 28, 2023. Follow-
up searches captured literature published February 28–July 7, 2023, and July 7–October 17,
2023. Thus, publications that appeared in the databases after October 17, 2023, are not included
in this report. Ad hoc searches were conducted if committee members added a search term and
for literature on POTS. The committee restricted its review to U.S. vaccine platforms but
included studies conducted outside of the United States.
Citations were uploaded to PICO Portal, an online platform used to screen abstracts and
full text. Abstracts were reviewed to screen out citations that did not address the potential harm
under the committee’s purview and studies that evaluated only vaccine platforms (e.g.,
inactivated virus vaccine) not approved in the United States. The committee focused its review
on original reports and systematic reviews, excluding narrative reviews or commentaries.
For systematic reviews, committee members screened each publication and excluded
those that were considered unreliable after consideration of the following: no defined criteria for
selection of studies, literature search not comprehensive for eligible studies, no assessment of
risk of bias in the included studies, and inappropriate methods for meta-analyses (when meta-
analyses were reported). Systematic reviews were examined to determine whether they studied
the potential harms of interest and for quality of evidence.
Committee members evaluated the full text of potentially relevant epidemiological
studies and eliminated those that had serious methodologic limitations and were judged unlikely
to contribute to the causality assessment. Studies were excluded for reasons such as
misclassification of the exposure (vaccination status) and outcomes (e.g., harms were more likely
to be recorded in a certain group even if they did not occur more frequently), uncontrolled
confounding, selection bias, and substantial missing data (e.g., vaccination status or outcome
status is unknown for a large proportion of participants). Misclassification of the exposure means
that the specific vaccine was not consistently identified. Misclassification of the outcome means
3 Public Access File materials can be requested by contacting the Public Access Records Office via link on this
project’s webpage, www.nationalacademies.org/our-work/review-of-relevant-literature-regarding-adverse-events-
associated-with-vaccines.
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INTRODUCTION 19
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that the potential harms could not be reliably identified. For instance, many studies used
diagnosis codes from health care encounters to identify health outcomes—for many outcomes,
the codes either are known to perform poorly (e.g., individuals with the code often do not have
the outcome, or the code is absent when individuals have experienced the outcome) or have
unknown accuracy for validated outcomes. Confounding can occur when an association between
vaccination status and the outcome is explained by a common cause that is not completely
controlled for in the design and analysis; this is one of the major problems for causal inference
using results from observational studies rather than randomized controlled trials (RCTs). Many
studies were unable to exclude the possibility of the harms occurring due to SARS-CoV-2
infection. Data extraction was performed on articles that were included at this stage.
Pharmacovigilance studies and case reports were identified through the literature search and
reviewed if the evidence from the epidemiological studies did not lead the committee to accept
or reject a causal relationship. A bibliography of all citations reviewed but not included in this
report are available through the project Public Access File.4
Evidence in Children
Adverse effects associated with vaccines may differ in children and adults. For this
reason, the committee conducted an in-depth review of the literature on potential harms from
COVID-19 vaccines specifically in children (those under 18). For context, the vaccines received
emergency use authorization (EUA) much later in children than adults, and even later in young
children (5–11 years and 6 months to 4 years) than adolescents (12–17 years) (Table 1-2).
TABLE 1-2 COVID-19 Vaccine U.S. Food and Drug Administration Emergency Use
Authorization Dates, Adults and Children
Vaccine Age Group EUA Date
BNT162b2
≥16 years December 11, 2020
12–15 years May 10, 2021
5–11 years October 29, 2021
6 months–4 years June 17, 2022
mRNA-1273
≥18 years
December 18, 2020
6 months–17 years June 17, 2022
NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name
Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name
Spikevax®. EUA: Emergency Use Authorization.
These much later EUA dates and a decrease in SARS-CoV-2 cases after vaccination of
adults led to lower immunization rates in children; in May 2023, these were only 13 percent, 39
4 Public Access File materials can be requested by contacting the Public Access Records Office via link on this
project’s webpage, www.nationalacademies.org/our-work/review-of-relevant-literature-regarding-adverse-events-
associated-with-vaccines.
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percent, and 68 percent in children aged 6 months to 4 years, 5–11, and 12–17, respectively,
according to the Centers for Disease Control and Prevention (AAP, 2023). For these reasons,
considerably less data exist on possible harms in children, especially in those under 11,
compared to adults. Ad26.COV2.S 5 was never given an EUA for individuals under 18. NVX-
CoV2373, although granted an EUA for those aged 12–17 on August 19, 2022, has had very
little uptake, so little data exist beyond the original clinical trial on potential harms in children.6
The committee therefore reviewed the available data on COVID-19 vaccines in children, which
consisted of data from BNT162b2 7 and mRNA-1273.8 Although there are numerous publications
on COVID-19 vaccines in children, the vast majority of these are editorial. commentary or
opinion pieces, or case reports or small case series. These publications typically do not provide
the quality of evidence needed for evaluation of the relationship of potential harms to vaccine
administration. Published data on COVID-19 vaccines in children was reviewed in depth by the
committee, and all publications that provided data that could be used to evaluate the relationship
of the vaccine to adverse events were included in the analysis. For children, and particularly for
children younger than 12 years of age, there was a paucity of data, due to later authorization of
COVID-19 vaccines for children and lower immunization rates in children as compared to
adults, resulting in less study of adverse events in children than adults.
Mechanistic Evidence
The committee aimed to understand immune mechanisms of the vaccine platforms
potentially related to harms, as described in Chapter 2, by conducting a general search. The first
search was limited to studies in humans and identified literature published January 2021–March
2023. A second search looked for information specific to the potential harms under study; it
identified literature published January 2000–April 2023 and explored general mechanisms
underlying vaccine–immune interactions, focusing on non-SARS-CoV-2 messenger ribonucleic
acid (mRNA) and adenovirus-vector (AV) vaccines. A final literature search was conducted in
September 2023. Included articles encompassed a broad spectrum of research, including human
trials, murine studies, other animal models, computational modeling, and in vitro studies. Ad hoc
searches conducted throughout the study were particularly informative as the committee
investigated possible mechanisms. The literature search aimed to identify studies elucidating the
mechanism underlying specific harms of COVID vaccination and to identify studies quantifying
the effect of vaccination on components of the immune system in general. In addition, ad hoc
literature searches were performed to review the mechanism of specific harms outside of the
vaccination context (e.g., Guillain-Barré syndrome). In the case of shoulder injury, the
mechanistic evidence was largely derived from imaging (e.g., MRI) provided in case reports and
case series.
5 Refers to the COVID-19 vaccine manufactured by Janssen.
6 Refers to the COVID-19 vaccine manufactured by Novavax.
7 Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®.
8 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®.
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CAUSALITY ASSESSMENT
Types of Evidence
The committee used different types of evidence to draw conclusions concerning possible
associations between vaccination and harms. Conclusions about causality were informed by the
totality of the evidence without applying arbitrary rules or thresholds regarding the number or
types of studies required to draw conclusions. Some study types were not available or were
considered uninformative for certain outcomes, so the following chapters do not necessarily
discuss all the study types described below. The committee reviewed the literature following a
well-accepted hierarchy of evidence, beginning with randomized clinical trials and controlled
observational epidemiological studies. The committee proceeded to review additional evidence
(uncontrolled epidemiological evidence and case reports) until the committee felt it reviewed
sufficient and appropriate evidence to support a specific causal conclusion. For example, the
committee did not review uncontrolled pharmacovigilance studies and case reports if they felt
the observational epidemiological literature was sufficient to support a conclusion or if they felt
evidence of those uncontrolled designs were unlikely to contribute to a causal conclusion. The
committee notes that uncontrolled studies would likely have been excluded from consideration if
they had followed strict inclusion and exclusion criteria, as is done in systematic reviews.
However, given the limited information regarding some of the potential harms being reviewed,
the committee felt it important to be broad in its consideration of evidence.
Clinical Trials
For each potential harm, the committee examined evidence in Phase III RCTs, including
published results from clinical trials and the documents reviewed and produced by FDA in
consideration of the applications by manufacturers for EUA and full approval, when available.
RCTs can produce valid causal estimates (e.g., because they minimize selection bias and
confounding). Associations detected in RCTs could support causal conclusions, especially for
increases in common harms or very large increases in uncommon harms. The committee was
aware that RCTs were not designed to assess rare harms, and RCTs did not enroll enough
participants to estimate rare events reliably. Some harms are so rare that they would not be
expected to occur in RCTs even if they were caused by vaccination. Lack of evidence from
RCTs would usually be considered uninformative (rather than evidence of no association).
Nonrandomized Studies
The committee also considered evidence from nonrandomized studies (controlled
observational studies and uncontrolled screening or pharmacovigilance studies) that used
appropriate methods to estimate causal effects. Although the committee determined that
controlled observational studies were at greater risk of bias compared with RCTs, estimates from
studies that minimized bias were considered potentially informative. Notably, positive
associations between vaccination and harms could provide evidence of causality. The committee
interpreted negative and null findings cautiously. Compared with RCTs, large observational
studies might estimate effects with greater precision but greater bias; consequently, it would be
difficult to exclude small causal effects based on evidence from nonrandomized studies alone.
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The committee also considered evidence from pharmacovigilance and surveillance
studies, although estimates from these studies were generally considered at greater risk of bias
compared with well-designed case-control and cohort studies.
Case Reports
The committee determined that case reports should inform causal conclusions when
temporal and biological relationships between vaccination and harm were readily observable in
the reports. In particular, case reports might provide useful evidence about shoulder injuries
(Chapter 10). For harms with unclear onset and myriad potential causes, the committee
determined that case reports were unlikely to be informative.
Mechanisms
The committee considered evidence concerning possible mechanisms of action, including
findings from human and other studies. Identifying a plausible mechanism could inform the
committee’s interpretation of evidence concerning associations in clinical trials and
observational studies but not necessarily lead to conclusions favoring causal associations.
Because mechanisms might be unknown, lack of mechanistic evidence did not preclude
conclusions that vaccination caused harm.
Extrapolation
The committee considered evidence about each specific vaccine and each harm and
discussed whether evidence for some vaccines should inform conclusions about others that used
the same platform (e.g., mRNA, adenovirus vector (AV)). For example, mechanistic and clinical
evidence establishing a causal relationship between one vaccine and a harm could inform
conclusions about the effects of similar vaccines. The committee extrapolated evidence from one
vaccine of a specific platform to another vaccine cautiously. In particular, the literature regarding
AV ChAdOx1-S (not available in the United States) was considered in assessing TTS risk from
Ad26.COV2.S (see Chapter 5).
Causal Conclusions
Working groups assigned to each outcome performed the initial screen, data abstraction,
and evidence review in advance of full committee discussions. Key elements in the data
abstraction included study design, sample size, comparison group, risk period, vaccine and
outcome ascertainment, and methodological strengths and limitations, including risk of bias
considerations. Evidence tables and narratives were presented to the full committee for extensive
discussion, including in depth re-examination of individual studies and the preliminary causality
conclusion in many circumstances in order to reach a common understanding of the strengths
and weaknesses of the evidence and consensus conclusions. This was particularly important
when a study was used by more than one working group; a particular research paper might have
serious limitations or utility to the committee for one outcomes, but not for every outcomes
studied. For each outcome, the committee discussed the totality of the evidence and used
consensus methods to draw conclusions about causality. Iterative discussions are particularly
important given the committee’s decision not to use a formal grading system for each published
article or for the causality conclusions. The committee used expert judgment based on clinical
and research expertise and analysis, paying careful attention to ensure that all outcomes under
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INTRODUCTION 23
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study were evaluated similarly to ensure a consistent approach to the causal conclusions was
maintained.
The committee adopted the wording of the causality conclusions developed by National
Academies/Institute of Medicine committees and approached the evaluation of evidence from a
position of neutrality, presuming neither causation nor lack of causation. The causal conclusion
categories are necessarily asymmetrical: although evidence can establish a causal relationship,
the committee determined it was unlikely that it could establish the absence of one for any
harm. Similar to other evidence-review efforts, the committee incorporated the potential role of
future research in determining the appropriate conclusion, as described below.
The following are the categories of causation used by the committee:
● Evidence establishes a causal relationship—The totality of the evidence suggests that
vaccination can cause this harm. Further research is unlikely to lead to a different
conclusion.
● Evidence favors acceptance of a causal relationship—The totality of the evidence
suggests that vaccination might cause this harm, but meaningful uncertainty remains.
Studies that better minimize bias and confounding, and studies that estimate effects
more precisely, could lead to a different conclusion.
● Evidence is inadequate to accept or reject a causal relationship—The available
evidence is too limited (e.g., few studies in humans, biased, imprecise) or inconsistent
to draw meaningful conclusions in support of or against causality. Future research
could lead to a different conclusion. This conclusion also applies to situations in
which no studies were identified.
● Evidence favors rejection of a causal relationship—The totality of the evidence
suggests that vaccination does not cause this harm, but meaningful uncertainty
remains. The committee acknowledges that individual causal effects are difficult to
ascertain and the limitations of applying population average effects to draw
conclusions about the causes of specific events in individual people. For example, it
is possible that both vaccination and disease cause certain harms. Thus, (1) an event
could be more common in an unvaccinated population than a vaccinated population
and (2) some of the events in the vaccinated population could be caused by
vaccination. Research demonstrating a clear mechanism of action, or research
demonstrating increased risk among vaccinated people compared with unvaccinated
people, could lead to a different conclusion.
OUTLINE OF THE REPORT
Chapter 2 contains a brief review of the major mechanisms by which vaccines affect the
immune system. Chapters 3–9 address the evidence regarding COVID-19 vaccines and the
specific outcomes listed in the Statement of Task. The structure of the chapters is similar but not
identical. Chapters other than Chapters 8 (Sudden Death) and 9 (Female Infertility) contain
conclusions about more than one outcome. Each outcome is addressed separately. Each outcome-
specific section begins with a description of the outcome under review. A brief description of
pathophysiologic mechanisms and the possible role of COVID-19 vaccines follows. The
epidemiologic evidence section contains the evidence the committee depended upon in reaching
a causal conclusion. Evidence that did not contribute is not described. The most influential
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24 VACCINE EVIDENCE REVIEW
evidence is portrayed in detail in tables within each section and described briefly in the text.
Each section ends with a summary of the most compelling argument in support of the conclusion
and the section ends with the causal conclusion. Chapter 10 reviews of the shoulder injuries after
intramuscular administration of any vaccine, not limited to COVID-19 vaccines. The report ends
with crosscutting summaries of the evidence in Chapter 11.
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REFERENCES
AAP (American Academy of Pediatrics). 2023. Summary of data publicly reported by the Centers for
Disease Control and Prevention. https://www.aap.org/en/pages/2019-novel-coronavirus-covid-
19-infections/children-and-covid-19-vaccination-trends (accessed December 12, 2023).
CDC (Centers for Disease Control and Prevention). 2021. Leading causes of death
https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm (accessed March 6, 2024).
CDC. 2023. COVID-19 vaccine effectiveness update. https://covid.cdc.gov/covid-data-tracker/#vaccine-
effectiveness (accessed March 8, 2024).
FDA (Food and Drug Administration). 2023. Emergency use authorization.
https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-
framework/emergency-use-authorization (accessed December 11, 2023).
FDA. 2023b. Re: Revocation of EUA 27205 - Janssen COVID-19 vaccine.
https://www.fda.gov/media/169003/download?attachment (accessed March 1, 2024).
Flaxman, S., C. Whittaker, E. Semenova, T. Rashid, R. M. Parks, A. Blenkinsop, H. J. T. Unwin, S.
Mishra, S. Bhatt, D. Gurdasani, and O. Ratmann. 2023. Assessment of COVID-19 as the
underlying cause of death among children and young people aged 0 to 19 years in the US. JAMA
Network Open 6(1):e2253590. https://doi.org/10.1001/jamanetworkopen.2022.53590.
GAO (Government Accountability Office). 2021. Operation Warp Speed: Accelerated COVID-19
vaccine development status and efforts to address manufacturing challenges (GAO-21-319).
https://www.gao.gov/products/gao-21-319 (accessed December 7, 2023).
Grimes, R. 2023. Overview of injury compensation programs—NASEM committee to review relevant
literature regarding adverse events associated with vaccines: Division of Injury Compensation
Programs. Health Resources and Services.
HHS (Department of Health and Human Services). 2024. COVID-19 vaccines.
https://www.hhs.gov/coronavirus/covid-19-vaccines/index.html (accessed March 6, 2024).
HRSA (Health Resources and Services Administration). 2023a. About the National Vaccine Injury
Compensation Program—what is the Vaccine Injury Compensation Trust Fund?
https://www.hrsa.gov/vaccine-compensation/about (accessed December 13, 2023).
HRSA. 2023c. National Vaccine Injury Compensation Program. https://www.hrsa.gov/vaccine-
compensation/ (accessed December 6, 2023).
HRSA. 2023b. Comparison of Countermeasures Injury Compensation Program (CICP) to the National
Vaccine Injury Compensation Program (VICP). https://www.hrsa.gov/cicp/cicp-vicp (accessed
December 11, 2023).
HRSA. 2023d. Vaccine injury table. Health Resources and Services Administration.
IOM (Institute of Medicine). 1991. Adverse effects of pertussis and rubella vaccines. Edited by C. P.
Howson, C. J. Howe, and H. V. Fineberg. Washington, DC: National Academy Press.
IOM. 2002. Immunization safety review: Hepatitis B vaccine and demyelinating neurological disorders.
Edited by K. Stratton, D. A. Almario, and M. C. McCormick. Washington, DC: The National
Academies Press.
IOM. 2011. Finding what works in health care: Standards for systematic reviews. Edited by J. Eden, L.
Levit, A. Berg, and S. Morton. Washington, DC: The National Academies Press.
IOM. 2012. Adverse effects of vaccines: Evidence and causality. Edited by K. Stratton, A. Ford, E. Rusch,
and E. W. Clayton. Washington, DC: The National Academies Press.
Junqueira, D. R., L. Zorzela, S. Golder, Y. Loke, J. J. Gagnier, S. A. Julious, T. Li, E. Mayo-Wilson, B.
Pham, R. Phillips, P. Santaguida, R. W. Scherer, P. C. Gøtzsche, D. Moher, J. P. A. Ioannidis,
and S. Vohra. 2023. Consort harms 2022 statement, explanation, and elaboration: Updated
guideline for the reporting of harms in randomised trials. British Journal of Medicine
381:e073725. https://doi.org/10.1136/bmj-2022-073725.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
26 VACCINE EVIDENCE REVIEW
NASEM (National Academies of Sciences, Engineering, and Medicine). 2023. Review of relevant
literature regarding adverse events associated with vaccines.
https://www.nationalacademies.org/our-work/review-of-relevant-literature-regarding-adverse-
events-associated-with-vaccines (accessed December 18, 2023).
Qureshi, R., E. Mayo-Wilson, and T. Li. 2022. Harms in systematic reviews paper 1: An introduction to
research on harms. Journal of Clinical Epidemiology 143:186–196.
https://doi.org/10.1016/j.jclinepi.2021.10.023.
WHO (World Health Organization). 2024. Number of COVID-19 deaths reported to WHO.
https://data.who.int/dashboards/covid19/deaths?n=c (accessed March 6, 2024).
Watson, O. J., G. Barnsley, J. Toor, A. B. Hogan, P. Winskill, and A. C. Ghani. 2022. Global impact of
the first year of COVID-19 vaccination: A mathematical modelling study. Lancet Infectious
Diseases 22(9):1293–1302. https://doi.org/10.1016/S1473-3099(22)00320-6.
Yadegarynia, D., S. Tehrani, F. Hadavand, S. Arshi, Z. Abtahian, A. Keyvanfar, A. Darvishi, A. Zarghi,
L. Gachkar, I. A. Darazam, and M. Farahbakhsh. 2023. Side effects after COVID-19 vaccination:
A comparison between the most common available vaccines in Iran. Iranian Journal of
Microbiology 15(2):189–195. https://doi.org/10.18502/ijm.v15i2.12467.
Zorzela, L., Y. Loke, J. P. A. Ioannidis, S. Golder, P. Santaguida, D. Altman, D. Moher, S. Vohra, and P.
h. group. 2016. PRISMA harms checklist: Improving harms reporting in systematic reviews.
British Journal of Medicine 352:i157. https://doi.org/10.1136/bmj.i15.
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2
Immunologic Response to COVID-19 Vaccines
The global pandemic stemming from the emergence of the novel SARS-CoV-2 virus in
late 2019 made it critical to develop efficacious vaccines. This public health crisis initiated
global efforts to produce vaccines to reduce viral transmission and protecting individuals from
life-threatening infections (Diamond and Pierson, 2020). Several COVID-19 vaccines were
rapidly developed using a variety of platforms. Concomitant with the release of vaccines,
concerns arose around vaccine-induced harms. To better understand how vaccine mediated
harms may arise, it is important to know how specific COVID-19 vaccines initiate an immune
response.
Charged with examining biological mechanisms, the committee conducted a
comprehensive review of the current literature, examining the available evidence encompassing
clinical trials, epidemiology studies, case reports, preclinical and translational in vitro or in silico
studies, and insights gained from animal models. The committee analyzed a diverse array of
vaccine-mediated harms and a variety of vaccine platforms and compiled a list of mechanisms
that were deemed most plausible in contributing to the emergence of vaccine-mediated adverse
reactions following COVID-19 vaccination. Throughout these deliberations, the committee
engaged in in-depth discussions regarding the pathophysiology that may be involved and the
requisite evidentiary support necessary to establish the presence of a particular mechanism.
FUNDAMENTALS OF THE IMMUNE RESPONSE
The human immune response is initiated by the innate immune system which activates
the adaptive immune system. Both the innate and adaptive arms of the immune response play a
pivotal role in combating pathogens, such as SARS-CoV-2, and establishing long-term
immunity. They are also both important in producing an effective immune response and long-
term immunity (immunological memory) after vaccination.
The innate immune system is the “first responder” to foreign agents, such as viral
infections or physical tissue damage. It comprises physical defenses, such as the skin, and
cellular components, such as macrophages, mast cells, dendritic cells, neutrophils, and natural
killer cells. The innate immune response is not pathogen specific at the single amino acid
(AA)/protein epitope level (i.e., antigen) but recognizes categories of pathogens, such as viruses,
bacteria, parasites, and tissue damage, based on molecular patterns that are specific to particular
microbes (Chaplin, 2010). A key element of this pathogen recognition system are pattern
recognition receptors (PRRs), with Toll-like receptors (TLRs) being a notable subgroup. For
example, TLR3 is involved in canonically recognizing double-stranded RNA, commonly
associated with viral infections, however, evidence of TLR3 recognition of single-stranded RNA
vaccines has been shown (Teijaro and Farber, 2021). TLR4, which recognizes
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lipopolysaccharides from Gram-negative bacteria, some viral infections, and self-like ATP from
damaged mitochondria, may play a role in responses to messenger ribonucleic acid (mRNA)
vaccines, which contain mRNA within lipid nanoparticles (LNPs) that augment innate immune
responses. TLR7 and TLR8, recognizing single-stranded RNA, are integral to the immune
response against RNA-based vaccines, such as certain COVID-19 vaccines. Meanwhile, TLR9,
which detects unmethylated CpG motifs in bacterial and viral DNA, is used in some vaccines as
an adjuvant (a substance in vaccines that enhances the immunological response to the antigen).
The activation of these TLRs triggers signaling pathways that lead to cytokine and type I
interferon production, crucial for initiating adaptive immune responses (Fitzgerald and Kagan,
2020).
After activation by the innate immune system, the adaptive immune system develops an
antigen-specific immune response to a specific pathogen that is based on particular amino acids
(AA)/protein sequences (antigens). Macrophages and dendritic cells are fundamental in
presenting antigens to adaptive immune cells, initiating an antigen-specific response crucial for
establishing long-lasting immunological memory. Because of the high specificity of the adaptive
immune response, it can distinguish not only a specific virus but also a specific strain of that
virus. Memory occurs primarily at the T cell and B cell levels. B cells develop into plasma cells
that release antigen-specific antibodies that are critical for rapidly clearing infections when they
are next encountered the next time. T cells, on the other hand, play a crucial role in immune
memory by recognizing and responding to previously encountered antigens, aiding in the rapid
mobilization of the immune system during subsequent infections. The development of strong
antigen-specific T cell and B cell-antibody memory is a primary goal of vaccine development.
All types of vaccines strongly stimulate an innate immune response to direct the adaptive
immune response to make protective antigen-specific T and B cells and antibody responses
against the target infection. COVID-19 vaccines (Figure 2-1), including traditional protein-based
vaccines (NVX-CoV2373 1), mRNA vaccines (e.g., BNT162b2 2 and mRNA-1273 3) and
adenovirus-vector (AV) vaccines (e.g., Ad26.COV2.S 4 and ChAdOx-2/nCoV-19 5), are
engineered to stimulate both innate and adaptive immune responses. The mRNA vaccines deliver
genetic material coding for the SARS-CoV-2 spike S-protein into host cells (Martinez-Flores et
al., 2021) so that an antigen-specific adaptive immune response will be generated against it. The
mRNA vaccine may be able to activate resident innate immune cells at the injection site, but it
primarily takes effect after the spike protein is generated within cells (Verbeke et al., 2022). The
mRNA strands are structurally optimized to prevent degradation by incorporating pseudouridines
(Kim et al., 2022) and mRNA into lipid nanoparticles (Ndeupen et al., 2021), which both further
protects the RNA transcript from degradation and facilitates cell entry (Pardi et al., 2015).
Certain components within the LNP layer may also act as adjuvants by activating TLRs on
antigen presenting cells and the innate immune response to induce an enhanced adaptive immune
response against the spike protein (Alameh et al., 2021). Protein-based vaccines often require an
adjuvant to stimulate the innate immune response; AV vaccines have an innate immune-
activating ability because they are viral vectors.
1 Refers to the COVID-19 vaccine manufactures by Novavax.
2 Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®.
3 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®.
4 Refers to the COVID-19 vaccine manufactured by Janssen.
5 Refers to the COVID-19 vaccine manufactured by Oxford-AstraZeneca.
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Innate antigen presenting cells, particularly mast cells, macrophages, and dendritic cells,
are instrumental in activating an adaptive immune response. They capture, process, and present
pathogen-specific antigens to T cells, inducing a highly targeted adaptive response and
immunological memory. Dendritic cells are particularly important in stimulating adaptive
immune responses from the draining lymph nodes while resident mast cells and macrophages
play key roles at tissue sites. In the milieu of COVID-19 vaccines, antigen presenting cells are
vital for identifying and presenting the vaccine-derived spike protein to helper T cells, thereby
producing spike protein–specific T and B cells.
T cells, comprising helper T cells (CD4+) and cytotoxic T cells (CD8+), play
multifaceted effector roles during an infection such as SARS-CoV-2. Helper T cells facilitate B
cell activation and enhance the function of cytotoxic T cells, which directly attack and destroy
virally infected cells. The adaptive immune cell memory induced by COVID-19 vaccines
ensures a rapid antigen-specific T and B cell/antibody response when the vaccinee encounters
SARS-CoV-2 in the future.
SARS-COV-2 AND VACCINE TARGET OF THE SPIKE PROTEIN
SARS-CoV-2 is characterized by several structural proteins; the spike (S) glycoprotein
and the nucleocapsid (N) protein are primary targets for the immune response (Krammer, 2020).
The spike protein is a major virus surface protein crucial for viral entry into host cells; it binds to
the angiotensin-converting enzyme 2 (ACE2) receptor on host cells (Walls et al., 2020).
Structurally, the spike protein is a class I viral fusion glycoprotein comprising of two subunits:
the S1 subunit, responsible for receptor binding, and the S2 subunit, involved in fusion. These
subunits are connected by a furin cleavage site, unique to SARS-CoV-2 (rather than all SARS
viruses), and the protein is cleaved post translationally at this furin cleavage site. The receptor-
binding domain (RBD) within the S1 subunit is particularly critical for viral entry to cells, as it
directly interacts with the ACE2 receptor, initiating conformational changes leading to
membrane fusion and viral entry (Kirchdoerfer et al., 2016; Wrapp et al., 2020). In addition, the
spike protein is the only SARS-CoV-2 antigen recognized to stimulate neutralizing antibodies
(Xiaojie et al., 2020). A number of other receptors are important in viral entry but not described
in this report.
The spike protein has been the primary focus in vaccine developments due to its essential
role in viral entry to host cells. Vaccines contain (subunit vaccines, such as NVX-CoV2373) or
generate production of (mRNA and AV vaccines) the spike protein to elicit an immune response
in the absence of infection. Typically, adjuvants are also needed to induce a strong immune
response because the antigen itself (without an active infection) does not do so in individuals
who have not encountered SARS-CoV-2. The goal of all vaccine platforms is to contain or
produce a stable form of the S protein that will not degrade or be cleared from the body without
activating the immune response.
Two main mRNA vaccine strategies have been employed to stabilize the spike protein in
its prefusion conformation, which is essential for preserving epitopes that are sensitive to
degradation. One method, used in both mRNA-1273 and BNT162b2 vaccines, introduces
mutations in the mRNA transcript (proline substitutions at positions 986 and 987), which
maintain the spike glycoprotein in the prefusion state (Pallesen et al., 2017; Wrapp et al., 2020).
Another strategy, not employed by the current vaccines, involves designing an mRNA construct
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where the full-length spike protein lacks the furin cleavage site (∆furin), preventing
posttranslational cleavage (Laczko et al., 2020; Lederer et al., 2020).
As an alternative to targeting the full-length spike protein, some vaccines focus solely on
RBD (Bettini and Locci, 2021), which contains multiple epitopes that can be effective targets for
virus neutralization, making it a potent target for vaccine strategies (Robbiani et al., 2020; Zost et
al., 2020). For instance, BNT162b1 vaccine candidate developed by BioNTech/Pfizer encodes a
secreted trimerized version of RBD. The choice of the full-length spike protein or smaller RBD
of the spike protein in vaccine design balances the benefits of eliciting a broader immune
response with the full-length protein versus focusing on the highly neutralizing epitopes in the
RBD. However, due to its favorable immunogenicity to reactogenicity profiles, BNT162b2,
encoding full length spike protein, was chosen as the leading vaccine candidate (Khehra et al.,
2021).
TYPES OF COVID-19 VACCINES
Several COVID-19 vaccines have been developed and authorized for use in the United
States, using several different vaccine platforms (Figure 2-1). The mRNA vaccines, such as
BNT162b2 and mRNA-1273, use LNP-encapsulated mRNA to encode the SARS-CoV-2 spike
protein. This technology prompts host cells to produce the spike protein, subsequently eliciting
innate and adaptive immune responses and, most importantly, immunological memory.
Adenovirus vector vaccines, such as Ad26.COV2.S (emergency use authorization was revoked
by FDA on June 1, 2023) and AZD1222 (not used in the United States), employ modified
adenoviruses to deliver DNA encoding the spike protein. Protein subunit vaccines, such as NVX-
CoV2373, consist of recombinantly produced viral proteins (such as the spike protein or its
epitopes) combined with the Matrix-M® adjuvant, which enhances the immunogenicity of the
protein antigen, leading to a more robust immune response. Each platform has distinct
immunogenic profiles and mechanisms for eliciting an immune response.
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FIGURE 2-1 COVID-19 vaccines contributing to this report and their mechanism of action.
NOTES: (A) mRNA Vaccines: Upon injection, mRNA encapsulated in lipid nanoparticles (LNPs) is
delivered into myocytes or bystander cells. The mRNA is released from LNPs and translated by
ribosomes to produce the viral antigen, such as the spike protein (S), which is secreted. Antigen-
presenting cells (APCs) such as dendritic cells (DCs) uptake the secreted antigen, initiating an immune
response. (B) Adenoviral Vector Vaccines: Adenoviral vectors containing viral DNA enter myocytes or
bystander cells, where they uncoat. The DNA, containing a nuclear localization signal, is transported to
the nucleus and transcribed into mRNA. The extrachromosomal DNA does not integrate into the host
genome. The mRNA is translated into protein, which is secreted and uptaken by APCs, initiating an
immune response. (C) Subunit Vaccines: Pre-formed viral protein, such as the spike protein (S), is
delivered. Antigen-presenting cells, particularly resident dendritic cells (DCs), uptake the protein to
initiate an immune response. Additionally, M-matrix adjuvants enhance this response. # Ad26.COV2.S is
no longer authorized under EUA in the United States as of June 1, 2023. *ChAdOx1-S is not used in the
United States. Created with BioRender.com.
mRNA Vaccines
The advent of mRNA vaccines has marked a revolutionary leap in the field of
immunology and vaccine development, particularly underscored by their critical role in
combating the COVID-19 pandemic. These vaccines represent a significant departure from
traditional vaccine platforms, providing a number of new advantages, including rapid
development, high efficacy and safety, and rapid adaptation to new viral strains (Welsh, 2021).
This technology holds promise for preventing serious outcomes and/or spread from viral
infections. Developing mRNA vaccines, although conceptually straightforward, involves a
complex design process. These vaccines function by delivering mRNA encoding a target antigen,
such as the SARS-CoV-2 spike protein, into host cells. Once in the cytoplasm, the cells use their
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own machinery to translate the mRNA into the target protein, which is released from the host
cell, usually in an extracellular vesicle (Trougakos et al., 2022), activating an innate immune
response that also prompts the adaptive immune system to mount a memory response against the
spike (S) protein. The next time the individual sees the spike protein during an active infection or
vaccine boost, the immune system rapidly mounts a highly protective T and B cell/antibody
response. For a detailed depiction of the sequence through which SARS-CoV-2 mRNA vaccines
elicit immune responses, from their administration to the priming of T cells and initiation of
germinal center reactions, refer to Figure 2-2.
FIGURE 2-2 Immune responses to intramuscular administration of SARS-CoV-2 mRNA vaccines.
NOTES: Immune responses triggered by SARS-CoV-2 mRNA vaccines involve a sequence of events
starting with their intramuscular administration. These vaccines, which include mRNA encapsulated in
lipid nanoparticles (mRNA-LNPs) or the antigen they produce, are first taken up by antigen-presenting
cells (APCs) such as dendritic cells. After uptake, these APCs migrate to the lymph nodes, where they
activate both CD4 and CD8 T lymphocytes. This process of T cell priming and its subsequent steps are
discussed comprehensively in scientific literature. Following priming, CD8 T cells may differentiate into
cytotoxic T lymphocytes capable of destroying virus-infected cells, while CD4 T cells may evolve into
either Th1 cells or T follicular helper (Tfh) cells. Tfh cells are pivotal in initiating the germinal center
reaction, a critical process for the development of high-affinity memory B cells and long-lived plasma
cells that secrete antibodies. The direction of Tfh cell differentiation towards a Th1 or Th2 phenotype
influences the isotype of antibodies produced by these plasma cells, affecting the body's immune response
to the vaccine.
SOURCE: Bettini and Locci, 2021.
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One of the initial challenges of mRNA vaccines was the inherent nature of unmodified
mRNA, which is extremely labile and highly immunogenic, making it unsuitable for direct use in
vaccines (Pardi et al., 2018). Karikó et al. tested various modifications to nucleosides in mRNA
molecules (Kariko et al., 2008). They tested modifications, such as pseudouridine, 5-
methylcytidine, N6-methyladenosine, 5-methyluridine, and 2-thiouridine. The substitution of
uridine with N1-methyl-pseudouridine (m1Ψ) led to a tenfold increase in translation efficiency
compared to unmodified mRNA (Karikó et al., 2008). Moreover, mRNA with this modification
was not recognized by the pathogen-associated molecular pattern (PAMP) sensing mechanisms,
such as TLRs or retinoic acid-inducible gene I (RIG-I), thus avoiding excessive inflammation,
RNA degradation, and potential harms (Karikó et al., 2008; Pardi et al., 2018). This m1Ψ
modification has been adopted in the design of several mRNA vaccine candidates, including the
widely used mRNA-1273 and BNT162b2 (Corbett et al., 2020; Walsh et al., 2020).
Although it is possible to inject naked mRNA directly for immunization, this approach is
generally inefficient (Cao and Gao, 2021). For the mRNA to be translated into proteins in the
host cell, it must penetrate the cell’s lipid membrane to reach the cellular ribosomes. To facilitate
efficient protein translation, delivery methods that ensure the cytosolic localization of mRNA are
essential. Although standard laboratory lipid encapsulation methods, such as lipofectamine, were
effective in vitro, they were cytotoxic and less efficient in vivo (Cao and Gao, 2021; Karikó et
al., 2008). The encapsulation of mRNA into LNPs significantly contributes to its stability and
uptake by the cells; LNPs effectively transport mRNA within the body and, upon intramuscular
injection, can be taken up by antigen-presenting cells at the injection site and in nearby lymph
nodes, facilitating both innate and adaptive immune responses. Furthermore, LNPs provide
protection against nuclease-mediated degradation of the mRNA. The composition of LNPs is
often proprietary, but they are known to contain a mixture of ionizable cationic lipids,
cholesterol, phospholipids, and polyethylene glycols (PEGs), which self-assemble into
nanoparticles of approximately 100 nanometers in diameter to encapsulate the mRNA (Cullis
and Hope, 2017; Maier et al., 2013). Many of these components are known to be immunogenic
and can act as adjuvants to stimulate the innate immune response to the spike protein. In fact, the
composition of the LNP can be tailored to enhance the immune system's response to the vaccine
by inducing robust Tfh cell and humoral responses, making LNPs not only a delivery vehicle but
also an adjuvant-like component of mRNA vaccines (Alameh et al., 2021).
Adenovirus Vector Vaccines
Adenovirus vector-based vaccines (AV) have emerged as a key player in COVID-19
vaccine development, leveraging the unique properties of adenoviruses. These linear double-
stranded DNA viruses, typically responsible for respiratory infections in children and adults,
possess stable genes and efficient transduction capabilities (ability to transfer genetic materials),
making them ideal vaccine vectors (Lukashev and Zamyatnin, 2016). Adenoviruses do not
integrate into the host genome but remain in a non-genome episomal state; meaning the injected
genetic material translocates into the nucleus but does not integrate into the host DNA
(Coughlan, 2020; Walsh et al., 2020). This aspect is significant because it mitigates concerns
about potential long-term genetic changes in the host’s cells. In some other types of viral vectors,
the viral DNA could integrate into the host’s genome, which could lead to unintended genetic
alterations (Bulcha et al., 2021). However, with AV vaccines, this risk is greatly reduced because
the adenovirus DNA remains separate from the host’s DNA.
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The adenovirus’s nucleocapsid is composed of fiber, penton, and hexon proteins,
contributing to its robustness and versatility as a vector. Over 150 primate adenoviruses have
been identified, with many being developed for vaccines due to their cost-effectiveness,
thermostability, and ability to induce strong immune responses (Chavda et al., 2023). A
significant challenge is pre-existing immunity to common adenovirus serotypes in humans. To
circumvent this, rare adenoviruses are employed, such as Ad26 or chimpanzee adenoviruses,
which are less likely to be neutralized by pre-existing human antibodies. These vectors have
demonstrated effectiveness in both animal models and human studies, despite the varying levels
of pre-existing immunity across populations (Ewer et al., 2017; Geisbert et al., 2011).
In the context of COVID-19 vaccines, AZD1222, also known as “Covishield” by the
Serum Institute of India, uses the ChAdOx1 AV. It carries the gene for the SARS-CoV-2 spike
protein (ChAdOx1-S), which is expressed in its trimeric prefusion conformation (Watanabe et
al., 2021).
Janssen Pharmaceuticals developed Ad26.COV2.S, using an Ad26 vector that encodes
the spike protein with specific modifications (K986P and V987P) to enhance immunogenicity by
locking the spike in its prefusion conformation (Bos et al., 2020). This vaccine is distinguished
by its single-dose regimen.
Protein Subunit Vaccines
Protein-based vaccines, a well-established class of vaccines, use specific proteins (or
protein fragments) from a pathogen to elicit an immune response without introducing the
complete pathogen. These vaccines are known for their safety, as they do not contain live
components of the pathogen, reducing the risk of vaccine-induced disease, but they are also less
immunogenic and require adjuvants or other interventions (Pollard and Bijker, 2021). These
vaccines fall into two main categories: subunit vaccines, which include only the parts of the virus
that best stimulate the immune system, and toxoid vaccines, which use a toxin produced by the
pathogen that has been made harmless but still triggers immunity. Toxoid vaccines include
diphtheria and tetanus vaccines, which use inactivated forms of the toxins produced by these
bacteria. Subunit vaccines include hepatitis B, which uses a surface protein from the virus, the
pertussis toxin component of the DtaP vaccine, and NVX-CoV2373.
NVX-CoV2373 comprises recombinantly produced spike proteins combined with
Novavax’s proprietary Matrix-M® adjuvant (Keech et al., 2020). The spike protein used in the
vaccine is produced by baculovirus expression in Spodoptera frugiperda insect cells, a method
known for its ability to yield complex, properly folded proteins (Jarvis, 2003). This strategy
ensures that the spike protein maintains its prefusion conformation, which is known to expose
critical neutralizing epitopes more effectively than the post-fusion conformation (Bowen et al.,
2021; Keech et al., 2020). The adjuvant is a critical component that significantly boosts the
innate immune response to the spike protein. It is based on saponin, derived from the Quillaja
saponaria tree, and combined with cholesterol and phospholipid to form nanoparticles. These
nanoparticles enhance the immune response by stimulating the entry of the antigen into antigen-
presenting cells and activating these innate cells. This adjuvant has been shown to boost both the
quantity and quality of the immune response, leading to higher levels of neutralizing antibodies
and a more robust T cell response (Stertman et al., 2023) to infection. In addition, adjuvants
enable the use of smaller amounts of antigen. Producing neutralizing antibodies is the goal for
most vaccines, as they bind to a pathogen and block its ability to infect cells, effectively
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
IMMUNOLOGIC RESPONSE 35
PREPUBLICATION COPY: Uncorrected Proofs
neutralizing its disease-causing capabilities. In addition to antibody production, the orchestration
of a robust T cell response is paramount, as these cells not only assist in the maturation of
antibody-producing B cells but also identify and eliminate infected host cells, thereby mitigating
the pathogen's proliferation and ensuring a comprehensive immunological defense.
This vaccine’s storage and handling requirements are less stringent than those of mRNA
vaccines, making it a valuable asset in global vaccination efforts, especially in regions with
limited cold chain infrastructure.
VACCINE IMMUNE RESPONSE ELICITATION
For non-single-dose COVID-19 vaccines, the first and second doses play distinct and
complementary roles in eliciting an effective immune response. The initial vaccine dose largely
primes the immune system, providing the antigen in a way that stimulates initial antibody
production and activates specific immune cells that lead to antigen-specific memory T and B
cells. Because the vaccine is not an actual infection, it may not provide the needed cues to mount
an optimal immune response. Thus, the second dose, or the booster, is crucial for amplifying and
broadening this response. It significantly enhances the quantity and quality of neutralizing
antibodies, solidifies memory B cell and T cell responses, and induces a more robust, durable
immunity. The booster dose thus ensures a more sustained and effective immune response,
including against virus variants (Chu et al., 2022). Table 2-1 presents a summary of antibody
responses and T cell responses in humans for each U.S. COVID-19 vaccine.
The immunogenicity of COVID-19 vaccines largely hinges on the adaptive immune
system recognizing the specific spike protein fragments. B cell receptors (BCRs) on B cells and
T cell receptors (TCRs) on T cells are key to this recognition when they interact with innate
immune antigen-presenting cells. BCRs directly bind to epitopes on the spike protein, initiating
B cell activation (Pettini et al., 2022). TCRs, however, recognize these epitopes when presented
on Major Histocompatibility Complex (MHC) molecules by antigen-presenting cells (Yang et
al., 2023). This dual recognition mechanism is essential for the coordinated activation of both
humoral and cellular arms of the adaptive immune response (Teijaro and Farber, 2021) for viral
proteins that are not superantigens.
Following vaccination, B cell activation predominantly occurs in germinal centers (GCs)
within secondary lymphoid organs (Figure 2-2), such as lymph nodes and the spleen. In general,
antigen-activated B cells undergo somatic hypermutation, which introduces random mutations
into their immunoglobulin genes (Laidlaw and Ellebedy, 2022; Turner et al., 2021) and leads to
B cells with high-affinity antibodies for the spike protein. B cells with the highest affinity are
selected and differentiated into long-lived plasma cells (LLPCs) and memory B cells (MBCs).
LLPCs secrete neutralizing antibodies, some of which are capable of mediating sterilizing
immunity, which prevents infection in the host including mucous membranes, and can
potentially persist for years, continuously producing antibodies. MBCs quickly activate and give
rise to a new wave of high-affinity antibody-secreting cells, providing rapid protection upon re-
exposure to the virus (Sadarangani et al., 2021; Tam et al., 2016). For COVID vaccines, in time,
mutations in the spike protein may result in lower affinity interaction between the antibodies
induced by one strain and a mutated spike protein.
The role of T cells, particularly CD4+ T cells, is multifaceted. T follicular helper (Tfh)
cells, a subset of CD4+ T cells, are critical for the development of germinal center reactions and
consequently for the maturation of B cell responses. Tfh cells assist B cells in the GCs by
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
36 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY: Uncorrected Proofs
providing necessary costimulatory signals and cytokines, facilitating the selection of high-
affinity B cells. These interactions are crucial for developing both LLPCs and MBCs, and
mRNA vaccines have been demonstrated to effectively induce Tfh cell responses, which are key
to generating robust and long-lasting neutralizing immunity (Bettini and Locci, 2021; Pardi et al.,
2018; Sadarangani et al., 2021). Clinically, however, immunity from COVID-19 vaccines is
observed to wane over time (Menegale et al., 2023), necessitating booster doses to counteract
this decline and to address the emergence of new, circulating common strains, thereby ensuring
sustained protection against the virus.
Cytotoxic CD8+ T cells, which directly eliminate virus-infected cells, are another crucial
component. These cells are characterized by the release of cytotoxic molecules, such as
granzyme B and perforin. Upon vaccination, polyfunctional antigen-specific CD8+ T cells
increase; these produce inflammatory cytokines, which are critical signaling molecules in the
immune system. These include IFNγ (interferon gamma), IL-2 (interleukin-2), and TNF (tumor
necrosis factor). IFNγ plays a crucial role in activating and directing other immune cells,
enhancing the overall immune response to the vaccine and the virus. IL-2 is vital for the growth,
proliferation, and differentiation of T cells, ensuring a robust and sustained immune response.
TNF is involved in systemic inflammation and capable of inducing apoptosis or cell death in
virus-infected cells. These cells exhibit markers of cytotoxic activity and contribute to the overall
defense against viral infection. The ability to activate CD8+ T cell responses varies among
vaccine candidates, with some inducing strong responses in both small and large animal models,
while others showing more variable results (Bettini and Locci, 2021; Creech et al., 2021).
Immunological memory is a hallmark of the adaptive immune response and a key goal of
vaccination. Most licensed vaccines, including those for COVID-19, confer protection by
eliciting long-lasting antibody responses.
The rapid and effective response to a pathogen upon re-exposure is primarily mediated by
memory B and T cells. Memory B cells, upon re-exposure to the antigen, differentiate into
antibody-secreting cells more quickly than naïve B cells, leading to a fast increase in antibody
titers. Similarly, memory T cells, both CD4+ and CD8+, are primed to respond more rapidly and
effectively than naïve T cells. Tfh cells are especially important in supporting memory B cell
responses in GCs. They facilitate the selection of high-affinity memory B cells and their
differentiation into LLPCs or MBCs (Pollard and Bijker, 2021). These interactions are critical
for maintaining long-lasting immunity and providing rapid protection upon subsequent exposures
to the virus. Upon activation in a future infection, memory B cells rapidly produce large amounts
of antigen-specific antibody, which can neutralize viral infection/entry into host cells—reducing
the severity of the infection.
The duration of immunity conferred by COVID-19 vaccines and the potential need for
booster doses are areas of ongoing research. Studies have shown that mRNA vaccines can induce
robust CD8+ T cell responses characterized by key cytokines and cytotoxic markers upon
rechallenge (Sadarangani et al., 2021; Teijaro and Farber, 2021). However, the longevity of these
responses and persistence of memory T cells after vaccination is still under investigation. Some
evidence suggests that the immune response elicited by these vaccines, particularly the
generation of memory B and T cells, may be long lasting, but further studies are required to
confirm the duration of this protection. Additionally, the need for booster doses may depend on
factors such as the emergence of new viral variants/strains and the longevity of the vaccine-
induced immune response (Teijaro and Farber, 2021).
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
IMMUNOLOGIC RESPONSE 39
PREPUBLICATION COPY: Uncorrected Proofs
POSSIBLE MECHANISMS OF VACCINE-MEDIATED REACTIONS
Although rare, vaccine-mediated harms can range from mild, transient reactions to more
serious conditions, underscoring the importance of ongoing safety monitoring and research.
Certain of the most common vaccine-associated harms can arise from a few different
immunological mechanisms, some of which are briefly discussed next (Table 2-2).
Immediate-type hypersensitivity reactions are rapid immunological responses observed in
certain individuals following vaccination. Mast cells and basophils play a crucial role; they
become activated by IgE when individuals are re-exposed to the same antigen during vaccination
(Stone et al., 2019), which triggers degranulation and the release of various mediators, such as
histamine, leukotrienes, prostaglandins, and cytokines, including IL-4 and IL-5. The clinical
manifestation ranges from urticaria (hives) to the more severe and potentially life-threatening
anaphylaxis (McLeod et al., 2015).
In contrast, delayed-type hypersensitivity reactions involve a different immune pathway.
T cells, particularly CD4+ helper T cells, are central to these reactions. Upon exposure to an
antigen that the immune system has seen before, T cells secrete cytokines, such as Interferon-
gamma (IFNγ), IL-2, and tumor necrosis factor-alpha (TNF-α). The symptoms associated with
this reaction, such as rash, fever, and joint pain, typically develop days to weeks after
vaccination, distinguishing them from the immediate-type reactions (Biedermann et al., 2000).
Autoimmune reactions in the context of vaccination encompass a variety of plausible
mechanisms (Chen et al., 2022a; Lamprinou et al., 2023):
● Molecular mimicry, where vaccine antigens closely resemble the body’s own
proteins, potentially leading to the production of autoantibodies or autoreactive T
cells that target self-tissues (Segal and Shoenfeld, 2018).
● Bystander activation, when localized inflammation exposes self-antigens, leading to
the activation of previously dormant self-reactive lymphocytes.
● Epitope spreading, particularly with repeat vaccinations, where the initial immune
response to vaccine antigens broadens to include self-antigens.
● Polyclonal activation and adjuvant-induced autoimmunity, where intense immune
stimulation, potentially exacerbated by adjuvants, overcomes the tolerance to self-
antigens, resulting in autoimmunity.
A current and significant concern is vaccine-induced immune thrombotic
thrombocytopenia (VITT), an extremely rare condition characterized by forming antibodies
against platelet factor 4 (PF4). This activates platelets and immune cells producing anti-PF4
antibodies (Dabbiru et al., 2023). The role of complement activation in promoting a
prothrombotic state is also being explored (see Chapter 5).
Vaccine-Associated Enhanced Disease (VAED) and Antibody-Dependent Enhancement
(ADE) are critical considerations in vaccine development, particularly highlighted by historical
challenges with the formalin-inactivated Respiratory Syncytial Virus (RSV) vaccine (Acosta et
al., 2015). VAED encompasses a spectrum of phenomena where vaccination paradoxically
exacerbates the disease upon exposure to the natural pathogen, mediated through mechanisms
such as ADE. In ADE, non-neutralizing or suboptimal antibodies generated by the vaccine
facilitate the pathogen's entry into host cells via Fc receptors, leading to increased viral
replication and severe disease manifestations (Gartlan et al., 2022). The formalin-inactivated
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
40 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY: Uncorrected Proofs
RSV vaccine is a notable example where immunization induced antibodies that not only failed to
confer protection but also potentiated respiratory disease upon subsequent natural RSV infection.
This outcome was partly attributed to the vaccine eliciting a skewed Th2-type immune response,
promoting eosinophilic infiltration and severe lung pathology, rather than a protective Th1-type
response (Gartlan et al., 2022). Additionally, immune complexes formed by the vaccine-induced
antibodies could activate complement pathways, contributing to tissue damage.
Furthermore, general vaccine reactions encompass a wide array of immune responses.
These involve the activation of antigen-presenting cells (APCs), B cells, and T cells. Cytokines,
such as IL-1, IL-6, IL-12, and TNF-α, play a significant role in the initial immune response to
vaccines, contributing to both their protective effects and potential harms.
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42
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8
.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
IMMUNOLOGIC RESPONSE 43
PREPUBLICATION COPY: Uncorrected Proofs
ADJUVANTS
Adjuvants in vaccines serve to enhance the body’s immune response to an antigen,
ensuring a stronger and longer-lasting immunity by activating TLRs on antigen-presenting cells
to stimulate a strong innate immune response that produces a strong adaptive immune response.
For example, aluminum salts create a depot effect for sustained antigen release, and oil-in-water
emulsions, such as MF59, increase cytokine release and antigen uptake (Wilkins et al., 2017).
Adjuvants such as AS01, AS02, AS03, and saponins stimulate APCs, such as dendritic cells, to
activate T cells, and CpG oligodeoxynucleotides activate Toll-like receptor 9 (TLR9) (Facciola
et al., 2022). These mechanisms, although crucial for vaccine efficacy, can sometimes lead to
adverse reactions, primarily localized ones, such as inflammation and soreness, due to
heightened immune activation at the site of injection. Table 2-3 lists some of the most commonly
used adjuvants and their mechanisms of action.
Matrix-M® is a saponin-based adjuvant in NVX-CoV2373, which is the only specifically
adjuvanted COVID-19 vaccine. It consists of Quillaja Saponaria Molina extracts, known for
their ability to stimulate both the innate and adaptive arms of the immune system. It enhances
immune responses by activating antigen-presenting cells and boosting cytokine production,
which facilitates a stronger T cell and antibody response to the vaccine antigen (Stertman et al.,
2023). Its mechanism of action increases the vaccine’s efficacy, but like other adjuvants, it can
also contribute to or cause reactions. In the United States, FDA approves adjuvants only as
components of vaccines, not as stand-alone products, because their properties can vary based on
their concentration and interaction with other ingredients in the vaccine formulation.
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
IMMUNOLOGIC RESPONSE 45
PREPUBLICATION COPY: Uncorrected Proofs
Potential harms of vaccination necessitate a thorough investigation of mechanisms.
Examining their immune response will help investigators gain insights into possible mechanisms
of vaccine-related harms.
Through an examination of clinical trials, epidemiology studies, case reports, preclinical
in vivo and in silico work, and insights from animal models, the committee has delved into
possible mechanisms that may contribute to adverse events. Understanding these mechanisms is
paramount in ensuring the safety and well-being of individuals receiving COVID-19 vaccines.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
46 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY: Uncorrected Proofs
REFERENCES
Acosta, P. L., M. T. Caballero, and F. P. Polack. 2015. Brief history and characterization of enhanced
respiratory syncytial virus disease. Clinical and Vaccine Immunology 23(3):189–195.
https://doi.org/10.1128/cvi.00609-15.
Alameh, M. G., I. Tombacz, E. Bettini, K. Lederer, C. Sittplangkoon, J. R. Wilmore, B. T. Gaudette, O.
Y. Soliman, M. Pine, P. Hicks, T. B. Manzoni, J. J. Knox, J. L. Johnson, D. Laczko, H.
Muramatsu, B. Davis, W. Meng, A. M. Rosenfeld, S. Strohmeier, P. J. C. Lin, B. L. Mui, Y. K.
Tam, K. Karikó, A. Jacquet, F. Krammer, P. Bates, M. P. Cancro, D. Weissman, E. T. Luning
Prak, D. Allman, M. Locci, and N. Pardi. 2021. Lipid nanoparticles enhance the efficacy of
mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral
responses. Immunity 54(12):2877–2892. https://doi.org/10.1016/j.immuni.2021.11.001.
Bettini, E., and M. Locci. 2021. SARS-CoV-2 mRNA vaccines: Immunological mechanism and beyond.
Vaccines 9(2). https://doi.org/10.3390/vaccines9020147.
Biedermann, T., M. Kneilling, R. Mailhammer, K. Maier, C. A. Sander, G. Kollias, S. L. Kunkel, L.
Hultner, and M. Rocken. 2000. Mast cells control neutrophil recruitment during T cell-mediated
delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage
inflammatory protein 2. Journal of Experimental Medicine 192(10):1441–1452.
https://doi.org/10.1084/jem.192.10.1441.
Bos, R., L. Rutten, J. E. M. van der Lubbe, M. J. G. Bakkers, G. Hardenberg, F. Wegmann, D. Zuijdgeest,
A. H. de Wilde, A. Koornneef, A. Verwilligen, D. van Manen, T. Kwaks, R. Vogels, T. J.
Dalebout, S. K. Myeni, M. Kikkert, E. J. Snijder, Z. Li, D. H. Barouch, J. Vellinga, J. P. M.
Langedijk, R. C. Zahn, J. Custers, and H. Schuitemaker. 2020. Ad26 vector–based COVID-19
vaccine encoding a prefusion-stabilized SARS-CoV-2 spike immunogen induces potent humoral
and cellular immune responses. NPJ Vaccines 5:91. https://doi.org/10.1038/s41541-020-00243-x.
Bowen, J. E., A. C. Walls, A. Joshi, K. R. Sprouse, C. Stewart, M. A. Tortorici, N. M. Franko, J. K.
Logue, I. G. Mazzitelli, S. W. Tiles, K. Ahmed, A. Shariq, G. Snell, N. T. Iqbal, J. Geffner, A.
Bandera, A. Gori, R. Grifantini, H. Y. Chu, W. C. Van Voorhis, D. Corti, and D. Veesler. 2021.
SARS-CoV-2 spike conformation determines plasma neutralizing activity. bioRxiv.
https://doi.org/10.1101/2021.12.19.473391.
Bulcha, J. T., Y. Wang, H. Ma, P. W. L. Tai, and G. Gao. 2021. Viral vector platforms within the gene
therapy landscape. Signal Transduction and Targeted Therapy 6(1):53.
https://doi.org/10.1038/s41392-021-00487-6.
Cao, Y., and G. F. Gao. 2021. mRNA vaccines: A matter of delivery. EClinicalMedicine 32:100746.
https://doi.org/10.1016/j.eclinm.2021.100746.
Chaplin, D. D. 2010. Overview of the immune response. Journal of Allergy and Clinical Immunology
125(2 Suppl 2):S3–S23. https://doi.org/10.1016/j.jaci.2009.12.980.
Chavda, V. P., R. Bezbaruah, D. Valu, B. Patel, A. Kumar, S. Prasad, B. B. Kakoti, A. Kaushik, and M.
Jesawadawala. 2023. Adenoviral vector–based vaccine platform for COVID-19: Current status.
Vaccines 11(2). https://doi.org/10.3390/vaccines11020432.
Chen, D. P., Y. H. Wen, W. T. Lin, and F. P. Hsu. 2022a. Association between the side effect induced by
COVID-19 vaccines and the immune regulatory gene polymorphism. Frontiers in Immunology
13:941497. https://doi.org/10.3389/fimmu.2022.941497.
Chen, Y., Z. Xu, P. Wang, X. M. Li, Z. W. Shuai, D. Q. Ye, and H. F. Pan. 2022b. New-onset
autoimmune phenomena post-COVID-19 vaccination. Immunology 165(4):386–401.
https://doi.org/10.1111/imm.13443.
Chu, L., K. Vrbicky, D. Montefiori, W. Huang, B. Nestorova, Y. Chang, A. Carfi, D. K. Edwards, J.
Oestreicher, H. Legault, F. J. Dutko, B. Girard, R. Pajon, J. M. Miller, R. Das, B. Leav, and R.
McPhee. 2022. Immune response to SARS-CoV-2 after a booster of mRNA-1273: An open-label
Phase 2 trial. Nature Medicine 28(5):1042–1049. https://doi.org/10.1038/s41591-022-01739-w.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
IMMUNOLOGIC RESPONSE 47
PREPUBLICATION COPY: Uncorrected Proofs
Corbett, K. S., B. Flynn, K. E. Foulds, J. R. Francica, S. Boyoglu-Barnum, A. P. Werner, B. Flach, S.
O’Connell, K. W. Bock, M. Minai, B. M. Nagata, H. Andersen, D. R. Martinez, A. T. Noe, N.
Douek, M. M. Donaldson, N. N. Nji, G. S. Alvarado, D. K. Edwards, D. R. Flebbe, E. Lamb, N.
A. Doria-Rose, B. C. Lin, M. K. Louder, S. O’Dell, S. D. Schmidt, E. Phung, L. A. Chang, C.
Yap, J. M. Todd, L. Pessaint, A. Van Ry, S. Browne, J. Greenhouse, T. Putman-Taylor, A.
Strasbaugh, T. A. Campbell, A. Cook, A. Dodson, K. Steingrebe, W. Shi, Y. Zhang, O. M.
Abiona, L. Wang, A. Pegu, E. S. Yang, K. Leung, T. Zhou, I. T. Teng, A. Widge, I. Gordon, L.
Novik, R. A. Gillespie, R. J. Loomis, J. I. Moliva, G. Stewart-Jones, S. Himansu, W. P. Kong, M.
C. Nason, K. M. Morabito, T. J. Ruckwardt, J. E. Ledgerwood, M. R. Gaudinski, P. D. Kwong, J.
R. Mascola, A. Carfi, M. G. Lewis, R. S. Baric, A. McDermott, I. N. Moore, N. J. Sullivan, M.
Roederer, R. A. Seder, and B. S. Graham. 2020. Evaluation of the mRNA-1273 vaccine against
SARS-CoV-2 in nonhuman primates. New England Journal of Medicine 383(16):1544–1555.
https://doi.org/10.1056/NEJMoa2024671.
Coughlan, L. 2020. Factors which contribute to the immunogenicity of non-replicating adenoviral
vectored vaccines. Frontiers in Immunology 11:909. https://doi.org/10.3389/fimmu.2020.00909.
Creech, C. B., S. C. Walker, and R. J. Samuels. 2021. SARS-CoV-2 vaccines. JAMA 325(13):1318–1320.
https://doi.org/10.1001/jama.2021.3199.
Cullis, P. R., and M. J. Hope. 2017. Lipid nanoparticle systems for enabling gene therapies. Molecular
Therapy 25(7):1467–1475. https://doi.org/10.1016/j.ymthe.2017.03.013.
Dabbiru, V. A. S., L. Muller, L. Schonborn, and A. Greinacher. 2023. Vaccine-induced immune
thrombocytopenia and thrombosis (VITT)—insights from clinical cases, in vitro studies and
murine models. Journal of Clinical Medicine 12(19). https://doi.org/10.3390/jcm12196126.
Diamond, M. S., and T. C. Pierson. 2020. The challenges of vaccine development against a new virus
during a pandemic. Cell Host & Microbe 27(5):699–703.
https://doi.org/10.1016/j.chom.2020.04.021.
Ewer, K., S. Sebastian, A. J. Spencer, S. Gilbert, A. V. S. Hill, and T. Lambe. 2017. Chimpanzee
adenoviral vectors as vaccines for outbreak pathogens. Human Vaccines & Immunotherapeutics
13(12):3020–3032. https://doi.org/10.1080/21645515.2017.1383575.
Facciola, A., G. Visalli, A. Lagana, and A. Di Pietro. 2022. An overview of vaccine adjuvants: Current
evidence and future perspectives. Vaccines 10(5). https://doi.org/10.3390/vaccines10050819.
FDA (Food and Drug Administration). 2021. BLA clinical review memorandum—Comirnaty
https://www.fda.gov/media/152256/download (accessed December 12, 2023).
FDA. 2022. BLA clinical review memorandum—Spikevax. https://www.fda.gov/media/156342/download
(accessed December 12, 2023).
Fitzgerald, K. A., and J. C. Kagan. 2020. Toll-like receptors and the control of immunity. Cell
180(6):1044–1066. https://doi.org/10.1016/j.cell.2020.02.041.
Gartlan, C., T. Tipton, F. J. Salguero, Q. Sattentau, A. Gorringe, and M. W. Carroll. 2022. Vaccine-
associated enhanced disease and pathogenic human coronaviruses. Frontiers in Immunology
13:882972. https://doi.org/10.3389/fimmu.2022.882972.
Geisbert, T. W., M. Bailey, L. Hensley, C. Asiedu, J. Geisbert, D. Stanley, A. Honko, J. Johnson, S.
Mulangu, M. G. Pau, J. Custers, J. Vellinga, J. Hendriks, P. Jahrling, M. Roederer, J. Goudsmit,
R. Koup, and N. J. Sullivan. 2011. Recombinant adenovirus serotype 26 (Ad26) and Ad35
vaccine vectors bypass immunity to ad5 and protect nonhuman primates against ebolavirus
challenge. Journal of Virology 85(9):4222–4233. https://doi.org/10.1128/jvi.02407-10.
Jackson, L. A., E. J. Anderson, N. G. Rouphael, P. C. Roberts, M. Makhene, R. N. Coler, M. P.
McCullough, J. D. Chappell, M. R. Denison, L. J. Stevens, A. J. Pruijssers, A. McDermott, B.
Flach, N. A. Doria-Rose, K. S. Corbett, K. M. Morabito, S. O’Dell, S. D. Schmidt, P. A.
Swanson, II, M. Padilla, J. R. Mascola, K. M. Neuzil, H. Bennett, W. Sun, E. Peters, M.
Makowski, J. Albert, K. Cross, W. Buchanan, R. Pikaart-Tautges, J. E. Ledgerwood, B. S.
Graham, J. H. Beigel, and mRNA-1273 Study Group. 2020. An mRNA vaccine against SARS-
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
48 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY: Uncorrected Proofs
CoV-2—preliminary report. New England Journal of Medicine 383(20):1920–1931.
https://doi.org/10.1056/NEJMoa2022483.
Jarvis, D. L. 2003. Developing baculovirus-insect cell expression systems for humanized recombinant
glycoprotein production. Virology 310(1):1–7. https://doi.org/10.1016/s0042-6822(03)00120-x.
Karikó, K., H. Muramatsu, F. A. Welsh, J. Ludwig, H. Kato, S. Akira, and D. Weissman. 2008.
Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with
increased translational capacity and biological stability. Molecular Therapy 16(11):1833–1840.
https://doi.org/10.1038/mt.2008.200.
Keech, C., G. Albert, I. Cho, A. Robertson, P. Reed, S. Neal, J. S. Plested, M. Zhu, S. Cloney-Clark, H.
Zhou, G. Smith, N. Patel, M. B. Frieman, R. E. Haupt, J. Logue, M. McGrath, S. Weston, P. A.
Piedra, C. Desai, K. Callahan, M. Lewis, P. Price-Abbott, N. Formica, V. Shinde, L. Fries, J. D.
Lickliter, P. Griffin, B. Wilkinson, and G. M. Glenn. 2020. Phase 1–2 trial of a SARS-CoV-2
recombinant spike protein nanoparticle vaccine. New England Journal of Medicine 383(24):2320-
2332. https://doi.org/10.1056/NEJMoa2026920.
Khehra, N., I. Padda, U. Jaferi, H. Atwal, S. Narain, and M. S. Parmar. 2021. Tozinameran (BNT162b2)
vaccine: The journey from preclinical research to clinical trials and authorization. AAPS
PharmSciTech 22(5):172. https://doi.org/10.1208/s12249-021-02058-y.
Kim, S. C., S. S. Sekhon, W. R. Shin, G. Ahn, B. K. Cho, J. Y. Ahn, and Y. H. Kim. 2022. Modifications
of mRNA vaccine structural elements for improving mRNA stability and translation efficiency.
Molecular & Cellular Toxicology 18(1):1–8. https://doi.org/10.1007/s13273-021-00171-4.
Kirchdoerfer, R. N., C. A. Cottrell, N. Wang, J. Pallesen, H. M. Yassine, H. L. Turner, K. S. Corbett, B.
S. Graham, J. S. McLellan, and A. B. Ward. 2016. Pre-fusion structure of a human coronavirus
spike protein. Nature 531(7592):118–121. https://doi.org/10.1038/nature17200.
Krammer, F. 2020. SARS-CoV-2 vaccines in development. Nature 586(7830):516–527.
https://doi.org/10.1038/s41586-020-2798-3.
Laczko, D., M. J. Hogan, S. A. Toulmin, P. Hicks, K. Lederer, B. T. Gaudette, D. Castano, F. Amanat, H.
Muramatsu, T. H. Oguin, III, A. Ojha, L. Zhang, Z. Mu, R. Parks, T. B. Manzoni, B. Roper, S.
Strohmeier, I. Tombacz, L. Arwood, R. Nachbagauer, K. Karikó, J. Greenhouse, L. Pessaint, M.
Porto, T. Putman-Taylor, A. Strasbaugh, T. A. Campbell, P. J. C. Lin, Y. K. Tam, G. D.
Sempowski, M. Farzan, H. Choe, K. O. Saunders, B. F. Haynes, H. Andersen, L. C. Eisenlohr, D.
Weissman, F. Krammer, P. Bates, D. Allman, M. Locci, and N. Pardi. 2020. A single
immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral
immune responses against SARS-CoV-2 in mice. Immunity 53(4):724–732.
https://doi.org/10.1016/j.immuni.2020.07.019.
Laidlaw, B. J., and A. H. Ellebedy. 2022. The germinal centre B cell response to SARS-CoV-2. Nature
Reviews: Immunology 22(1):7–18. https://doi.org/10.1038/s41577-021-00657-1.
Lamprinou, M., A. Sachinidis, E. Stamoula, T. Vavilis, and G. Papazisis. 2023. COVID-19 vaccines
adverse events: Potential molecular mechanisms. Immunologic Research 71(3):356–372.
https://doi.org/10.1007/s12026-023-09357-5.
Lederer, K., D. Castano, D. Gomez Atria, T. H. Oguin, III, S. Wang, T. B. Manzoni, H. Muramatsu, M. J.
Hogan, F. Amanat, P. Cherubin, K. A. Lundgreen, Y. K. Tam, S. H. Y. Fan, L. C. Eisenlohr, I.
Maillard, D. Weissman, P. Bates, F. Krammer, G. D. Sempowski, N. Pardi, and M. Locci. 2020.
SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses
associated with neutralizing antibody generation. Immunity 53(6):1281–1295.
https://doi.org/10.1016/j.immuni.2020.11.009.
Lukashev, A. N., and A. A. Zamyatnin, Jr. 2016. Viral vectors for gene therapy: Current state and clinical
perspectives. Biochemistry 81(7):700–708. https://doi.org/10.1134/S0006297916070063.
Maier, M. A., M. Jayaraman, S. Matsuda, J. Liu, S. Barros, W. Querbes, Y. K. Tam, S. M. Ansell, V.
Kumar, J. Qin, X. Zhang, Q. Wang, S. Panesar, R. Hutabarat, M. Carioto, J. Hettinger, P.
Kandasamy, D. Butler, K. G. Rajeev, B. Pang, K. Charisse, K. Fitzgerald, B. L. Mui, X. Du, P.
Cullis, T. D. Madden, M. J. Hope, M. Manoharan, and A. Akinc. 2013. Biodegradable lipids
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
IMMUNOLOGIC RESPONSE 49
PREPUBLICATION COPY: Uncorrected Proofs
enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAI therapeutics.
Molecular Therapy 21(8):1570–1578. https://doi.org/10.1038/mt.2013.124.
Marfe, G., S. Perna, and A. K. Shukla. 2021. Effectiveness of COVID-19 vaccines and their challenges
(review). Experimental and Therapeutic Medicine 22(6):1407.
https://doi.org/10.3892/etm.2021.10843.
Martinez-Flores, D., J. Zepeda-Cervantes, A. Cruz-Resendiz, S. Aguirre-Sampieri, A. Sampieri, and L.
Vaca. 2021. SARS-CoV-2 vaccines based on the spike glycoprotein and implications of new viral
variants. Frontiers in Immunology 12:701501. https://doi.org/10.3389/fimmu.2021.701501.
McLeod, J. J., B. Baker, and J. J. Ryan. 2015. Mast cell production and response to IL-4 and IL-13.
Cytokine 75(1):57–61. https://doi.org/10.1016/j.cyto.2015.05.019.
Menegale, F., M. Manica, A. Zardini, G. Guzzetta, V. Marziano, V. d'Andrea, F. Trentini, M. Ajelli, P.
Poletti, and S. Merler. 2023. Evaluation of waning of SARS-CoV-2 vaccine-induced immunity: A
systematic review and meta-analysis. JAMA Network Open 6(5):e2310650.
https://doi.org/10.1001/jamanetworkopen.2023.10650.
Ndeupen, S., Z. Qin, S. Jacobsen, A. Bouteau, H. Estanbouli, and B. Z. Igyarto. 2021. The mRNA-LNP
platform’s lipid nanoparticle component used in preclinical vaccine studies is highly
inflammatory. iScience 24(12):103479. https://doi.org/10.1016/j.isci.2021.103479.
Pallesen, J., N. Wang, K. S. Corbett, D. Wrapp, R. N. Kirchdoerfer, H. L. Turner, C. A. Cottrell, M. M.
Becker, L. Wang, W. Shi, W. P. Kong, E. L. Andres, A. N. Kettenbach, M. R. Denison, J. D.
Chappell, B. S. Graham, A. B. Ward, and J. S. McLellan. 2017. Immunogenicity and structures of
a rationally designed prefusion MERS-COV spike antigen. Proceedings of the National Academy
of Sciences of the United States of America 114(35):E7348–E7357.
https://doi.org/10.1073/pnas.1707304114.
Pardi, N., S. Tuyishime, H. Muramatsu, K. Karikó, B. L. Mui, Y. K. Tam, T. D. Madden, M. J. Hope, and
D. Weissman. 2015. Expression kinetics of nucleoside-modified mRNA delivered in lipid
nanoparticles to mice by various routes. Journal of Controlled Release 217:345–351.
https://doi.org/10.1016/j.jconrel.2015.08.007.
Pardi, N., M. J. Hogan, F. W. Porter, and D. Weissman. 2018. mRNA vaccines—a new era in
vaccinology. Nature Reviews Drug Discovery 17(4):261–279.
https://doi.org/10.1038/nrd.2017.243.
Pettini, E., D. Medaglini, and A. Ciabattini. 2022. Profiling the B cell immune response elicited by
vaccination against the respiratory virus SARS-CoV-2. Frontiers in Immunology 13:1058748.
https://doi.org/10.3389/fimmu.2022.1058748.
Pollard, A. J., and E. M. Bijker. 2021. A guide to vaccinology: From basic principles to new
developments. Nature Reviews: Immunology 21(2):83–100. https://doi.org/10.1038/s41577-020-
00479-7.
Robbiani, D. F., C. Gaebler, F. Muecksch, J. C. C. Lorenzi, Z. Wang, A. Cho, M. Agudelo, C. O. Barnes,
A. Gazumyan, S. Finkin, T. Hagglof, T. Y. Oliveira, C. Viant, A. Hurley, H. H. Hoffmann, K. G.
Millard, R. G. Kost, M. Cipolla, K. Gordon, F. Bianchini, S. T. Chen, V. Ramos, R. Patel, J.
Dizon, I. Shimeliovich, P. Mendoza, H. Hartweger, L. Nogueira, M. Pack, J. Horowitz, F.
Schmidt, Y. Weisblum, E. Michailidis, A. W. Ashbrook, E. Waltari, J. E. Pak, K. E. Huey-
Tubman, N. Koranda, P. R. Hoffman, A. P. West, Jr., C. M. Rice, T. Hatziioannou, P. J.
Bjorkman, P. D. Bieniasz, M. Caskey, and M. C. Nussenzweig. 2020. Convergent antibody
responses to SARS-CoV-2 in convalescent individuals. Nature 584(7821):437–442.
https://doi.org/10.1038/s41586-020-2456-9.
Sadarangani, M., A. Marchant, and T. R. Kollmann. 2021. Immunological mechanisms of vaccine-
induced protection against COVID-19 in humans. Nature Reviews: Immunology 21(8):475–484.
https://doi.org/10.1038/s41577-021-00578-z.
Sadoff, J., G. Gray, A. Vandebosch, V. Cárdenas, G. Shukarev, B. Grinsztejn, P. A. Goepfert, C. Truyers,
H. Fennema, B. Spiessens, K. Offergeld, G. Scheper, K. L. Taylor, M. L. Robb, J. Treanor, D. H.
Barouch, J. Stoddard, M. F. Ryser, M. A. Marovich, K. M. Neuzil, L. Corey, N. Cauwenberghs,
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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T. Tanner, K. Hardt, J. Ruiz-Guiñazú, M. Le Gars, H. Schuitemaker, J. Van Hoof, F. Struyf, and
M. Douoguih. 2021. Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-
19. New England Journal of Medicine 384(23):2187–2201.
https://doi.org/10.1056/NEJMoa2101544.
Segal, Y., and Y. Shoenfeld. 2018. Vaccine-induced autoimmunity: The role of molecular mimicry and
immune crossreaction. Cellular & Molecular Immunology 15(6):586–594.
https://doi.org/10.1038/cmi.2017.151.
Stertman, L., A. E. Palm, B. Zarnegar, B. Carow, C. Lunderius Andersson, S. E. Magnusson, C. Carnrot,
V. Shinde, G. Smith, G. Glenn, L. Fries, and K. Lovgren Bengtsson. 2023. The matrix-M
adjuvant: A critical component of vaccines for the 21(st) century. Human Vaccines &
Immunotherapeutics 19(1):2189885. https://doi.org/10.1080/21645515.2023.2189885.
Stone, C. A., Jr., C. R. F. Rukasin, T. M. Beachkofsky, and E. J. Phillips. 2019. Immune-mediated
adverse reactions to vaccines. British Journal of Clinical Pharmacology 85(12):2694–2706.
https://doi.org/10.1111/bcp.14112.
Tam, H. H., M. B. Melo, M. Kang, J. M. Pelet, V. M. Ruda, M. H. Foley, J. K. Hu, S. Kumari, J.
Crampton, A. D. Baldeon, R. W. Sanders, J. P. Moore, S. Crotty, R. Langer, D. G. Anderson, A.
K. Chakraborty, and D. J. Irvine. 2016. Sustained antigen availability during germinal center
initiation enhances antibody responses to vaccination. Proceedings of the National Academy of
Sciences of the United States of America 113(43):E6639–E6648.
https://doi.org/10.1073/pnas.1606050113.
Teijaro, J. R., and D. L. Farber. 2021. COVID-19 vaccines: Modes of immune activation and future
challenges. Nature Reviews: Immunology 21(4):195–197. https://doi.org/10.1038/s41577-021-
00526-x.
Trougakos, I. P., E. Terpos, H. Alexopoulos, M. Politou, D. Paraskevis, A. Scorilas, E. Kastritis, E.
Andreakos, and M. A. Dimopoulos. 2022. Adverse effects of COVID-19 mRNA vaccines: The
spike hypothesis. Trends in Molecular Medicine 28(7):542–554.
https://doi.org/10.1016/j.molmed.2022.04.007.
Turner, J. S., J. A. O'Halloran, E. Kalaidina, W. Kim, A. J. Schmitz, J. Q. Zhou, T. Lei, M. Thapa, R. E.
Chen, J. B. Case, F. Amanat, A. M. Rauseo, A. Haile, X. Xie, M. K. Klebert, T. Suessen, W. D.
Middleton, P. Y. Shi, F. Krammer, S. A. Teefey, M. S. Diamond, R. M. Presti, and A. H.
Ellebedy. 2021. SARS-CoV-2 mRNA vaccines induce persistent human germinal centre
responses. Nature 596(7870):109–113. https://doi.org/10.1038/s41586-021-03738-2.
Verbeke, R., M. J. Hogan, K. Lore, and N. Pardi. 2022. Innate immune mechanisms of mRNA vaccines.
Immunity 55(11):1993–2005. https://doi.org/10.1016/j.immuni.2022.10.014.
Walls, A. C., Y. J. Park, M. A. Tortorici, A. Wall, A. T. McGuire, and D. Veesler. 2020. Structure,
function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 183(6):1735.
https://doi.org/10.1016/j.cell.2020.11.032.
Walsh, E. E., R. W. Frenck, Jr., A. R. Falsey, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, K. Neuzil,
M. J. Mulligan, R. Bailey, K. A. Swanson, P. Li, K. Koury, W. Kalina, D. Cooper, C. Fontes-
Garfias, P. Y. Shi, O. Tureci, K. R. Tompkins, K. E. Lyke, V. Raabe, P. R. Dormitzer, K. U.
Jansen, U. Sahin, and W. C. Gruber. 2020. Safety and immunogenicity of two RNA-based
COVID-19 vaccine candidates. New England Journal of Medicine 383(25):2439–2450.
https://doi.org/10.1056/NEJMoa2027906.
Watanabe, Y., L. Mendonca, E. R. Allen, A. Howe, M. Lee, J. D. Allen, H. Chawla, D. Pulido, F.
Donnellan, H. Davies, M. Ulaszewska, S. Belij-Rammerstorfer, S. Morris, A. S. Krebs, W.
Dejnirattisai, J. Mongkolsapaya, P. Supasa, G. R. Screaton, C. M. Green, T. Lambe, P. Zhang, S.
C. Gilbert, and M. Crispin. 2021. Native-like SARS-CoV-2 spike glycoprotein expressed by
ChAdOx1 nCoV-19/AZD1222 vaccine. ACS Central Science 7(4):594–602.
https://doi.org/10.1021/acscentsci.1c00080.
Welsh, J. 2021. Coronavirus variants—will new mRNA vaccines meet the challenge? Engineering
7(6):712–714. https://doi.org/10.1016/j.eng.2021.04.005.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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IMMUNOLOGIC RESPONSE 51
PREPUBLICATION COPY: Uncorrected Proofs
Widge, A. T., N. G. Rouphael, L. A. Jackson, E. J. Anderson, P. C. Roberts, M. Makhene, J. D. Chappell,
M. R. Denison, L. J. Stevens, A. J. Pruijssers, A. B. McDermott, B. Flach, B. C. Lin, N. A. Doria-
Rose, S. O’Dell, S. D. Schmidt, K. M. Neuzil, H. Bennett, B. Leav, M. Makowski, J. Albert, K.
Cross, V. V. Edara, K. Floyd, M. S. Suthar, W. Buchanan, C. J. Luke, J. E. Ledgerwood, J. R.
Mascola, B. S. Graham, J. H. Beigel, and mRNA-1273 Study Group 2021. Durability of
responses after SARS-CoV-2 mRNA-1273 vaccination. New England Journal of Medicine
384(1):80–82. https://doi.org/10.1056/NEJMc2032195.
Wilkins, A. L., D. Kazmin, G. Napolitani, E. A. Clutterbuck, B. Pulendran, C. A. Siegrist, and A. J.
Pollard. 2017. AS03- and Mf59-adjuvanted influenza vaccines in children. Frontiers in
Immunology 8:1760. https://doi.org/10.3389/fimmu.2017.01760.
Wrapp, D., N. Wang, K. S. Corbett, J. A. Goldsmith, C. L. Hsieh, O. Abiona, B. S. Graham, and J. S.
McLellan. 2020. Cryo-em structure of the 2019-nCoV spike in the prefusion conformation.
bioRxiv. https://doi.org/10.1101/2020.02.11.944462.
Xiaojie, S., L. Yu, Y. Lei, Y. Guang, and Q. Min. 2020. Neutralizing antibodies targeting SARS-CoV-2
spike protein. Stem Cell Research 50:102125. https://doi.org/10.1016/j.scr.2020.102125.
Yang, G., J. Wang, P. Sun, J. Qin, X. Yang, D. Chen, Y. Zhang, N. Zhong, and Z. Wang. 2023. SARS-
CoV-2 epitope-specific T cells: Immunity response feature, TCR repertoire characteristics and
cross-reactivity. Frontiers in Immunology 14:1146196.
https://doi.org/10.3389/fimmu.2023.1146196.
Zost, S. J., P. Gilchuk, R. E. Chen, J. B. Case, J. X. Reidy, A. Trivette, R. S. Nargi, R. E. Sutton, N.
Suryadevara, E. C. Chen, E. Binshtein, S. Shrihari, M. Ostrowski, H. Y. Chu, J. E. Didier, K. W.
MacRenaris, T. Jones, S. Day, L. Myers, F. Eun-Hyung Lee, D. C. Nguyen, I. Sanz, D. R.
Martinez, P. W. Rothlauf, L. M. Bloyet, S. P. J. Whelan, R. S. Baric, L. B. Thackray, M. S.
Diamond, R. H. Carnahan, and J. E. Crowe, Jr. 2020. Rapid isolation and profiling of a diverse
panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. Nature
Medicine 26(9):1422–1427. https://doi.org/10.1038/s41591-020-0998-x.
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3
Neurologic Conditions and COVID-19 Vaccines
This chapter describes the potential relationship between COVID-19 vaccines and potential
neurological harms Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating
polyneuropathy, Bell’s palsy (BP), transverse myelitis (TM), chronic headache, and postural
orthostatic tachycardia syndrome (POTS) (see Boxes 3-1 through 3-6 for all conclusions in this
chapter).
GUILLAIN-BARRÉ SYNDROME
BOX 3-1
Conclusions for Guillain-Barré syndrome
Conclusion 3-1: The evidence favors rejection of a causal relationship between the
BNT162b2 vaccine and Guillain-Barré syndrome.
Conclusion 3-2: The evidence favors rejection of a causal relationship between the mRNA-
1273 vaccine and Guillain-Barré syndrome.
Conclusion 3-3: The evidence favors acceptance of a causal relationship between the
Ad26.COV2.S vaccine and Guillain-Barré syndrome.
Conclusion 3-4: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and Guillain-Barré syndrome.
Background
GBS is an acute, monophasic, immune-mediated disorder, or group of disorders, that
primarily affects the peripheral nerves and roots. The typical clinical features include progressive
symmetric muscle weakness and absent or depressed deep tendon reflexes. Patients may also
experience tingling or prickling sensations (paresthesia) along with autonomic dysfunction,
including fluctuations in blood pressure, heart rate, and respiratory distress. Cranial nerve
involvement can result in facial weakness, difficulty swallowing, and speech problems, and some
individuals experience significant pain, particularly in the back or legs. Symptoms usually progress
over 1–2 weeks and generally plateau before 4 weeks (Fokke et al., 2014).
Diagnosing GBS is a multifaceted process that involves a comprehensive clinical
evaluation, cerebrospinal fluid (CSF) analysis, and electrodiagnostic studies. A thorough clinical
history and neurological examination are critical to assess the pattern of weakness and reflex
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abnormalities. Analysis of CSF often reveals elevated protein levels without a significant increase
in white blood cells. Electrophysiological tests can confirm the diagnosis by revealing evidence of
nerve demyelination in demyelinating variants of GBS and identifying pathological changes
affecting both the roots and nerves.
GBS is a relatively rare disease, with a global incidence of 0.81–1.91 cases per 100,000
person-years (Shahrizaila et al., 2021). The U.S. incidence of GBS is generally in line with the
global average, with an estimated 1–2 cases per 100,000 individuals each year (Bragazzi et al.,
2021). Although all age groups are affected, the incidence increases by approximately 20 percent
with every 10-year increase beyond the first decade of life, with a peak incidence reported between
50–69 years and a slight male predominance (Leonhard et al., 2022).
The pathophysiology of GBS remains incompletely understood and is likely heterogeneous,
reflecting phenotypic variability among what is likely a group of related disorders rather than a
single nosological entity. Despite this heterogeneity, more than two-thirds of patients report a
history of upper respiratory tract or gastrointestinal infection weeks before the onset of neurologic
symptoms, suggesting infection plays an important pathogenic role in all GBS variants (Leonhard
et al., 2022). Although GBS is a global disease, regional differences occur in the distribution of
variants. Demyelinating forms dominate in Europe and North America, but acute inflammatory
demyelinating polyradiculoneuropathy (AIDP) accounts for 80–90 percent of cases and is
characterized by ascending limb weakness. Other demyelinating variants with prominent and early
cranial nerve involvement affecting eye movements and facial muscles, including the Miller-Fisher
and facial diplegia with limb paresthesia variant, are rare. Axonal subtypes, such as acute motor
axonal neuropathy (AMAN), dominate in Asia, particularly Bangladesh and north China
(Leonhard et al., 2022). Seasonal variation of incidence track with infections. The risk is higher
during the winter, particularly in Europe and North America, where it is associated primarily with
upper respiratory infections. A summer peak occurs in Northern China, India, Bangladesh, and
Latin America, where diarrheal illnesses can be more common. Incidence can also rise during
outbreaks of infection, such as with Zika virus in South America or other arthropod infections,
such as dengue and chikungunya (Shahrizaila et al., 2021). Globally, commonly implicated
pathogens include Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma
pneumoniae, Haemophilus influenzae, influenza A virus, and Zika virus (Shahrizaila et al., 2021).
C. Jejuni is the most commonly and extensively reported, and robust evidence suggests that
molecular mimicry between microbial antigens and nerves is implicated in developing GBS.
In addition to infection, GBS cases after vaccination have also been reported, especially
with the 1976 swine-influenza and seasonal 2009 H1N1 monovalent influenza vaccines. However,
the overall risk of influenza vaccines if present at all appears to be small, approximately 1–2 excess
cases of GBS per million people vaccinated (Vellozzi et al., 2014). While some have reported an
increased risk of GBS after SARS-CoV-2 infection, the actual incidence of GBS decreased during
the pandemic, possibly due to an overall reduction in other communicable diseases (Keddie et al.,
2021).
The latency period between exposure to a triggering event (infection or vaccination) and
GBS can vary, but it typically occurs within a few days to a few weeks. It is crucial to understand
that not everyone exposed to these risk factors will develop GBS, and the exact mechanisms
continue to be the subject of ongoing research. The epidemiology of GBS can be influenced by
various factors, including changes in diagnostic techniques, vaccination practices, and evolving
patterns of infectious diseases, so ongoing surveillance and research are crucial to continually
monitor and understand it.
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Mechanisms
GBS is heterogeneous because it is likely a group of related disorders. Demyelinating
variants, such AIDP, differ from axonal variants, such as AMAN, in both the range and extent of
pathological changes. Nevertheless, nerve injury appears to be immune mediated, with antecedent
infection being a common potential trigger. Autopsy studies demonstrate infiltrates of lymphocytes
and macrophages involved in macrophage-mediated demyelination (Asbury et al., 1969; Wanschitz
et al., 2003). Complement deposition can be demonstrated within the endoneurium, on the surface
of myelinated fibers, and on mononuclear cells at sites of myelin breakdown, particularly in acute
cases of less than 4 weeks duration, suggesting a role for antibody-mediated injury, whereas
granzyme-expressing CD8+ T cells (i.e., cytotoxic T cells) are described in cases of longer
duration (Wanschitz et al., 2003). By contrast, patients with AMAN demonstrate primary axonal
injury with a paucity of inflammatory infiltrates or demyelination. IgG and complement-mediated
humoral immune response are directed against epitopes in the axonal membrane. Animal models of
GBS have been generated by immunizing rats with myelin proteins, galactocerebroside, adoptive
transfer of myelin-specific T cells (AIDP), or immunization with GM1 ganglioside, resulting in
circulating anti-GM1 antibodies (AMAM) (Figure 3-1) (Shahrizaila et al., 2021). These animal
models implicate T cells and macrophages in AIDP but suggest that autoantibodies may play a
greater role in AMAM (Shahrizaila et al., 2021). The mechanism of antibody-mediated damage
may include interference with ion channel function, complement-dependent cytotoxicity, and/or
interference with nerve regeneration; different clinical subtypes of GBS are associated with
different anti-ganglioside antibodies (Shahrizaila et al., 2021).
FIGURE 3-1 Overview of the pathogenesis and therapeutic targets of the two major Guillain-Barré
syndrome subtypes.
SOURCE: Shahrizaila et al., 2021.
Evidence for molecular mimicry is best supported for C. jejuni-associated AMAN, where
the reasoning is as follows (Yuki et al., 2004):
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
56 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
● Patients with GBS after C. jejuni, but not patients with C. jejuni enteritis, have
antibodies to GM1 ganglioside in their serum (Sheikh et al., 1998).
● The specific serotype of C. jejuni most commonly isolated from patients with GBS
(PEN19) is rare in patients with C. jejuni enteritis.
● The GM1 ganglioside has an antigenic similarity with the lipopolysaccharide of C.
jejuni serotype PEN19 (Yuki et al., 1993).
● Rabbits sensitized to C. jejuni LPS develop AMAM and flaccid limb weakness with
pathological findings similar to GBS.
● Anti-GM1 IgG from patients with GBS can block muscle action potentials in muscle-
spinal cord coculture, although they do not induce weakness when injected into mice
(Yuki et al., 2004).
C. jejuni infection can also generate antibodies against GQ1b gangliosides, which are
associated with the Miller-Fisher GBS variant (Jacobs et al., 1997). Anti-ganglioside antibodies,
however, are not found in association with all GBS variants. In addition, as mentioned in the
background section, GBS is associated with a variety of pathogens, including potentially SARS-
CoV-2, arguing against molecular mimicry as the single unifying mechanism in all forms of it.
A few in silico studies have sought peptide antigens in SARS-CoV-2 with the potential to
induce antibodies that cross-react with proteins in the peripheral or central nervous system, thereby
activating complement and mediating neuronal damage (Chen et al., 2022b; Kadkhoda, 2022). One
such study demonstrated similarity between a peptide in SARS-CoV2 and the NCAM L1–like
protein in the myelin sheath and argued that cross-reactive antibodies might explain GBS after
infection (Kadkhoda, 2022; Morsy, 2020). However, the shared peptide was in the SARS-CoV-2
envelope protein, not the spike protein, and would not provide mechanistic evidence for GBS
occurring after COVID-19 vaccination.
Epidemiological evidence suggests a possible association between adenoviral vector (AV)
COVID-19 vaccines and GBS but not for the messenger ribonucleic acid (mRNA) vaccines
(Hanson et al., 2022; Keh et al., 2023). This suggests the possibility of a platform-specific
mechanism or immune response as opposed to one related to immune responses to the spike
protein itself (such as molecular mimicry) (Rzymski, 2023). One study found high levels of
complement-fixing antibodies to cytomegalovirus in a cohort of patients with GBS but no
comparable antibodies to adenovirus in the same patients (Dowling et al., 1977), and adenovirus
has not been historically linked with GBS in epidemiological studies. This suggests that natural
adenoviral infection may not be associated with GBS.
ChAdOx1-S 1 has high affinity for the coxsackie and adenoviral receptor (CAR), whereas
HAdV26 has much lower CAR affinity (Baker et al., 2021; Hemsath et al., 2022; Rzymski, 2023).
CAR is widely expressed in the body, including the central nervous system (Zussy et al., 2016);
however, whether it is expressed in the peripheral nervous system has not been established.
Therefore, it is unknown whether ChAdOx1-S could target peripheral nerves directly.
Epidemiological Evidence
Clinical trial results submitted to FDA for Emergency Use Authorization and full approval
do not indicate a signal regarding GBS and any of the vaccines under study (FDA, 2021, 2023a,
2023b, 2023c). Table 3-1 presents eight studies that contributed to the causality assessment.
1 Refers to the COVID-19 vaccine manufactured by Oxford-AstraZeneca.
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,
2
0
2
2
.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 63
PREPUBLICATION COPY—Uncorrected Proofs
Keh et al. (2023) retrospectively analyzed data from the National Immunoglobulin
Database linked to the National Immunisation Management System, which records all intravenous
immunoglobulin (IVIg) prescriptions for GBS patients in England (IVIg is given to an estimated
86 percent of UK patients with GBS). IVIg approval requires adjudication by an independent
physician panel (Keh et al., 2023). The study included 11.5 million doses of BNT162b2 2 and
300,000 doses of mRNA-1273.3 Of 196 postvaccinal cases, 21 occurred with BNT162b2 and one
with mRNA-1273. Using case numbers from days 43–84 after first-dose vaccination as a
comparison group, the first 42 days postvaccination with BNT162b2 had no excess risk of GBS
(Keh et al., 2023).
Patone et al. (2021) investigated the association between BNT162b2 and GBS among 32.6
million vaccinees, 12.1 million of whom received BNT162b2. This retrospective self-controlled
cohort study compared the incidence rate of GBS in England at several intervals (1–7, 8–14, 15–
21, 22–28, and 1–28 days after vaccination) with the rate of GBS during periods outside of this
interval. GBS was defined using International Classification of Diseases 10 (ICD-10) codes and
identified as the first hospital admission or as a cause of death recorded on the death certificate.
Vaccination status was identified in the English National Immunisation Database of COVID-19
vaccination. Only 34 cases of GBS were observed for BNT162b2 during the risk interval. The
study found no association between BNT162b2 and GBS at any interval, including the 1–28-day
period; incidence rate ratio (IRR) 0.86 (95% confidence interval [CI]: 0.54–1.36) (Patone et al.,
2021). The results do not suggest increased incidence, but the estimate is imprecise; the results are
consistent with no association but could also be consistent with a small increased risk (Patone et
al., 2021).
Klein et al. (2021) conducted a surveillance study within the Vaccine Safety Datalink
(VSD), which includes data from eight U.S. integrated health care organizations with electronic
health records. They compared incidence of GBS among vaccine recipients 1–21 days after either
dose 1 or 2 of a messenger ribonucleic acid (mRNA) vaccine with that of concurrent comparators
who, on the same calendar day, had received their most recent dose 22–42 days earlier. After 11.8
million doses (57 percent BNT162b2), 10 GBS cases were identified in the risk interval compared
with six in the controlled interval, RR 0.70 (95% CI: 0.22–2.31) (Klein et al., 2021). Few events
were observed, so the authors were unable to precisely estimate the measure of association. The
results would be consistent with no association but could also be consistent with a small increase in
risk.
Hanson et al. (2022) also analyzed data from VSD. In their primary analysis, they
compared the incidence of GBS cases among vaccine recipients at two time intervals, 1–21 and 1–
42 days with that of vaccinated concurrent comparators, who, on the same calendar day, had
received their most recent dose 22–42 and 43–84 days earlier, respectively. In addition, incidence
of GBS for individual vaccines was compared to prepandemic historical background rate (Hanson
et al., 2022). GBS cases were physician adjudicated according to Brighton Collaboration criteria
(Sejvar et al., 2011), and the analysis included Brighton Criteria 1–4. Level 1 has the highest level
of diagnostic certainty; Level 4 includes suspected cases. The study included 14.6 million doses of
mRNA vaccines (BNT162b2 or mRNA-1273) and 483,053 doses of Ad26.COV2.S.4 During the
1–84 days following mRNA vaccines, 36 cases of GBS were confirmed, with nine cases meeting
Brighton criteria 1–3 in the 1–21 days risk period. Eleven cases of GBS were confirmed 1–84 days
2 Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®.
3 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®.
4 Refers to the COVID-19 vaccine manufactured by Janssen.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
64 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
after Ad.26.COV2.S, with eight cases meeting Brighton criteria 1–3 in the 1–21 days period. Scan
statistics identified days 1–14 after vaccination as a statistically significant cluster (p = .003). In a
comparison of Ad26.COV2.S and mRNA vaccines, the adjusted rate ratio in the 1–21 days risk
period was 20.56 (95% CI: 6.94–64.66) (Hanson et al., 2022). No association appeared between
GBS and any of the vaccines based on the comparison with unvaccinated comparators (Hanson et
al., 2022). However, the unadjusted incidence rate at 1–21 and 1–42 days after Ad26.COV2.S was
higher than the historical background rate (p < .001). Excluding Brighton Level 4 cases did not
significantly alter results.
Sturkenboom et al. (2022) conducted a cross-national multi-database retrospective dynamic
cohort study using primary and/or secondary health care data from four European countries: Italy,
the Netherlands, the United Kingdom, and Spain. They compared the incidence of GBS in vaccine
recipients with nonvaccinated persons in 2020 within 28 days after each dose. Of 25.7 million
people, 16 GBS cases were identified after BNT162b2, two after Ad26.COV2.S, and none after
mRNA-1273. They found an increased risk of GBS 28 days after Ad26.COV2.S (IRR 5.65, 95%
CI: 1.40–22.83), but no increased risk after BNT162b2 (IRR 1.10, 95% CI: 0.56–2.15). Results for
BNT162b2 suggest no association, but the authors were unable to precisely estimate risk, and
results could also be consistent with a small increase in risk (Sturkenboom et al., 2022).
Walker et al. (2022) analyzed primary care data from over 17 million patients in England
linked to emergency care, hospital admission, and mortality records in OpenSAFELY, which is a
secure analytics platform for the National Health Service electronic health records. They used a
self-controlled case-series analytical approach where the risk interval was 4–28 days after
vaccination. Among 5.7 million recipients of BNT162b2, 283 GBS cases were identified during
the risk and controlled intervals; none were identified among 255,446 recipients of mRNA-1273.
The results from the study suggested no association between the first dose of BNT162b2 and GBS,
although the measure was imprecise and could suggest a small increase in risk (IRR 1.09, 95% CI:
0.75–1.57). Adjusting for calendar time and history of COVID-19 infection did not significantly
change the measure of association (IRR 1.00, 95% CI: 0.61–1.64).
Li et al. (2022) compared rates of GBS identified through medical records among vaccinees
with historical background rates. They used the Clinical Practice Research Datalink (CPRD)
AURUM, which contains routinely collected data from UK primary care practices and Spain’s
Information System for Research in Primary Care (SIDIAP), a primary care database that covers
80 percent of the population in Catalonia. The study included 3.6 million people who received
BNT162b2, 244,913 who received mRNA-1273, 120,731 who received Ad26.CoV.2.S, and 14.3
million people from the general population (Li et al., 2022). Of the BNT162b2 vaccinees, <5 cases
occurred within 1–21 days after a first and second dose in CPRD AURUM, compared with 10.4
and 9 expected. SIDIAP showed five cases after the first dose of BNT162b2 and <5 cases after the
second dose, compared with 6.3 and 5.3 expected, respectively. For mRNA-1273, <5 cases were
diagnosed after the second dose compared with 0.7 expected. No cases were observed with the first
dose of mRNA-1273 or after Ad26.COV2.S (Li et al., 2022).
Morciano et al. (2023) investigated the association between COVID-19 vaccines and GBS
in the population older than 12 years using a self-controlled case-series design with data from
several regional health care databases in Italy. They evaluated relative incidence (RI) of GBS
during a risk interval of 0–42 days after vaccination and an unexposed interval defined as any time
of observation before, between, or after the risk intervals. Of 1.7 million individuals who received
mRNA-1273, 25 developed GBS during the study period, with seven and five cases observed with
the first and second doses, respectively, during the risk interval (RI 6.83, 95% CI: 2.14–21.85 for
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 65
PREPUBLICATION COPY—Uncorrected Proofs
dose 1 and RI 7.41, 95% CI: 2.35–23.38 for dose 2) (Morciano et al., 2023). This corresponded
with an estimated 0.4 and 0.3 excess number of cases per 100,000 vaccinated for doses 1 and 2,
respectively. The RI of GBS was not significantly increased in the 10.8 million and 581,796
individuals who received BNT162b and Ad26.COV2.S (Morciano et al., 2023).
Loo et al. (2022) conducted a retrospective case-control study of all patients admitted for
acute polyradiculoneuropathy to two UK neuroscience centers between January 1 and June 30,
2021. They compared vaccinees from the preceding 4 weeks to all GBS patients admitted to their
centers between 2005 and 2019. A 2.6-fold (95% CI: 1.98–3.51) increase in admissions for GBS
was noted during the time frame, compared to the same period in the preceding 3 years. Of 24 GBS
patients, 16 were postvaccine, and all but two (one BNT162b, one mRNA-1273) occurred after
ChAdOx1-S (Loo et al., 2022).
Although some studies relied on physician adjudication for case ascertainment (Hanson et
al., 2022; Keh et al., 2023; Loo et al., 2022), others relied on ICD codes from electronic data
without chart confirmation. Some GBS cases identified by the ICD codes might not be true cases,
which could have biased the measure of association. In addition, some studies used historical
cohorts as a comparator group. Several studies have shown that annual GBS incidence decreased
during the pandemic, which could have biased the measure of association.
Pharmacovigilance and Surveillance
Table 3-2 presents five pharmacovigilance studies that contributed to the committee’s
assessment based on their size, design, analytic approach, and region surveilled.
Ev
i
d
e
n
c
e
R
e
v
i
e
w
o
f
t
h
e
A
d
v
e
r
s
e
E
f
f
e
c
t
s
o
f
C
O
V
I
D
-
1
9
V
a
c
c
i
n
a
t
i
o
n
a
n
d
I
n
t
r
a
m
u
s
c
u
l
a
r
V
a
c
c
i
n
e
A
d
m
i
n
i
s
t
r
a
t
i
o
n
Co
p
y
r
i
g
h
t
N
a
t
i
o
n
a
l
A
c
a
d
e
m
y
o
f
S
c
i
e
n
c
e
s
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
66
VA
C
C
I
N
E
E
V
I
D
E
N
C
E
R
E
V
I
E
W
PR
E
P
U
B
L
I
C
A
T
I
O
N
C
O
P
Y
—Un
c
o
r
r
e
c
t
e
d
P
r
o
o
f
s
TA
B
L
E
3
-2
Ph
a
r
m
a
c
o
v
i
g
i
l
a
n
c
e
S
t
u
d
i
e
s
i
n
t
h
e
G
u
i
l
l
a
i
n
-Ba
r
r
é
S
y
n
d
r
o
m
e
E
v
i
d
e
n
c
e
R
e
v
i
e
w
Au
t
h
o
r
St
u
d
y
De
s
i
g
n
a
n
d
Co
n
t
r
o
l
Gr
o
u
p
Lo
c
a
t
i
o
n
Da
t
a
S
o
u
r
c
e
Va
c
c
i
n
e
(
s
)
Ag
e
Ran
g
e
N
Nu
m
b
e
r
o
f
Ev
e
n
t
s
Re
s
u
l
t
s
(9
5
%
C
I
)
Ab
a
r
a
e
t
a
l
.
(2
0
2
3
)
Co
h
o
r
t
/
hi
s
t
o
r
i
c
a
l
ba
c
k
g
r
o
u
n
d
US
VA
E
R
S
(p
h
y
s
i
c
i
a
n
ad
j
u
d
i
c
a
t
e
d
)
BN
T
1
6
2
b
2
≥1
8
ye
a
r
s
26
6
.
9
mi
l
l
i
o
n
do
s
e
s
21
d
a
y
s
:
2
0
9
42
d
a
y
s
:
2
5
3
O:
E
<
1
mR
N
A
-12
7
3
20
2
.
8
mi
l
l
i
o
n
do
s
e
s
O:
E
<
1
Ad
2
6
.
C
O
V
2
.
S
17
.
9
mi
l
l
i
o
n
do
s
e
s
1–21
d
a
y
s
O:
E
3
.
7
9
(
2
.
8
8
–4.
8
8
)
1–42
d
a
y
s
O:
E
2
.
3
4
(
1
.
8
3
–2.
9
4
)
Ga
r
c
i
a
-
Gr
i
m
s
h
a
w
e
t
al
.
(
2
0
2
2
)
Co
h
o
r
t
/
hi
s
t
o
r
i
c
a
l
ba
c
k
g
r
o
u
n
d
Me
x
i
c
o
Me
x
i
c
a
n
Ep
i
d
e
m
i
o
l
o
g
ic
a
l
Su
r
v
e
i
l
l
a
n
c
e
Sy
s
t
e
m
/
EM
R
(p
h
y
s
i
c
i
a
n
ad
j
u
d
i
c
a
t
e
d
)
BN
T
1
6
2
b
2
≥1
8
ye
a
r
s
16
.
6
mi
l
l
i
o
n
do
s
e
s
32
Un
a
d
j
u
s
t
e
d
I
n
c
i
d
e
n
c
e
1.
9
2
(
1
.
3
6
– 2.
7
1
)
mR
N
A
- 12
7
3
2.
3
mi
l
l
i
o
n
do
s
e
s
3
Un
a
d
j
u
s
t
e
d
I
n
c
i
d
e
n
c
e
1.
2
9
(
0
.
4
4
–3.
8
1
)
Ad
2
6
.
C
O
V
2
.
S
1.
0
mi
l
l
i
o
n
do
s
e
s
4
Un
a
d
j
u
s
t
e
d
I
n
c
i
d
e
n
c
e
3.
8
6
(
1
.
5
0
–9.
9
3
)
Ch
A
d
O
x
1
-S
38
.
5
mi
l
l
i
o
n
do
s
e
s
37
Un
a
d
j
u
s
t
e
d
i
n
c
i
d
e
n
c
e
0.
9
6
(
0
.
7
0
–1.
3
2
)
Ev
i
d
e
n
c
e
R
e
v
i
e
w
o
f
t
h
e
A
d
v
e
r
s
e
E
f
f
e
c
t
s
o
f
C
O
V
I
D
-
1
9
V
a
c
c
i
n
a
t
i
o
n
a
n
d
I
n
t
r
a
m
u
s
c
u
l
a
r
V
a
c
c
i
n
e
A
d
m
i
n
i
s
t
r
a
t
i
o
n
Co
p
y
r
i
g
h
t
N
a
t
i
o
n
a
l
A
c
a
d
e
m
y
o
f
S
c
i
e
n
c
e
s
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
NE
U
R
O
L
O
G
I
C
CO
N
D
I
T
I
O
N
S
67
PR
E
P
U
B
L
I
C
A
T
I
O
N
C
O
P
Y
—Un
c
o
r
r
e
c
t
e
d
P
r
o
o
f
s
TA
B
L
E
3
-2
Co
n
t
i
n
u
e
d
Au
t
h
o
r
St
u
d
y
De
s
i
g
n
a
n
d
Co
n
t
r
o
l
Gr
o
u
p
Lo
c
a
t
i
o
n
Da
t
a
S
o
u
r
c
e
Va
c
c
i
n
e
(
s
)
Ag
e
ra
n
g
e
N
Nu
m
b
e
r
o
f
Ev
e
n
t
s
Re
s
u
l
t
s
(9
5
%
C
I
)
Ha
e
t
a
l
.
(2
0
2
3
)
Co
h
o
r
t
So
u
t
h
Ko
r
e
a
Gy
e
o
n
g
g
i
In
f
e
c
t
i
o
u
s
Di
s
e
a
s
e
Co
n
t
r
o
l
Ce
n
t
e
r
/
EM
R
(p
h
y
s
i
c
i
a
n
ad
j
u
d
i
c
a
t
e
d
)
BN
T
1
6
2
b
,
mR
N
A
-12
7
3
,
Ad
2
6
.
C
O
V
2
.
S
≥1
2
ye
a
r
s
38
.
8
mi
l
l
i
o
n
do
s
e
s
mR
N
A
va
c
c
i
n
e
s
:
2
6
ca
s
e
s
Ad
e
n
o
v
i
r
u
s
-
ve
c
t
o
r
e
d
va
c
c
i
n
e
s
:
2
9
ca
s
e
s
mR
N
A
va
c
c
i
n
e
s
I
R
0.
8
0
p
e
r
m
i
l
l
i
o
n
d
o
s
e
s
(0
.
4
9
–1.
1
1
)
Ad
e
n
o
v
i
r
u
s
-ve
c
t
o
r
e
d
I
R
4.
4
9
p
e
r
m
i
l
l
i
o
n
d
o
s
e
s
(2
.
8
5
–6.
1
2
)
Pe
g
a
t
e
t
a
l
.
(2
0
2
1
)
Co
h
o
r
t
/
m
R
NA
va
c
c
i
n
e
s
t
o
Ad
e
n
o
v
i
r
u
s
- ve
c
t
o
r
e
d
va
c
c
i
n
e
s
US
,
U
K
,
Eu
r
o
p
e
Vi
g
i
B
a
s
e
(p
h
y
s
i
c
i
a
n
ad
j
u
d
i
c
a
t
e
d
)
BN
T
1
6
2
b
,
mR
N
A
-12
7
3
,
Ad
2
6
.
C
O
V
2
.
S
,
Ch
A
d
O
x
1
No
t
st
a
t
e
d
48
8
m
R
N
A
va
c
c
i
n
e
s
va
c
c
i
n
e
e
s
78
8
Ad
e
n
o
v
i
r
u
s
-ve
c
t
o
r
e
d
va
c
c
i
n
e
s
va
c
c
i
n
e
e
s
14
2
/
1
,
2
5
6
of
G
B
S
c
a
s
e
s
wi
t
h
f
a
c
i
a
l
pa
r
e
s
i
s
(
2
6
mR
N
A
va
c
c
i
n
e
s
,
28
ad
e
n
o
v
i
r
u
s
-
ve
c
t
o
r
e
d
)
Fa
c
i
a
l
p
a
r
e
s
i
s
m
o
r
e
f
r
e
q
u
e
n
t
wi
t
h
a
d
e
n
o
v
i
r
u
s
v
e
c
t
o
r
e
d
va
c
c
i
n
e
s
Ta
k
u
v
a
e
t
al
.
(
2
0
2
1
)
Op
e
n
-la
b
e
l
ph
a
s
e
3
b
im
p
l
e
m
e
n
t
a
ti
o
n
s
t
u
d
y
/
hi
s
t
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 69
PREPUBLICATION COPY—Uncorrected Proofs
Abara et al. (2023) analyzed data from the Vaccine Adverse Event Reporting System,
which is comanaged by the Centers for Disease Control and Prevention and Food and Drug
Administration. Of 487.7 million COVID-19 vaccine doses, 209 and 253 reports of GBS
occurred within 21 and 42 days, respectively. Observed-to-expected ratios (O:E) were 3.79 (95%
CI: 2.88–4.88) for days 1–21 and 2.34 (95% CI: 1.83–2.94) for days 1–42 after Ad26.COV2.S
and less than 1 (not significantly increased) after BNT162b2 and mRNA-1273 for both
postvaccination periods (Abara et al., 2023).
Pegat et al. (2022) analyzed data from VigiBase, the World Health Organization
pharmacovigilance database, and the French pharmacovigilance database to compare the
frequency of facial paralysis in GBS cases after adenovirus-vector (AV) vaccines to that after
mRNA vaccines and found that 142 of 1,256 GBS patients in VigiBase had associated facial
paralysis (11.3 percent). This included 26 of 488 who received mRNA vaccines (12/328
BNT162b2, 14/160 mRNA-1273), 114 of 744 who received AV vaccines (28/114
Ad26.COV2.S, 86/630 ChAdOx1-S), and 2 of 24 who received other vaccines. Facial paralysis
was significantly more frequent after AV vaccines (χ2: p = 6.44 × 10−8) (Pegat et al., 2022).
García-Grimshaw et al. (2022) conducted a retrospective analysis of a nationwide passive
registry of GBS among recipients of 81.8 million doses of seven COVID-19 vaccines in Mexico.
The overall observed incidence was 1.19 per 1 million doses (95% CI: 0.97–1.45), which was
higher for Ad26.COV2.S (3.86 per 1 million doses, 95% CI: 1.50–9.93) and BNT162b2 (1.92
per 1 million doses, 95% CI: 1.36–2.71) (García-Grimshaw et al., 2022).
Ha et al. (2023) conducted a prospective regional surveillance study for GBS in the
Gyeonggi Province, South Korea. Out of 38.8 million vaccine doses, 55 cases of physician
adjudicated GBS were identified. The incidence rate of GBS after AV vaccines (Ad26.COV2.S,
ChAdOx1-S) was 4.49 per million doses (95% CI: 2.85–6.12), compared to 0.80 per million
doses after mRNA vaccines (BNT162b2, mRNA-1273) (95% CI: 0.49–1.11) (Ha et al., 2023).
Takuva et al. (2022) evaluated the incidence rate of GBS in all health care workers in
South Africa registered in the national Electronic Vaccination Data System after receiving
Ad26.COV2.S. Four cases of GBS were recorded, with an observed-to-expected ratio of 5.09
(95% CI: 1.39–13.02) (Takuva et al., 2022).
From Evidence to Conclusions
The totality of the evidence included several large studies that minimized confounding
bias by using self-controlled or concurrent cohort design or by relying on chart review for case
ascertainment; none of the epidemiological studies reported a significant risk of GBS after
BNT162b2. This is reinforced by the pharmacovigilance data; although they were more prone to
confounding bias, multiple large studies surveilling different population cohorts worldwide
consistently identified an increased risk with AV but not mRNA vaccines despite potential
differing coding trends, seasonality, co-infections, and co-administration of other vaccines.
Conclusion 3-1: The evidence favors rejection of a causal relationship between the
BNT162b2 vaccine and Guillain-Barré syndrome.
In general, relatively few mRNA-1273 doses were included in the studies. Only one
study reported an increased risk of GBS after the first and second dose, although the CIs for the
measure of association were very wide (Morciano et al., 2023). The study also reported that the
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
70 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
excess number of cases was very small (<1 case per 100,000 doses). Morciano et al. (2023) was
the only study to utilize the relatively longer risk period of 0–42 days without relying on chart
review for case ascertainment. Although the study used a self-controlled strategy to minimize
bias, its reliance on ICD codes combined with the prolonged risk interval may have led to
inclusion of some historical cases rather than true incident cases. Two other studies included a
larger number of vaccines and used a vaccinated concurrent cohort design (Hanson et al., 2022;
Klein et al., 2021). As noted, the pharmacovigilance data also favored lack of an association
between GBS and the mRNA vaccines, and the platforms used in mRNA-1273 and BNT162b2
are similar. Additionally, strong mechanistic evidence linking mRNA vaccines to GBS is
lacking.
Conclusion 3-2: The evidence favors rejection of a causal relationship between the
mRNA-1273 vaccine and Guillain-Barré syndrome.
Four epidemiology studies included patients who received Ad26.COV2.S. One study
found an increased risk of GBS compared to a historical cohort, even though it did not find an
association in its primary analysis, which used a vaccinated concurrent cohort design (Hanson et
al., 2022). Unlike other studies reviewed, cases were physician adjudicated according to
Brighton Criteria, and the increased risk was still observed when Level 4 cases (suspected GBS)
were excluded. Although the analysis included two risk periods, 1–21 and 1–42 days, the vast
majority of cases occurred in the first period, which is in keeping with expected latency based on
historical precedent and presumed mechanism. Sturkenboom et al. (2022) also found an
increased risk when comparing Ad26.COV2.S recipients with a 2020 cohort of unvaccinated
individuals, although the total number of events was small and the CI wide. No association was
observed in the other two studies (Li et al., 2022; Morciano et al., 2023). Li et al. had a
comparatively low number of vaccinees.
Although ChAdOx1-S was not formally within the purview of the committee, five of the
studies observed an increased risk of GBS (Keh et al., 2023; Loo et al., 2022; Morciano et al.,
2023; Patone et al., 2021; Walker et al., 2022). These included studies with a large number of
participants and designs that minimize confounding bias. Additionally, two studies reported a
higher rate of the facial paresis variant in patients who received either AV vaccine compared to
historical cohorts (Hanson et al., 2022; Loo et al., 2022). This trend was not observed in Keh et
al. (2023) despite reporting an increased risk of GBS after ChAdOx1-S. Evidence from
pharmacovigilance databases spanning different regions worldwide also documented an
increased risk with the AV vaccines, and one study (Pegat et al., 2022) observed an increased
rate of facial paresis associated with AV but not mRNA vaccines.
The epidemiological association between GBS and ChAdOx1-S but not mRNA vaccines
suggests that the mechanism is unlikely to relate to immune responses to the spike protein itself.
In addition, the reported increased rates of a rare variant (facial paresis) after vaccination with
both related, albeit not identical, AV vaccines suggest a potential shared mechanism, although no
definitive one was identified by the committee in the mechanistic literature, and this pattern was
not observed in all studies. Differences in the AV platforms and their respective receptor,
however, should give pause when extrapolating from one such vaccine to another.
The totality of evidence for Ad26.COV2.S includes two well-designed, positive
epidemiological studies and pharmacovigilance data, strong supporting epidemiological evidence
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 71
PREPUBLICATION COPY—Uncorrected Proofs
from ChAdOx1-S, and the potential for a platform-specific mechanism in both AV vaccines. No
epidemiological literature evaluated the relationship between NVX-CoV2373 5 and GBS.
Conclusion 3-3: The evidence favors acceptance of a causal relationship between the
Ad26.COV2.S vaccine and Guillain-Barré syndrome.
Conclusion 3-4: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and Guillain-Barré syndrome.
5 Refers to the COVID-19 vaccine manufactured by Novavax.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
72 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY
BOX 3-2
Conclusions for Chronic Inflammatory Demyelinating Polyneuropathy
Conclusion 3-5: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and chronic inflammatory demyelinating polyneuropathy.
Conclusion 3-6: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and chronic inflammatory demyelinating
polyneuropathy.
Conclusion 3-7: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and chronic inflammatory demyelinating
polyneuropathy.
Conclusion 3-8: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and chronic inflammatory demyelinating
polyneuropathy.
Background
Chronic inflammatory demyelinating polyneuropathy (CIDP), also known as “chronic
inflammatory demyelinating polyradiculoneuropathy,” is an acquired, immune-mediated
disorder affecting the peripheral nerve and roots. As with GBS, CIDP is now considered a group
of disorders all sharing clinical and electrodiagnostic features but with probable heterogenous
underlying mechanisms. Typical CIDP, the most prevalent CIDP variant, accounts for 50–60
percent of cases, presents as relapsing-remitting or gradually progressive symmetric limb
weakness over a period of months. Sensory loss is common, and deep tendon reflexes are absent
or reduced. Cranial nerve involvement occurs in 10–20 percent of cases. Acute onset resembling
GBS can occur in 5–16 percent of cases but, unlike GBS, where symptom progression ends
within 4 weeks, symptoms continue to progress beyond 8 weeks (McCombe et al., 1987; Thomas
et al., 1987) (a minimum of 2 months of symptoms is required to make the diagnosis per CIDP
diagnostic criteria; Van den Bergh et al., 2010).
The reported incidence of CIDP is 0.3–1.6 cases per 100,000 person-years (Laughlin et
al., 2009), with a male predominance and incidence rising with advancing age and some studies
reporting a mean age at presentation of 60 years (Hafsteinsdottir and Olafsson, 2016).
Electrodiagnostic evidence of nerve demyelination and elevated CSF protein with a normal
leukocyte count supports the diagnosis. A nerve biopsy demonstrating segmental demyelination
with or without inflammation can be diagnostic but is rarely needed. CIDP variants are
recognized, and their distinctive clinical characteristics are included in European Academy of
Neurology/Peripheral Nerve Society diagnostic criteria (Van den Bergh et al., 2021). These
include typical, distal (or distal acquired demyelinating distal neuropathy), multifocal (or
multifocal acquired demyelinating sensory and motor neuropathy), focal, motor, and sensory
CIDP (Van den Bergh et al., 2021). Definitions of what constitute CIDP continue to evolve, and
certain conditions classed as CIDP variants in the past, including chronic immune sensory
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 73
PREPUBLICATION COPY—Uncorrected Proofs
polyradiculopathy and the autoimmune paranodopathies, were excluded from the most recent
criteria because the underlying nerve injury is not definitively demyelinating.
Mechanisms
Although the pathophysiology of CIDP and its variants is not known, evidence supports
an immune-mediated mechanism as the main cause. Characteristic features include segmental
demyelination and remyelination and varying degrees of endoneurial macrophage infiltration
(Dalakas, 2011). Levels of T helper 17 cells are increased in the peripheral blood and CSF, as are
levels of soluble adhesion molecules, chemokines, and metalloproteinases (Dalakas, 2011). The
apparent effectiveness of plasmapheresis, which purportedly removes pathogenic antibodies
along with other inflammatory mediators, suggests that circulating humoral factors and
autoantibodies may be involved. Complement fixation on the myelin sheath of nerves of some
with CIDP also suggests a potential antibody-mediated mechanism (Dalakas and Engel, 1980).
Antibodies directed against nodal and paranodal proteins, such as contactin-1, and neurofascin
isoforms, are found in a subset of patients with clinical features suggestive of CIDP. However,
nerve biopsies in these patients do not show the distinctive features of CIDP, and this is now
considered a separate entity (autoimmune paranodopathies) (Van den Bergh et al., 2021).
One study identified potentially cross-reactive epitopes shared between the SARS-CoV-2
spike protein and neuronal structures using a bioinformatics approach (Felipe Cuspoca et al.,
2022), suggesting that molecular mimicry as a cause of potential neurological harms of COVID-
19 vaccines is plausible, but evidence supporting this hypothesis is lacking.
Epidemiological Evidence
Clinical trial results submitted to FDA for Emergency Use Authorization and/or full
approval do not indicate a signal regarding CIDP and any of the vaccines under study (FDA,
2021, 2023a, 2023b, 2023c). Table 3-3 summarizes one study that contributed to the causality
assessment.
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2
.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 75
PREPUBLICATION COPY—Uncorrected Proofs
Loo et al. (2021) conducted a retrospective case-control study of all patients admitted
with acute-onset polyradiculoneuropathy to two UK neuroscience centers, January 1–June 30,
2021. Of 24 GBS patients, 16 were postvaccination and all but two (1 BNT162b, 1 mRNA-1273)
were after ChAdOx1-S. Four cases initially classified as GBS were eventually reclassified as
acute-onset CIDP due to progression or relapse past 8 weeks from onset; all four had received
ChAdOx1-S.6
From Evidence to Conclusions
Epidemiological and mechanistic evidence are absent. Only one small case-control study
evaluated the association between COVID-19 vaccines and CIDP; four cases initially classified
as GBS were later reclassified as acute-onset CIDP, and no historical background rate was
offered for comparison.
Conclusion 3-5: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and chronic inflammatory demyelinating
polyneuropathy.
Conclusion 3-6: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1723 vaccine and chronic inflammatory demyelinating
polyneuropathy.
Conclusion 3-7: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and chronic inflammatory demyelinating
polyneuropathy.
Conclusion 3-8: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and chronic inflammatory demyelinating
polyneuropathy.
6 ChAdOx1-S refers to the COVID-19 vaccine manufactured by Oxford-AstraZeneca.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
76 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
BELL’S PALSY
BOX 3-3
Conclusions for Bell’s Palsy
Conclusion 3-9: The evidence favors rejection of a causal relationship between the
BNT162b2 vaccine and Bell’s Palsy.
Conclusion 3-10: The evidence favors rejection of a causal relationship between the
mRNA-1273 vaccine and Bell’s Palsy.
Conclusion 3-11: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and Bell’s Palsy.
Conclusion 3-12: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and Bell’s Palsy.
Background
BP is an idiopathic, unilateral, self-limited, acute facial nerve paresis or paralysis. It
occurs with equal frequency on either side of the face and usually resolves within weeks or
months. It can lead to severe temporary oral insufficiency and an incapability to close the
eyelids, resulting in potentially permanent eye injury. In approximately 25 percent of patients,
moderate-to-severe facial asymmetry may persist and affect quality of life (Zhang et al., 2020b).
BP is the most common acute mononeuropathy (Zhang et al., 2020b), with an incidence
of 11.5–53.3 per 100,000 person-years (Baugh et al., 2013). It is estimated that every year, about
40,000 U.S. people are affected (NORD, 2022). The risk factors are poorly understood. Risk may
increase with age, but no indication exists that one sex or geographical area is more at risk (Kim
and Park, 2021). BP symptoms typically develop quickly, with maximum symptoms occurring
within 72 hours (W. Zhang et al., 2020).
Mechanisms
The etiology of BP is unknown, but theories fall into five categories: anatomical, viral,
ischemic, inflammatory, and due to cold exposure (based on season or local climate) (W. Zhang
et al., 2020). When considering the possibility of a vaccine trigger of BP, it is unlikely that
anatomy, ischemia, or cold stimulation would play a role.
Evidence supporting inflammation includes demonstrated gadolinium enhancement of the
facial nerve on MRI of the brain and CSF pleocytosis in many patients with BP (Steiner and
Mattan, 1999). Histopathology from one autopsy study demonstrated a lymphohistiocytic
infiltrate within all layers of the nerve and inflammation that extended to the geniculate ganglion
but spared most ganglion cells (Liston and Kleid, 1989).
Infection may be a cause of BP. Infectious facial palsy has been most clearly linked to
Borrelia burgdorferi (the bacteria that causes Lyme disease), and varicella zoster virus
reactivation (Ramsay Hunt syndrome). Many have argued for a link between herpes simplex
virus type 1 (HSV-1) reactivation and BP (W. Zhang et al., 2020), and acyclovir is routinely
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 77
PREPUBLICATION COPY—Uncorrected Proofs
prescribed to patients with BP. Arguments against a pathophysiological role for HSV-1 include
that it resides in the peripheral sensory ganglia and reactivation is not associated with motor
weakness, that it tends to recur, whereas BP tends to be monophasic, and that HSV-1 outbreaks
are common, whereas BP is rare (Steiner and Mattan, 1999). Finally, in a randomized controlled
trial with a factorial design in which patients received 10 days of prednisolone, acyclovir, both,
and placebo, prednisolone significantly improved outcomes, whereas acyclovir did not (Sullivan
et al., 2007).
Infection may also cause BP via a post-infectious immune-mediated mechanism rather
than by direct invasion of the nerve. Such mechanisms could include bystander activation,
epitope spreading or polyclonal activation of previously dormant self-reactive lymphocytes
(Chapter 2). Arguments favoring an infectious trigger of BP include that it can occur in epidemic
clusters (Leibowitz, 1969) and displays seasonal variation (Kim and Park, 2021). Potential
triggers include cytomegalovirus, Epstein-Barr virus, mumps, rubella, and HIV (Steiner and
Mattan, 1999). An intranasal influenza vaccine which has since been removed from the market
was associated with BP (Wratten et al., 1977). In this case-control study, BP most often occurred
within 31-60 days following vaccination arguing against a direct toxic effect and in favor of an
immune-mediated mechanism. Recent evidence has suggested a possible association between
COVID-19 infection and BP (Rafati et al., 2023). The fact that there are multiple putative viral
triggers argues against molecular mimicry as a mechanism.
Patients with BP have been shown to have elevated levels of the cytokines IL-6, IL-8,
and TNF-alpha compared to controls (Yılmaz et al., 2002). Some have argued that cytokine-
mediated neuronal damage, in particular by type 1 interferon (type 1 IFN), might mediate
neurological adverse events after COVID-19 vaccination (Chen et al., 2022a; Shemer et al.,
2021). Because BP has been seen as a complication of type 1 IFN treatment for hepatitis C
(Hwang et al., 2004), some have postulated that an elevation of type 1 IFN after COVID-19
vaccination could be associated with it (Shemer et al., 2021). Single-cell transcriptomics
demonstrate a strong interferon signature after booster mRNA vaccination (Arunachalam et al.,
2021), but this has not been correlated with neurological harms. Adenoviral vaccines have also
been shown to induce an interferon signature, at least in mice (Sheerin et al., 2021). However, no
studies link cytokine responses after vaccination to neurological events.
Epidemiological Evidence
Clinical trial results submitted to FDA for Emergency Use Authorization and/or full
approval do not indicate a signal regarding Bell’s Palsy and any of the vaccines under study
(FDA, 2021, 2023a, 2023b, 2023c). Table 3-4 presents 11 studies that contributed to the
causality assessment.
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CI
:
c
o
n
f
i
d
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n
c
e
i
n
t
e
r
v
a
l
;
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M
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s
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d
a
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d
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d
in
c
i
d
e
n
c
e
r
a
t
i
o
.
SO
U
R
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E
S
:
Ab
R
a
h
m
a
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t
a
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.
,
2
0
2
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;
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a
;
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;
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2
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;
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.
,
2
0
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;
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i
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,
20
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;
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.
,
2
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;
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t
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t
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.
,
2
0
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;
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a
k
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c
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t
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l
.
,
2
0
2
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;
W
a
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k
e
r
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t
a
l
.
,
2
0
2
2
.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 83
PREPUBLICATION COPY—Uncorrected Proofs
Patone et al. (2021) investigated the association between BNT162b2 and BP among 12.1
million vaccinees in England using a self-controlled case series (SCCS) study. They compared
the incidence rate of BP in the interval of 1–28 days after vaccination with that during periods
outside of this interval. BP was defined using ICD-10 codes and identified as the first hospital
admission or as a cause of death recorded on the death certificate (Patone et al., 2021).
Vaccination status was identified in the English National Immunization Database of COVID-19
vaccination; they identified 250 BP cases and found no association with BNT162b2 (incidence
rate ratio (IRR) 1.06 (95 percent confidence interval (CI): 0.80–1.25) (Patone et al., 2021).
Walker et al. (2022) analyzed primary care data from more than 17 million patients in
England linked to emergency care, hospital admission, and mortality records in the
OpenSAFELY platform (Walker et al., 2022). They excluded BP cases that occurred before the
study start date. Cases were determined from any primary care, emergency department, hospital
admission, or mortality records. They used an SCCS analytical approach where the risk interval
was 4–28 days after vaccination. Among 5.7 million recipients of BNT162b2, 3,609 BP cases
were identified, and among 255,446 recipients of mRNA-1273, 78 BP cases were identified.
They found no association between the first dose of BNT162b2 and BP (IRR 0.89, 95% CI:
0.76–1.03) or the second dose (IRR 0.92, 95% CI: 0.78–1.10). Similarly, no association appeared
with mRNA-1273 after the first or second dose (IRR 0.59, 95% CI: 0.13–2.62 and IRR 0.80,
95% CI: 0.24–2.62, respectively) (Walker et al., 2022).
Ab Rahman et al. (2022) conducted a self-controlled case-series study among
hospitalized BP cases in Malaysia. Vaccination status was determined from the national COVID-
19 register data. The incidence of BP was assessed during a 21-day risk interval after vaccination
relative to a control period using conditional Poisson regression with adjustment for calendar
time. After more than 15 million doses of BNT162b2, 27 cases of BP were identified in the risk
interval. Compared with the control interval, no significant increased risk of BP occurred after
the first (IRR 1.32, 95% CI: 0.77–2.24) or second (IRR 0.88, 95% CI: 0.45–1.73) dose. The IRR
after any dose was 1.11 (95% CI: 0.77–1.75) (Ab Rahman et al., 2022).
Li et al. (2022b) evaluated the association between vaccination and BP using two study
designs: a population-based cohort design where they compared rates of BP identified through
medical records among vaccinees with historical background rates and an SCCS analysis. They
used CPRD AURUM and SIDIAP. The study included 3.6 million people who received
BNT162b2, 244,913 who received mRNA-1273, 120,731 who received Ad26.CoV.2, and 14.3
million people from the general population. Of the BNT162b2 vaccinees, 46 and 24 BP cases
occurred after a first and second dose in CPRD AURUM, compared with 116.4 and 99.5
expected. The standardized incidence ratio (SIR) was 0.40 (95 percent CI: 0.30–0.53) for the first
and 0.24 (95 percent CI: 0.16–0.36) for the second dose. SIDIAP had 100 and 85 BP cases after
the first and second dose of BNT162b2, compared with 116.7 and 97.1 expected. SIR was 0.86
(95% CI: 0.70–1.04) for the first and 0.88 (95% CI: 0.71–1.08) for the second dose. For mRNA-
1273, 14 and 5 cases occurred after the first and second dose compared with 15.2 and 11.3
expected. The corresponding SIRs are 0.92 (95% CI: 0.54–1.55) and 0.4 (95% CI: 0.18–1.06).
For Ad26.COV2.S, six BP cases were identified compared with 5.2 expected, corresponding to
an SIR of 1.15 (95% CI: 0.52–2.56) (Li et al., 2022). The SCCS analysis was only sufficiently
powered to study those with a first dose of BNT162b2 and mRNA-1273. In CPRD AURUM, the
adjusted IRR of BP 1–21 days after vaccination was 0.83 (95% CI: 0.61–1.10) for BNT162b2. In
SIDIAP, the adjusted IRR was 0.83 (95% CI: 0.66–1.02) for BNT162b2 and 0.99 (95% CI:
0.54–1.64) for mRNA-1273 (Li et al., 2022).
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Shibli et al. (2021) used data from the computerized database of Clalit Health Services,
which provides inclusive health care for more than half of the Israeli population, to assess
whether BNT162b2 was associated with increased risk by comparing BP rates in vaccinees with
historical rates in the general population. They assessed rates 21 days after the first dose and 30
days after the second dose. Overall, 132 cases of BP were reported in 2.6 million vaccinees with
the first dose compared with 97.1 expected, and 152 cases in 2.4 million vaccinees were reported
compared with 130.49 expected after the second dose. The age- and sex-weighted SIRs were
1.36 (95% CI: 1.14–1.61) and 1.16 (95% CI: 0.99–1.36) after the first and second doses,
respectively. Although more cases were observed than expected, the attributable risk fraction
was 0.26 for the first and 0.14 for the second dose. The attributable risk per 100,000 vaccinees
was 1.35 for the first and 0.86 for the second dose (Shibli et al., 2021).
Shasha et al. (2021) conducted a matched cohort study in which they compared risk of
BP in 233,159 BNT162b2 vaccinees with that in 233,159 age- and sex-matched unvaccinated
individuals. BP cases were identified by ICD-10 code and confirmed by chart review. Of the 123
cases identified by ICD-10 codes, 76 were excluded because they were not incident cases or not
consistent with BP. Vaccinated and unvaccinated individuals had 23 versus 24 cases of BP (RR
0.96, 95% CI: 0.54–1.70).
Sturkenboom et al. (2022) conducted a cross-national multi-database retrospective
dynamic cohort study using primary and/or secondary health care data from four European
countries: Italy, the Netherlands, the United Kingdom, and Spain. Individuals were required to
have at least 365 days of data availability before cohort entry. The end of follow-up was the
earliest dates of BP occurrence, last data collection, or death. Person-time after the start of the
study was divided in two main periods, nonvaccinated and vaccinated; the latter started at the
first of any of the COVID-19 vaccine and lasted for a maximum of 28 days after dose 1 and 28
days after dose 2 or until the date of last data available. Of the 25.7 million people included, 149
BP cases were identified after BNT162b2, 27 after mRNA-1273, and 6 after Ad26.COV2.S.
They found no increased risk of BP 28 days after BNT162b2 (IRR 0.87, 95% CI: 0.69–1.10),
mRNA-1273 (IRR 0.99, 95% CI: 0.68–1.45), or Ad26.COV2.S (IRR 1.08, 95% CI: 0.45–2.60)
(Sturkenboom et al., 2022).
Shemer et al. (2021) conducted a case-control study using data from the emergency
department of a tertiary referral center in central Israel. Patients admitted for facial nerve palsy
(37 BP confirmed cases) were matched by age, sex, and date of admission with 72 controls
admitted for other reasons and assessed against the odds of BNT162b2 vaccination. The odds of
vaccination were not different between cases and controls. The odds ratio for vaccination was
0.84 (95% CI: 0.37–1.90) (Shemer et al., 2021).
Shoaibi et al. (2023) conducted an SCCS study of BNT162b2 and mRNA-1273 among
U.S. Medicare beneficiaries aged 65+ to evaluate association with BP after only a booster dose
(Shoaibi et al., 2023). The study included 6.2 million individuals. Of 79 cases identified through
electronic health records, chart reviews determined that 10 were confirmed or probable, for a
positive predictive value of 12.66 percent. After adjusting for outcome misclassification, they
found no significant association between BNT162b2 and BP (IRR 1.13, 95% CI: 0.77–1.65) or
mRNA-1273 and BP (IRR 1.02, 95% CI: 0.70–1.50) (Shoaibi et al., 2023).
In addition to these studies that evaluated individual vaccines, two studies evaluated the
association of mRNA vaccines with risk of BP. Takeuchi et al. (2022) evaluated BP risk after
any BNT162b2 and mRNA-1273 in administrative claims data using a cohort study design and
an SCCS design. BP was defined by ICD codes from hospitalized claims data. The study
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 85
PREPUBLICATION COPY—Uncorrected Proofs
included 136,644 people who received one dose, 127,268 who received two doses, and 183,990
unvaccinated. The vaccinees had two BP cases 21 days after dose 1 and one BP case after dose 2
compared with 18 cases among the unvaccinated. The adjusted IRR of BP was 1.14 (95% CI:
0.27–4.89) and 0.60 (95% CI 0.08–4.49) after dose 1 and dose 2, respectively, compared with
unvaccinated. The results of the SCCS analysis indicated no increased risk of BP after dose 1
(IRR 1.03, 95% CI: 0.20–5.31) or dose 2 (IRR 0.47, 95% CI: 0.05–4.18) (Takeuchi et al., 2022).
Klein et al. (2021) conducted a surveillance study within VSD. They compared incidence
of BP 1–21 days after either dose 1 or 2 of an mRNA vaccine with that of concurrent
comparators who, on the same calendar day, had received their most recent dose 22–42 days
earlier. After 11.8 million doses, 535 BP cases were identified in the risk interval compared with
301 in the controlled interval. The adjusted IRR was 1.00 (95% CI: 0.86–1.17). In a
supplemental analysis comparing vaccinated with unvaccinated people, they found no risk
association with an mRNA vaccine (RR 1.06, 95% CI: 0.95–1.17) (Klein et al., 2021).
From Evidence to Conclusions
Among the 11 epidemiology studies reviewed, only one reported a significantly increased
risk of BP after the first dose of BNT162b2 (Shibli et al., 2021). Its results are prone to
confounding because it used historical BP rate as the comparator. Factors associated with that
rate may be very different from those during the pandemic. Furthermore, comparing vaccinated
with unvaccinated is problematic because, without randomization, it is practically impossible to
balance their confounding factors. Although informative, this study weakly contributed to the
final conclusion because of its limitations including using historical background rates as
comparators; studies using concurrent comparators did not find an association between BP and
mRNA vaccines. The main limitation is that most of the studies relied on ICD codes from
electronic data without chart confirmation. Some cases of BP identified by the ICD codes might
not be true or incident cases, which could have biased the measure of association. Studies may
have missed cases because they were not based on active surveillance, and the majority of the
cases included are likely more severe, as those with mild symptoms may not have sought
medical attention during the pandemic. Furthermore, some studies may have incompletely
measured or adjusted for some confounding.
Conclusion 3-9: The evidence favors rejection of a causal relationship between the
BNT162b2 vaccine and Bell’s Palsy.
Conclusion 3-10: The evidence favors rejection of a causal relationship between the
mRNA-1273 vaccine and Bell’s Palsy.
Only two of the 11 studies evaluated the relationship between Ad26.COV2.S and BP;
neither showed an increased risk. No studies evaluated the relationship between BP and NVX-
CoV2373.
Conclusion 3-11: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and Bell’s Palsy.
Conclusion 3-12: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and Bell’s Palsy.
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Copyright National Academy of Sciences. All rights reserved.
86 VACCINE EVIDENCE REVIEW
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TRANSVERSE MYELITIS
BOX 3-4
Conclusions for Transverse Myelitis
Conclusion 3-13: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and transverse myelitis.
Conclusion 3-14: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and transverse myelitis.
Conclusion 3-15: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and transverse myelitis.
Conclusion 3-16: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and transverse myelitis.
Background
Spinal cord dysfunction of any cause is referred to as “myelopathy”; “myelitis”
designates inflammation of the spinal cord. Acute TM refers to a group of acquired, acute-onset,
focal inflammatory myelopathies. Consensus diagnostic criteria that rely on clinical and
radiographic features have been published, and the diagnosis requires bilateral (although not
necessarily symmetric) weakness and sensory deficits, with a clearly defined sensory level,
evidence of inflammation by CSF or MRI gadolinium enhancement, and clinical progression to
nadir between 4 hours and 21 days (Transverse Myelitis Consortium Working Group, 2002).
This clinicoradiologic syndrome can be a manifestation of other inflammatory central nervous
system disorders (disease-associated TM), including demyelinating disorders, such as
neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis (ADEM), where
up to 50 percent of patients have antibodies to myelin oligodendrocyte glycoprotein, and
multiple sclerosis (MS) (Lopez Chiriboga, 2021). Spinal cord infections, paraneoplastic
autoimmune syndromes, and systemic inflammatory disorders can also present as disease-
associated TM (Flanagan et al., 2016; Jain et al., 2023). When the etiology is unknown, it is
called “idiopathic TM.” Confusingly, noninflammatory causes of myelopathy, such as ischemic
or hemorrhagic stroke, nutritional deficiencies, and neoplasms, can mimic this clinical and
radiographic picture. In one study, 70 percent of patients referred to a tertiary care center with a
diagnosis of idiopathic TM had a more specific disease-associated TM, such as myelin
oligodendrocyte glycoprotein antibody–associated disease or MS, but a quarter of them did not
have an inflammatory myelopathy at all (Zalewski et al., 2019). Idiopathic TM is therefore a
diagnosis of exclusion (of known causes of disease-associated TM and noninflammatory
myelopathies that can mimic TM). Another study, based on retrospective review of Veterans
Health Administration electronic medical records, found that 57.6 percent of patients assigned an
ICD code of TM lacked CSF testing, which is a core feature of current diagnostic criteria
(Abbatemarco et al., 2021). As the aforementioned studies suggest, existing criteria lack
specificity, which can affect the accuracy of epidemiological studies, especially those relying on
ICD codes.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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NEUROLOGIC CONDITIONS 87
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Idiopathic TM is rare, with a reported incidence of 1.34–4.6 per million per year, with
bimodal peaks between ages 10–19 and 30–39 years and no sex predisposition (Bhat et al.,
2010). It has been reported a few weeks after vaccination, although a large retrospective cohort
study from VSD, a collaboration between the Centers for Disease Control and Prevention’s
Immunization Safety Office and several integrated health care systems across the United States,
did not find an increased risk in association with routine vaccines (Baxter et al., 2016).
Mechanisms
The pathophysiology of idiopathic TM is unknown, but postinfectious immune-mediated
injury is the most widely accepted mechanism. This could be due to bystander activation, epitope
spreading or polyclonal activation of previously dormant self-reactive lymphocytes (Chapter 2).
Up to 40 percent of TM cases follow an infection, most commonly Coxsackie viruses and
mycoplasma pneumoniae, and infectious agents have sometimes been isolated from the spinal
fluid (Bhat et al., 2010; Krishnan et al., 2004). TM has also been reported after a variety of
vaccines, including hepatitis B, rabies, and rubella (Agmon-Levin et al., 2009). The fact that TM
has been associated with many different viruses and vaccines argues against molecular mimicry
as a mechanism. In England in 1922–1923, over 200 cases of encephalomyelitis were reported
after smallpox and rabies vaccination, and autopsy studies revealed inflammatory cells and
demyelination in the spinal cord (Krishnan et al., 2004; Rivers, 1932). More recent pathological
studies demonstrate focal infiltrates of monocytes and lymphocytes in the spinal cord and
perivascular space, astroglial and microglial activation, and involvement of both white and gray
matter (Krishnan et al., 2004). In the acute phase, heavy infiltration by CD4+ and CD8+ T cells
and monocytes is found, whereas the subacute phase is characterized by macrophage infiltration
and demyelination (Krishnan et al., 2004). Most patients with TM have CSF pleocytosis
suggesting breakdown of the blood–brain barrier (Bhat et al., 2010; Krishnan et al., 2004).
Patients with TM have been shown to have elevated levels of interleukin-6 (IL-6) in their
CSF and, in acute TM, CSF IL-6 levels correlate with the ultimate level of clinical disability
(Kaplin et al., 2005). In an animal model, IL-6 can be shown to mediate cord injury by inducing
nitric oxide production, which is associated with oligodendrocyte injury, demyelination, and
axonal injury (Kaplin et al., 2005).
Epidemiological Evidence
Clinical trial results submitted to FDA for Emergency Use Authorization and/or full
approval do not indicate a signal regarding TM and any of the vaccines under study (FDA, 2021,
2023a, 2023b, 2023c). Table 3-5 presents five studies that contributed to the causality
assessment.
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Klein et al. (2021) conducted a surveillance study within VSD comparing TM incidence
1–21 days after either dose 1 or 2 of a mRNA vaccine with that of vaccinated concurrent
comparators who, on the same calendar day, had received their most recent dose 22–42 days
earlier. After 11.8 million doses (57 percent BNT162b2), two cases were identified in the risk
interval compared with one in the controlled interval, with an adjusted rate ratio of 1.45 (95% CI:
0.10–47.73) and excess cases of 0.1 (95% CI: -1.6–0.2) risk interval per million doses (Klein et
al., 2021).
Li et al. (2022b) compared TM rates identified through medical records among vaccinees
with historical background rates and conducted an SCCS analysis. They used data from CPRD
AURUM and SIDIAP. The study included 3.6 million people who received BNT162b2, 244,913
who received mRNA-1273, 120,731 who received Ad26.CoV.2, and 14.3 million people from
the general population. Of the BNT162b2 vaccinees, fewer than five cases occurred within 1–21
days after a first dose in CPRD AURUM, compared with 4.7 expected. SIDIAP had <5 cases
after the first dose of BNT162b2, compared with 0.9 expected. For mRNA-1273, <5 cases were
diagnosed after the second dose compared with 0.1 expected. No cases were observed with the
second dose of BNT162b2, first dose of mRNA-1273, or Ad26.COV2.S.
Walker et al. (2022) analyzed primary care data from more than 17 million patients in
England linked to emergency care, hospital admission, and mortality records in OpenSAFELY.
They used an SCCS analytical approach where the risk interval was 4–28 days after vaccination.
Among 5.7 million recipients of BNT162b2, 109 TM cases were identified during the risk and
controlled periods, and none were identified among 255,446 recipients of mRNA-1273. They
found no significant association between the first dose of BNT162b2 and TM (IRR 1.62, 95%
CI: 0.86–3.03). Few events were observed, so they were unable to precisely estimate the risk
association. Adjusting for calendar time or history of COVID-19 infection did not significantly
change the measure of association (IRR 1.49, 95% CI: 0.71–3.10) (Walker et al., 2022).
Sturkenboom et al. (2022) conducted a cross-national multi-database retrospective
dynamic cohort study using primary and/or secondary health care data from four European
countries: Italy, the Netherlands, the United Kingdom, and Spain. They compared TM incidence
in vaccine recipients with nonvaccinated persons in 2020 within 28 days after each dose. Of 25.7
million people, nine cases were identified after BNT162b2 (IRR 1.88, 95% CI: 0.37–9.6) and
none after mRNA-1273 and Ad26.COV2.S (Sturkenboom et al., 2022). The results are consistent
with an increased risk, but few events were observed, and the authors were unable to precisely
estimate risk and results; this could also be consistent with no or decreased risk.
Patone et al. (2021) investigated the association between BNT162b2 with potential
neurological harms among 32.6 million vaccinees, 12.1 million of whom received BNT162b2
(Patone et al., 2021). An ICD-10 code for TM was included in the category “acute demyelinating
events” (ADE), which contained ICD-10 codes for other demyelinating syndromes, such as
ADEM. This retrospective self-controlled cohort study compared the incidence rate at several
intervals (1–7, 8–14, 15–21, 22–28, and 1–28 days) after vaccination with that during periods
outside of this interval. Sixty-eight events were observed after BNT162b2 during the risk period.
They found no association for BNT162b2 at any interval, including in the 1–28 days period (IRR
1.02, 95% CI: 0.75–1.40). Few events were observed, so the authors were unable to precisely
estimate the risk; the results would be consistent with no increased risk but also with slightly
increased risk.
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From Evidence to Conclusions
The main limitation of the reviewed studies is their reliance on ICD codes from electronic
data without chart confirmation. In addition, the studies used varying nomenclature when
designating cases of vaccine-associated myelitis. Most had TM as a stand-alone adverse event,
but one (Patone et al., 2021) included ICD codes for TM within the larger category “acute
demyelinating events,” which also included ICD codes for other central nervous system
inflammatory disorders. Three studies (Klein et al., 2021; Li et al., 2022; Patone et al., 2021)
included a separate category “encephalitis/myelitis/encephalomyelitis,” and cases clinically and
radiographically consistent with TM may have been classed within this category based on their
ICD code, resulting in a lower number of total reported events.
None of the five epidemiology studies suggested a causal association between TM and
BNT162b2, and no evidence suggests a large association. However, the limited number of
studies, along with the overall low number of events reported, raises the concern that a small
association may have been missed, given that TM is a very rare disorder. Four studies included a
few mRNA-1273 recipients, with no TM cases reported in two of the studies. Only one study
included patients who received Ad26.COV2.S, with a comparatively low number of vaccinees
and no cases reported (Li et al., 2022).
Conclusion 3-13: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and transverse myelitis.
Conclusion 3-14: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and transverse myelitis.
Conclusion 3-15: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and transverse myelitis.
Conclusion 3-16: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and transverse myelitis.
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CHRONIC HEADACHE
BOX 3-5
Conclusions for Chronic Headache
Conclusion 3-17: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and chronic headache.
Conclusion 3-18: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and chronic headache.
Conclusion 3-19: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and chronic headache.
Conclusion 3-20: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and chronic headache.
Background
Headache is a frequently reported symptom of systemic illness, cerebrovascular
disorders, intracranial disease, or craniocervical trauma. It is also reported commonly and can be
a symptom of substance withdrawal. When a headache results from a separate medical condition,
it is called a “secondary headache.” Most headaches, however, occur as the principal
manifestation of a primary headache disorder; these are characterized by recurrent headaches of
varying characteristics, frequency, and accompanying symptoms and signs. Although the
frequency and severity of individual headache episodes vary over the lifetime, primary headache
disorders are usually considered lifelong conditions. They have no biological markers, and their
diagnosis is made with reasonable precision based on consensus diagnostic criteria set forth in
the International Classification of Headache Disorders (ICHD-3), which was last revised in 2018
(International Headache Society, 2018). Ancillary studies, mostly brain and vascular imaging
and occasionally lumbar puncture, are used to rule out various forms of secondary headaches.
Tension-type headache (TTH) and migraine are by far the more common primary
headache disorders, with an estimated lifetime prevalence in the general population of 46 and 14
percent, respectively (Stovner et al., 2007). Geographic variations exist, but it is unclear whether
these are driven by genetic differences or methodological differences between studies. Other
primary headache disorders, such as cluster headache, are much rarer, with a lifetime prevalence
of 0.06–0.3 percent (Jensen and Stovner, 2008). The frequency, duration, and severity of
headache varies significantly even within the same primary headache disorder: from infrequent,
short, and mild to continuous and/or disabling. Migraine is more common in women compared to
men, with a ratio of 2:1 to 3:1 (Jensen and Stovner, 2008). The female:male ratio for TTH is 5:4
(Jensen and Stovner, 2008). The prevalence of migraine peaks between the second and third
decades of life but can affect people of all ages, including children. Data regarding age
dependence in TTH are more limited, but prevalence peaks around the fourth decade of life.
Cluster headache has a male:female ratio of 4.3:1 (Fischera et al., 2008), with prevalence
peaking between the second and fourth decades of life.
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No single consensus diagnostic criteria exist for chronic headache. Rather, ICHD-3
provides diagnostic criteria for chronic forms of individual headache subtypes based on
frequency and duration. These include chronic migraine headache, chronic TTH, chronic cluster
headache, hemicrania continua, new daily persistent headache, and medication overuse
headache, which is a form of secondary headache (International Headache Society, 2018). In
most, but not all, chronicity is based on a frequency of more than 15 headache days per month
for longer than 3 months. Although ICHD-3 criteria for secondary headache does not specify
measures of chronicity, they do specify that when a pre-existing primary headache becomes
chronic shortly after a known causative disorder, both chronic primary headache and secondary
headache diagnoses should be given (International Headache Society, 2018). Data on chronic
headaches is relatively scarce, but prevalence as a group is estimated as 3–4 percent in the
general population (Jensen and Stovner, 2008).
Systemic infection, including with COVID-19, can be associated with headache (Togha
et al., 2022), and “headache attributed to systemic infection” is included as a subtype of
secondary headache in ICHD-3. Headache was also a frequently reported symptom in the clinical
trials for the various COVID-19 vaccines (Baden et al., 2021; Heath et al., 2021; Polack et al.,
2020; Sadoff et al., 2021). Most of these headaches occurred within 24 hours of vaccination and
were frequently accompanied by systemic symptoms, such as fatigue, fever, chills, and myalgia
(Göbel et al., 2021a, 2021b). In most, headaches lasted less than 72 hours, with only a small
minority reporting more than 3 days. Pre-existing migraine was associated with more severe and
long-lasting headaches in some but not all studies (Silvestro et al., 2021) and may predispose
someone to postvaccine headache (Sekiguchi et al., 2022). Although ICHD-3 does include
“headache attributed to use or exposure to a substance” as a subtype of secondary headache,
vaccines are not listed within the known causes (International Headache Society, 2018).
Evidence suggests that headache may be common with other vaccines as well, and some have
proposed that postvaccination headache should be included in the next iteration of the ICHD
(Garces et al., 2022). Headache is also one of the main symptoms of cerebral venous sinus
thrombosis (CVST), a manifestation of vaccine-induced immune thrombotic thrombocytopenia
(VITT). VITT has been reported in association with the AV COVID-19 vaccines and is
discussed elsewhere in this report (See et al., 2021). Unlike the more common postvaccination
headache, which occurs shortly after vaccination, the headache secondary to VITT-associated
CVST is approximately a week after vaccination (García-Azorín et al., 2021).
Mechanism
The pathophysiology of primary headache disorders remains ill-defined and is different
for individual disorders. Postvaccination headache is not included as a type of secondary
headache in ICHD-3; however, it may bear some resemblance to “headache attributed to
systemic infection,” which is included. The more widely accepted hypothesis is that
postvaccination headache is secondary to downstream effects stemming from the immune
response to the vaccine (Garces et al., 2022). Vaccines, including COVID-19 vaccines, are
associated with the release of inflammatory mediators, such as prostaglandin E, and
proinflammatory cytokines. It is conjectured that these are responsible for the headache and
frequently associated systemic symptoms. Some have proposed that inflammatory mediators
may modulate the release of calcitonin gene–related peptide (CGRP), which plays an important
role in migraine via activation of the trigeminovascular system. Similarly, substance P, a
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nociceptive neuropeptide released by trigeminal sensory fibers and implicated in migraine, is
also produced by mast cells, suggesting a link between immune activation and migraines (Suvas,
2017). Data supporting this hypothesis are limited. One study found increased levels of
inflammatory and nociceptive molecules in COVID-19 hospitalized patients with headache
compared to those without; CGRP levels, however, did not differ significantly between the two
groups (Bolay et al., 2021). Finally, some have hypothesized direct modulation of the trigeminal
nerve when the spike protein, which is either synthetized intracellularly or introduced directly
after vaccination, binds the ACE2 receptor. However, it remains unclear whether ACE2 is
expressed in the relevant neural structures (Caronna et al., 2023), and some studies suggest that
headache is more common after the second dose (Ceccardi et al., 2022), which appears
counterintuitive given the probable presence of neutralizing antibodies against the spike protein
Epidemiological Evidence
Chronic headache is not a single diagnostic entity with widely accepted diagnostic
criteria. The committee relied on ICHD-3, which provides diagnostic criteria for the subtypes.
Although a self-limited headache was a commonly reported symptom after BNT162b2, mRNA-
1273, Ad26.COV2.S, and NVX-CoV2373, none of the studies reviewed included a stand-alone
category for chronic headache, nor did they include chronic headache subtypes as defined in
ICHD-3. Clinical trial results submitted to FDA for Emergency Use Authorization and/or full
approval do not indicate a signal regarding chronic headache and any of the vaccines under study
(FDA, 2021, 2023a, 2023b, 2023c). None were included in the final report for analysis.
From Evidence to Conclusions
The epidemiological and mechanistic literature are absent regarding the relationship
between COVID-19 vaccines and chronic headache.
Conclusion 3-17: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and chronic headache.
Conclusion 3-18: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and chronic headache.
Conclusion 3-19: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and chronic headache.
Conclusion 3-20: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and chronic headache.
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POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME
BOX 3-6
Conclusions for Postural Orthostatic Tachycardia Syndrome
Conclusion 3-21: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and postural orthostatic tachycardia syndrome.
Conclusion 3-22: The evidence is inadequate to accept or reject a causal relationship
between the mRNA -1273 vaccine and postural orthostatic tachycardia syndrome.
Conclusion 3-23: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and postural orthostatic tachycardia syndrome.
Conclusion 3-24: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and postural orthostatic tachycardia syndrome.
Background
POTS is marked by symptoms of orthostatic intolerance despite relative preservation of
autonomic reflexes. The hallmark is an exaggerated increase in heart rate in response to standing
or tilt without a drop in blood pressure as seen in classic autonomic failure (Cutsforth-Gregory,
2020). POTS is defined as a sustained heart rate increase of 30 beats per minute (bpm) or
increase to 120 bpm within the first 10 minutes of orthostasis, along with symptoms of
orthostatic intolerance, including dizziness, palpitations, weakness, and tremulousness. For
children and adolescents (12–19 years), the required increment is 40 bpm (Vernino et al., 2021).
POTS predominantly affects a younger and primarily female (at a ratio of 4:1)
demographic, with the typical age range of onset being 12–50 (Vernino et al., 2021).
Epidemiologically, it is a relatively common condition in developed countries, with prevalence
estimates of 0.2–1.0 percent of the U.S. population, which represents 1–3 million people
(Cutsforth-Gregory, 2020; Vernino et al., 2021).
Orthostatic symptoms are probably driven by both cerebral hypoperfusion (dizziness,
lightheadedness, vision, and hearing changes) and sympathoexcitation (palpitations, chest pain,
difficulty breathing, tremulousness, sweating, and coldness of the extremities) (Cutsforth-
Gregory, 2020). Particularly tachycardia, can be triggered either directly by influencing the sinus
rate control system via adrenergic and muscarinic receptors or indirectly as a compensatory
response to peripheral vasodilation. This indirect response may involve adrenergic, angiotensin,
and other potential vasoactive receptors (Figure 3-2). POTS patients, however, frequently
experience other symptoms as well, including sleep disturbances, headache, fatigue, cognitive
impairment, gastrointestinal complaints, urinary frequency, and exercise intolerance (Vernino et
al., 2021). The sheer variety and nonspecificity of these symptoms make it difficult to attribute
all of them to a single clinical entity sharing the same underlying mechanism. A variety of
comorbid conditions are associated with POTS, including migraine, somatic hypervigilance,
irritable bowel syndrome, hypermobile Ehlers-Danlos syndrome (EDS), mast cell activation
syndrome, systemic autoimmune disease, small-fiber neuropathy, and fibromyalgia and chronic
fatigue syndrome (Gradin et al., 1987; Low et al., 2009; Shibao et al., 2005). It is unclear
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whether the presence of these diagnoses defines unique pathophysiological subsets (Vernino et
al., 2021). In either case, the diagnostic criteria emphasize symptoms and heart rate increment in
response to an orthostatic challenge as the core feature, which is appropriate, as an excessive
heart rate is the most consistent and reproducible of various indexes of orthostatic intolerance
(Vernino et al., 2021). Symptoms alone in the absence of orthostatic tachycardia cannot be used
to make the diagnosis and the syndrome must be present for at least 3 months (Vernino et al.,
2021). The diagnostic approach begins with a comprehensive clinical assessment focused on
orthostatic intolerance symptoms. Excessive increase in heart rate without orthostatic
hypotension within 3–10 minutes from standing should be confirmed at bedside or with a tilt-
table test (Freeman et al., 2011; Vernino et al., 2021). Laboratory tests play an important role in
excluding other conditions that might mimic POTS symptoms. Further autonomic testing and/or
skin biopsy may be warranted to explore the full spectrum of autonomic dysfunction and assess
for underlying small-fiber neuropathy (Vernino et al., 2021). A 12-lead electrocardiography
should be performed in all patients, but expanded cardiac evaluation, may be indicated in some
(Cutsforth-Gregory, 2020).
Between 20 and 50 percent of patients report a viral illness before the onset of symptoms.
In these cases, POTS symptoms appear to arise abruptly weeks after the acute illness, but in
others, the symptoms appear slowly (Thieben et al., 2007). Other triggers include surgery, and
head trauma, although these are less well established (Olshansky et al., 2020). Patients have
developed POTS symptoms at the time of or within 6 weeks of acute SARS-CoV-2 infection
(Goodman et al., 2021), but latency can be longer, and POTS is considered a phenotype of
postacute or “long” COVID-19 (Fedorowski and Sutton, 2023). POTS has also been reported in
association with the COVID-19 vaccine (Kwan et al., 2022).
Mechanisms
The pathophysiology of POTS remains ill defined, and it is unlikely that it is a single
disorder. Rather, it is probably a heterogeneous syndrome that can arise in various clinical
scenarios resulting from distinct but overlapping pathophysiologic mechanisms (Benarroch,
2012). Several mechanisms have been proposed and account for some of its phenotypic
variability. These include catecholamine excess (hyperadrenergic POTS), sympathetic
denervation leading to impaired vasoconstriction of the lower limbs (neuropathic POTS), volume
dysregulation, and deconditioning (Vernino et al., 2021).
The clinical picture with hyperadrenergic POTS is dominated by palpitations, sweating,
tremulousness, and orthostatic hypertension. Some of these patients have high plasma
norepinephrine concentrations during orthostasis (Fedorowski and Sutton, 2023), although in
others, the hyperadrenergic state may be secondary to medications, such a tricyclic
antidepressants or methylphenidate (Cheshire, 2016). Neuropathic POTS may be secondary to a
length-dependent autonomic neuropathy leading to impaired vasomotor tone in the lower limbs.
Autonomic testing in some patients demonstrates loss of sweating in the feet and reduced
increment of norepinephrine in the lower limbs when standing, which is consistent with a length-
dependent autonomic neuropathy. The etiology of this autonomic neuropathy is not usually
evident, although several lines of evidence suggest a potential immune-mediated mechanism in
some cases. Reports of an earlier viral illness in up to one-half of patients suggests a
postinfectious autoimmune process (Sandroni et al., 1999; Vernino et al., 2021). In addition,
several small studies have demonstrated higher levels of functionally active antibodies to G-
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protein-coupled adrenergic receptors α1 and α2 in individuals with POTS than in healthy
controls (Fedorowski and Sutton, 2023; Kharraziha et al., 2020; Li et al., 2014; Vernino et al.,
2021). These findings, plus reports of the successful treatment of POTS with intravenous
immunoglobulin (Rodriguez et al., 2021; Weinstock et al., 2018), suggest an autoimmune
etiology, at least in a subset of patients. However, a recent randomized control trial of IVIg in
POTS found no difference in symptom response compared to albumin infusion (Vernino, 2023).
Most patients have some degree of hypovolemia. Studies have demonstrated that many of
them have low levels of plasma-renin activity and aldosterone compared with controls (Raj et al.,
2005), and some have reduced ACE2 activity (Stewart et al., 2009). The excessive venous
pooling that occurs with vasomotor impairment in neurogenic POTS can lead to reduced cardiac
preload and capillary leakage upon standing with associated net loss of plasma volume
(Cutsforth-Gregory, 2020). In those with poor oral intake or excess fluid loss, such as in irritable
bowel syndrome, managing the primary disorder will improve orthostatic intolerance. Finally,
physical deconditioning can lead to orthostatic intolerance. Many patients show evidence of
deconditioning: reduced stroke volume and left ventricular mass and persistent tachycardia and
reduced peak oxygen when standing or exercising (Fu et al., 2010; Masuki et al., 2007).
POTS has been reported in association with SARS-CoV-2 infection (Kwan et al., 2022;
Miglis et al., 2020), including in patients with post-acute COVID-19 (Fedorowski and Sutton,
2023). However, caution is needed when assessing the literature because, although orthostatic
intolerance is commonly reported in patients with post-acute COVID-19, many may not meet
diagnostic criteria for POTS. In one study of patients with de novo orthostatic intolerance after
COVID-19, only 22 percent fulfilled criteria for POTS (Shouman et al., 2021); the symptoms
may be driven by deconditioning in some of these patients. In addition to POTS, small-fiber
neuropathy, which can cause autonomic dysfunction and a POTS phenotype, has been described
after COVID-19, including in post-acute COVID-19 (Abrams et al., 2022; Oaklander et al.,
2022). POTS has also been reported after COVID-19 vaccination (Kwan et al., 2022). Many of
these reports postulate an immune-mediated mechanism, but definitive evidence is lacking. One
study demonstrated elevated inflammatory cytokines and markers of autoimmunity in patients
presenting with POTS after COVID-19, although this study did not include relevant controls.
One in silico study identified a variety of SARS-CoV-2 amino acid sequences, including in the
spike protein, that are also present in vagal nuclei and ganglia (Marino Gammazza et al., 2020).
This raises the theoretical possibility that molecular mimicry could induce cross-reactive
immune responses resulting in low vagal tone after infection or vaccination.
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FIGURE 3-2 Postulated mechanisms of orthostatic intolerance and tachycardia in POTS.
SOURCE: Fedorowski et al., 2017.
Epidemiological Evidence
Clinical trial results submitted to FDA for Emergency Use Authorization and/or full
approval do not indicate a signal regarding POTS and any of the vaccines under study (FDA,
2021, 2023a, 2023b, 2023c). Table 3-6 summarizes one study that contributed to the causality
assessment.
TABLE 3-6 Epidemiological Study in the Postural Orthostatic Tachycardia Syndrome Evidence
Review
Author
Study
Design and
Control
Group Location
Data
Source Vaccine(s)
Age
Range
Sample
Size
Number of
Events
Results
(95%
CI)
Kwan
et al.
(2022)
Cohort/self-
controlled US EMR
BNT162b2
≥12
years
284,592
patients
(62.2%)
763 events
per
100,000
POTS
cases
during
OR
1.52
(1.36–
1.71) mRNA-
1273 31%
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Ad26.COV
2.S 6.9%
exposure
period
compared
to 501 per
100,000
pre-
exposure
NVX-
CoV2373
<1%
other*
NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name
Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name
Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen.
NVX-CoV2373 refers to the COVID-19 vaccine manufactured by Novavax. *<0.1% of other vaccines
includes ChAdOx1-S, NVX-CoV2373, and CoronaVac. Number of events refers to events in vaccinees
only. CI: confidence interval; EMR: electronic medical record; OR: odds ratio.
SOURCE: Kwan et al., 2022.
Kwan et al. (2022) derived cohorts from the diverse patient population of the Cedars-
Sinai Health System in Los Angeles County, California. The authors identified patients who had
at least one COVID-19 vaccination between 2020 and 2022 and excluded those with a
documented COVID-19 infection 90 days before or after vaccination (n = 5,070). The final
sample was 284,592 patients (age 52 ± 20 years; 57 percent female; 63 percent White, 10 percent
Asian, 8.9 percent African American, and 12 percent Hispanic). Among the sample, 62 percent
received BNT162b2, 31 percent mRNA-1273, 6.9 percent Ad26.COV2.S, and less than 0.1
percent other vaccines. POTS was identified using diagnosis codes (ICD-9 I49.8; ICD-10 G90.9)
and modeled as both a single diagnosis and a combination of POTS-associated diagnoses (POTS
diagnosis codes, Fatigue, Dysautonomia, EDS, and mast cell disorders). Only outpatient
encounters were used. From the 90-day prevaccination to 90-day postvaccination periods, the
incidence of new diagnoses of POTS increased from 176 per 100,000 to 268 per 100,000
vaccinees (the authors did not report incidence per 100,000 for the combined diagnoses).
Relative to the prevaccination period, the odds of a new diagnosis of POTS and POTS-associated
diagnoses increased 52 percent, OR 1.52 (95% CI: 1.36–1.71) and 33 percent, OR 1.33 (95% CI:
1.25–1.41) in the postvaccination period, respectively. Limitations exist from unmeasured
confounding, lack of inclusion of COVID-19 infection, and open nature of the dataset, as
patients could have had encounters in other health systems as well. In addition, the measure of
effect was calculated for all vaccines combined, and conclusions cannot be drawn regarding a
potential association between POTS and individual vaccines or platforms.
The committee also reviewed a case series (Eldokla and Numan, 2022) of five patients
who developed de novo POTS within 21 days of an mRNA vaccine (four BNT162b, one mRNA-
1273). All five underwent detailed autonomic testing and met diagnostic criteria for POTS. Two
had elevated proinflammatory cytokines, and two had mildly elevated autoantibodies (thyroid
peroxidase antibodies and antinuclear antibodies), without other signs or symptoms of systemic
autoimmune disease. One had a low titer of acetylcholine receptor ganglionic antibodies; at
higher titers, this has been associated with autoimmune autonomic failure.
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From Evidence to Conclusions
The totality of the evidence included one epidemiological study with methodological
limitations and one case series with adequate case identification but no comparator group. No
definitive mechanism was identified in the literature.
Conclusion 3-21: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and postural orthostatic tachycardia syndrome.
Conclusion 3-22: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and postural orthostatic tachycardia syndrome.
Conclusion 3-23: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and postural orthostatic tachycardia syndrome.
Conclusion 3-24: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and postural orthostatic tachycardia syndrome.
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REFERENCES
Ab Rahman, N., M. T. Lim, F. Y. Lee, S. C. Lee, A. Ramli, S. N. Saharudin, T. L. King, E. B. Anak Jam,
N. A. Ayub, R. K. Sevalingam, R. Bahari, N. N. Ibrahim, F. Mahmud, S. Sivasampu, and K. M.
Peariasamy. 2022. Risk of serious adverse events after the BNT162b2, CoronaVac, and
ChAdOx1 vaccines in Malaysia: A self-controlled case series study. Vaccine 40(32):4394–4402.
https://doi.org/10.1016/j.vaccine.2022.05.075.
Abara, W. E., J. Gee, P. Marquez, J. Woo, T. R. Myers, A. DeSantis, J. A. G. Baumblatt, E. J. Woo, D.
Thompson, N. Nair, J. R. Su, T. T. Shimabukuro, and D. K. Shay. 2023. Reports of Guillain-
Barré syndrome after COVID-19 vaccination in the United States. JAMA Network Open
6(2):e2253845. https://doi.org/10.1001/jamanetworkopen.2022.53845.
Abbatemarco, J. R., J. R. Galli, M. L. Sweeney, N. G. Carlson, V. C. Samara, H. Davis, S. Rodenbeck, K.
H. Wong, M. M. Paz Soldan, J. E. Greenlee, J. W. Rose, A. Delic, and S. L. Clardy. 2021.
Modern look at transverse myelitis and inflammatory myelopathy: Epidemiology of the National
Veterans Health Administration population. Neurology Neuroimmunology & Neuroinflammation
8(6). https://doi.org/10.1212/nxi.0000000000001071.
Abrams, R. M. C., D. M. Simpson, A. Navis, N. Jette, L. Zhou, and S. C. Shin. 2022. Small fiber
neuropathy associated with SARS-CoV-2 infection. Muscle and Nerve 65(4):440–443.
https://doi.org/10.1002/mus.27458.
Agmon-Levin, N., S. Kivity, M. Szyper-Kravitz, and Y. Shoenfeld. 2009. Transverse myelitis and
vaccines: A multi-analysis. Lupus 18(13):1198–1204.
https://doi.org/10.1177/0961203309345730.
Arunachalam, P. S., M. K. D. Scott, T. Hagan, C. Li, Y. Feng, F. Wimmers, L. Grigoryan, M. Trisal, V.
V. Edara, L. Lai, S. E. Chang, A. Feng, S. Dhingra, M. Shah, A. S. Lee, S. Chinthrajah, S. B.
Sindher, V. Mallajosyula, F. Gao, N. Sigal, S. Kowli, S. Gupta, K. Pellegrini, G. Tharp, S.
Maysel-Auslender, S. Hamilton, H. Aoued, K. Hrusovsky, M. Roskey, S. E. Bosinger, H. T.
Maecker, S. D. Boyd, M. M. Davis, P. J. Utz, M. S. Suthar, P. Khatri, K. C. Nadeau, and B.
Pulendran. 2021. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature
596(7872):410–416. https://doi.org/10.1038/s41586-021-03791-x.
Asbury, A. K., B. G. Arnason, and R. D. Adams. 1969. The inflammatory lesion in idiopathic
polyneuritis. Its role in pathogenesis. Medicine 48(3):173–215. https://doi.org/10.1097/00005792-
196905000-00001.
Baden, L. R., H. M. El Sahly, B. Essink, K. Kotloff, S. Frey, R. Novak, D. Diemert, S. A. Spector, N.
Rouphael, C. B. Creech, J. McGettigan, S. Khetan, N. Segall, J. Solis, A. Brosz, C. Fierro, H.
Schwartz, K. Neuzil, L. Corey, P. Gilbert, H. Janes, D. Follmann, M. Marovich, J. Mascola, L.
Polakowski, J. Ledgerwood, B. S. Graham, H. Bennett, R. Pajon, C. Knightly, B. Leav, W. Deng,
H. Zhou, S. Han, M. Ivarsson, J. Miller, and T. Zaks. 2021. Efficacy and safety of the mRNA-
1273 SARS-CoV-2 vaccine. New England Journal of Medicine 384(5):403–416.
https://doi.org/10.1056/NEJMoa2035389.
Baker, A. T., R. J. Boyd, D. Sarkar, A. Teijeira-Crespo, C. K. Chan, E. Bates, K. Waraich, J. Vant, E.
Wilson, C. D. Truong, M. Lipka-Lloyd, P. Fromme, J. Vermaas, D. Williams, L. Machiesky, M.
Heurich, B. M. Nagalo, L. Coughlan, S. Umlauf, P. L. Chiu, P. J. Rizkallah, T. S. Cohen, A. L.
Parker, A. Singharoy, and M. J. Borad. 2021. ChAdOx1 interacts with CAR and PF4 with
implications for thrombosis with thrombocytopenia syndrome. Science Advances 7(49):eabl8213.
https://doi.org/10.1126/sciadv.abl8213.
Baugh, R. F., G. J. Basura, L. E. Ishii, S. R. Schwartz, C. M. Drumheller, R. Burkholder, N. A. Deckard,
C. Dawson, C. Driscoll, M. B. Gillespie, R. K. Gurgel, J. Halperin, A. N. Khalid, K. A. Kumar,
A. Micco, D. Munsell, S. Rosenbaum, and W. Vaughan. 2013. Clinical practice guideline: Bell’s
palsy executive summary. Otolaryngology—Head and Neck Surgery 149(5):656–663.
https://doi.org/10.1177/0194599813506835.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
102 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
Baxter, R., E. Lewis, K. Goddard, B. Fireman, N. Bakshi, F. DeStefano, J. Gee, H. F. Tseng, A. L.
Naleway, and N. P. Klein. 2016. Acute demyelinating events following vaccines: A case-centered
analysis. Clinical Infectious Diseases 63(11):1456–1462. https://doi.org/10.1093/cid/ciw607.
Benarroch, E. E. 2012. Postural tachycardia syndrome: A heterogeneous and multifactorial disorder.
Mayo Clinic Proceedings 87(12):1214–1225. https://doi.org/10.1016/j.mayocp.2012.08.013.
Bhat, A., S. Naguwa, G. Cheema, and M. E. Gershwin. 2010. The epidemiology of transverse myelitis.
Autoimmunity Reviews 9(5):A395–A399. https://doi.org/10.1016/j.autrev.2009.12.007.
Bolay, H., Ö. Karadas, B. Oztürk, R. Sonkaya, B. Tasdelen, T. D. S. Bulut, Ö. Gülbahar, A. Özge, and B.
Baykan. 2021. HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with
headache: A window to the infection-related headache mechanism. Journal of Headache and
Pain 22(1):94. https://doi.org/10.1186/s10194-021-01306-7.
Bragazzi, N. L., A. A. Kolahi, S. A. Nejadghaderi, P. Lochner, F. Brigo, A. Naldi, P. Lanteri, S.
Garbarino, M. J. M. Sullman, H. Dai, J. Wu, J. D. Kong, H. Jahrami, M. R. Sohrabi, and S. Safiri.
2021. Global, regional, and national burden of Guillain-Barré syndrome and its underlying causes
from 1990 to 2019. Journal of Neuroinflammation 18(1):264. https://doi.org/10.1186/s12974-
021-02319-4.
Caronna, E., T. C. van den Hoek, H. Bolay, D. Garcia-Azorin, A. B. Gago-Veiga, M. Valeriani, T.
Takizawa, K. Messlinger, R. E. Shapiro, P. J. Goadsby, M. Ashina, C. Tassorelli, H. C. Diener,
G. M. Terwindt, and P. Pozo-Rosich. 2023. Headache attributed to SARS-CoV-2 infection,
vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A
comprehensive review. Cephalalgia 43(1). https://doi.org/10.1177/03331024221131337.
Ceccardi, G., F. Schiano di Cola, M. Di Cesare, P. Liberini, M. Magoni, C. Perani, R. Gasparotti, R. Rao,
and A. Padovani. 2022. Post COVID-19 vaccination headache: A clinical and epidemiological
evaluation. Frontiers in Pain Research 3:994140. https://doi.org/10.3389/fpain.2022.994140.
Chen, Y., Z. Xu, P. Wang, X. M. Li, Z. W. Shuai, D. Q. Ye, and H. F. Pan. 2022a. New-onset
autoimmune phenomena post-COVID-19 vaccination. Immunology 165(4):386–401.
https://doi.org/10.1111/imm.13443.
Chen, Y. J., P. L. Cheng, W. N. Huang, H. H. Chen, H. W. Chen, J. P. Chen, C. T. Lin, K. T. Tang, W. T.
Hung, T. Y. Hsieh, Y. H. Chen, Y. M. Chen, and T. H. Hsiao. 2022b. Single-cell RNA
sequencing to decipher the immunogenicity of ChAdOx1 NCOV-19/AZD1222 and mRNA-1273
vaccines in patients with autoimmune rheumatic diseases. Frontiers in Immunology 13:920865.
https://doi.org/10.3389/fimmu.2022.920865.
Cheshire, W. P. 2016. Stimulant medication and postural orthostatic tachycardia syndrome: A tale of two
cases. Clinical Autonomic Research 26(3):229–233. https://doi.org/10.1007/s10286-016-0347-9.
Cutsforth-Gregory, J. K. 2020. Postural tachycardia syndrome and neurally mediated syncope. Continuum
26(1):93–115. https://doi.org/10.1212/con.0000000000000818.
Dalakas, M. C. 2011. Advances in the diagnosis, pathogenesis and treatment of CIDP. Nature Reviews:
Neurology 7(9):507–517. https://doi.org/10.1038/nrneurol.2011.121.
Dalakas, M. C., and W. K. Engel. 1980. Immunoglobulin and complement deposits in nerves of patients
with chronic relapsing polyneuropathy. Archives of Neurology 37(10):637–640.
https://doi.org/10.1001/archneur.1980.00500590061010.
Dowling, P., J. Menonna, and S. Cook. 1977. Cytomegalovirus complement fixation antibody in Guillain-
Barré syndrome. Neurology 27(12):1153–1156. https://doi.org/10.1212/wnl.27.12.1153.
Eldokla, A. M., and M. T. Numan. 2022. Postural orthostatic tachycardia syndrome after mRNA COVID-
19 vaccine. Clinical Autonomic Research 32(4):307–311. https://doi.org/10.1007/s10286-022-
00880-3.
FDA (Food and Drug Administration). 2021. Emergency use authorization (EUA) amendment for an
unapproved product review memorandum. Food and Drug Administration.
https://www.fda.gov/media/153439/download (accessed May 3, 2023).
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 103
PREPUBLICATION COPY—Uncorrected Proofs
FDA. 2023a. BLA clinical review memorandum - COMIRNATY. Food and Drug Administration.
https://www.fda.gov/media/172333/download?attachment (accessed December 5, 2023).
FDA. 2023b. BLA clinical review memorandum - SPIKEVAX. Food and Drug Administration.
https://www.fda.gov/media/172357/download?attachment (accessed December 5, 2023).
FDA. 2023c. Emergency use authorization (EUA) for an unapproved product review memorandum. Food
and Drug Administration. https://www.fda.gov/media/168233/download?attachment (accessed
December 5, 2023).
Fedorowski, A. 2019. Postural orthostatic tachycardia syndrome: Clinical presentation, aetiology and
management. Journal of Internal Medicine 285(4):352–366. https://doi.org/10.1111/joim.12852.
Fedorowski, A., H. Li, X. Yu, K. A. Koelsch, V. M. Harris, C. Liles, T. A. Murphy, S. M. S. Quadri, R.
H. Scofield, R. Sutton, O. Melander, and D. C. Kem. 2017. Antiadrenergic autoimmunity in
postural tachycardia syndrome. Europace: European Pacing, Arrhythmias, and Cardiac
Electrophysiology 19(7):1211–1219. https://doi.org/10.1093/europace/euw154.
Fedorowski, A., and R. Sutton. 2023. Autonomic dysfunction and postural orthostatic tachycardia
syndrome in post-acute COVID-19 syndrome. Nature Reviews: Cardiology 20(5):281–282.
https://doi.org/10.1038/s41569-023-00842-w.
Felipe Cuspoca, A., P. Isaac Estrada, and A. Velez-van-Meerbeke. 2022. Molecular mimicry of SARS-
CoV-2 spike protein in the nervous system: A bioinformatics approach. Computational and
Structural Biotechnology Journal 20:6041–6054. https://doi.org/10.1016/j.csbj.2022.10.022.
Fischera, M., M. Marziniak, I. Gralow, and S. Evers. 2008. The incidence and prevalence of cluster
headache: A meta-analysis of population-based studies. Cephalalgia 28(6):614–618.
https://doi.org/10.1111/j.1468-2982.2008.01592.x.
Flanagan, E. P., T. J. Kaufmann, K. N. Krecke, A. J. Aksamit, S. J. Pittock, B. M. Keegan, C. Giannini,
and B. G. Weinshenker. 2016. Discriminating long myelitis of neuromyelitis optica from
sarcoidosis. Annals of Neurology 79(3):437–447. https://doi.org/10.1002/ana.24582.
Fokke, C., B. van den Berg, J. Drenthen, C. Walgaard, P. A. van Doorn, and B. C. Jacobs. 2014.
Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain 137(Pt 1):33–43.
https://doi.org/10.1093/brain/awt285.
Freeman, R., W. Wieling, F. B. Axelrod, D. G. Benditt, E. Benarroch, I. Biaggioni, W. P. Cheshire, T.
Chelimsky, P. Cortelli, C. H. Gibbons, D. S. Goldstein, R. Hainsworth, M. J. Hilz, G. Jacob, H.
Kaufmann, J. Jordan, L. A. Lipsitz, B. D. Levine, P. A. Low, C. Mathias, S. R. Raj, D. Robertson,
P. Sandroni, I. Schatz, R. Schondorff, J. M. Stewart, and J. G. van Dijk. 2011. Consensus
statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural
tachycardia syndrome. Clinical Autonomic Research 21(2):69–72.
https://doi.org/10.1007/s10286-011-0119-5.
Fu, Q., T. B. Vangundy, M. M. Galbreath, S. Shibata, M. Jain, J. L. Hastings, P. S. Bhella, and B. D.
Levine. 2010. Cardiac origins of the postural orthostatic tachycardia syndrome. Journal of the
American College of Cardiology 55(25):2858–2868. https://doi.org/10.1016/j.jacc.2010.02.043.
Garces, K. N., A. N. Cocores, P. J. Goadsby, and T. S. Monteith. 2022. Headache after vaccination: An
update on recent clinical trials and real-world reporting. Current Pain and Headache Reports
26(12):895–918. https://doi.org/10.1007/s11916-022-01094-y.
García-Azorín, D., T. P. Do, A. R. Gantenbein, J. M. Hansen, M. N. P. Souza, M. Obermann, H. Pohl, C.
J. Schankin, H. W. Schytz, A. Sinclair, G. G. Schoonman, and E. S. Kristoffersen. 2021. Delayed
headache after COVID-19 vaccination: A red flag for vaccine induced cerebral venous
thrombosis. Journal of Headache and Pain 22(1):108. https://doi.org/10.1186/s10194-021-
01324-5.
García-Grimshaw, M., J. A. Galnares-Olalde, O. Y. Bello-Chavolla, A. Michel-Chávez, A. Cadena-
Fernández, M. E. Briseño-Godínez, N. E. Antonio-Villa, I. Núñez, A. Gutiérrez-Romero, L.
Hernández-Vanegas, M. Del Mar Saniger-Alba, R. Carrillo-Mezo, S. E. Ceballos-Liceaga, G.
Carbajal-Sandoval, F. D. Flores-Silva, J. L. Díaz-Ortega, R. Cortes-Alcalá, J. R. Pérez-Padilla, H.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
104 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
López-Gatell, E. Chiquete, G. Reyes-Terán, A. Arauz, and S. I. Valdés-Ferrer. 2022. Incidence of
Guillain-Barré syndrome following SARS-CoV-2 immunization: Analysis of a nationwide
registry of recipients of 81 million doses of seven vaccines. European Journal of Neurology
29(11):3368-3379. https://doi.org/10.1111/ene.15504.
Göbel, C. H., A. Heinze, S. Karstedt, M. Morscheck, L. Tashiro, A. Cirkel, Q. Hamid, R. Halwani, M. H.
Temsah, M. Ziemann, S. Görg, T. Münte, and H. Göbel. 2021a. Clinical characteristics of
headache after vaccination against COVID-19 (coronavirus SARS-CoV-2) with the BNT162b2
mRNA vaccine: A multicentre observational cohort study. Brain Communications 3(3):fcab169.
https://doi.org/10.1093/braincomms/fcab169.
Göbel, C. H., A. Heinze, S. Karstedt, M. Morscheck, L. Tashiro, A. Cirkel, Q. Hamid, R. Halwani, M. H.
Temsah, M. Ziemann, S. Görg, T. Münte, and H. Göbel. 2021b. Headache attributed to
vaccination against COVID-19 (coronavirus SARS-CoV-2) with the ChAdOx1 NCOV-19
(AZD1222) vaccine: A multicenter observational cohort study. Pain Therapy 10(2):1309–1330.
https://doi.org/10.1007/s40122-021-00296-3.
Goodman, B. P., J. A. Khoury, J. E. Blair, and M. F. Grill. 2021. COVID-19 dysautonomia. Frontiers in
Neurology 12:624968. https://doi.org/10.3389/fneur.2021.624968.
Gradin, K., J. Hedner, T. Hedner, A. C. Towle, A. Pettersson, and B. Persson. 1987. Effects of chronic
salt loading on plasma atrial natriuretic peptide (ANP) in the spontaneously hypertensive rat. Acta
Physiologica Scandinavica 129(1):67–72. https://doi.org/10.1111/j.1748-1716.1987.tb08041.x.
Ha, J., S. Park, H. Kang, T. Kyung, N. Kim, D. K. Kim, H. Kim, K. Bae, M. C. Song, K. J. Lee, E. Lee,
B. S. Hwang, J. Youn, J. M. Seok, and K. Park. 2023. Real-world data on the incidence and risk
of Guillain-Barré syndrome following SARS-CoV-2 vaccination: A prospective surveillance
study. Scientific Reports 13(1):3773. https://doi.org/10.1038/s41598-023-30940-1.
Hafsteinsdottir, B., and E. Olafsson. 2016. Incidence and natural history of idiopathic chronic
inflammatory demyelinating polyneuropathy: A population-based study in Iceland. European
Neurology 75(5–6):263–268. https://doi.org/10.1159/000445884.
Hanson, K. E., K. Goddard, N. Lewis, B. Fireman, T. R. Myers, N. Bakshi, E. Weintraub, J. G. Donahue,
J. C. Nelson, S. Xu, J. M. Glanz, J. T. B. Williams, J. D. Alpern, and N. P. Klein. 2022. Incidence
of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA
Network Open 5(4):e228879. https://doi.org/10.1001/jamanetworkopen.2022.8879.
Heath, P. T., E. P. Galiza, D. N. Baxter, M. Boffito, D. Browne, F. Burns, D. R. Chadwick, R. Clark, C.
Cosgrove, J. Galloway, A. L. Goodman, A. Heer, A. Higham, S. Iyengar, A. Jamal, C. Jeanes, P.
A. Kalra, C. Kyriakidou, D. F. McAuley, A. Meyrick, A. M. Minassian, J. Minton, P. Moore, I.
Munsoor, H. Nicholls, O. Osanlou, J. Packham, C. H. Pretswell, A. San Francisco Ramos, D.
Saralaya, R. P. Sheridan, R. Smith, R. L. Soiza, P. A. Swift, E. C. Thomson, J. Turner, M. E.
Viljoen, G. Albert, I. Cho, F. Dubovsky, G. Glenn, J. Rivers, A. Robertson, K. Smith, and S.
Toback. 2021. Safety and efficacy of NVX-CoV2373 COVID-19 vaccine. New England Journal
of Medicine 385(13):1172–1183. https://doi.org/10.1056/NEJMoa2107659.
Hemsath, J. R., A. M. Liaci, J. D. Rubin, B. J. Parrett, S. C. Lu, T. V. Nguyen, M. A. Turner, C. Y. Chen,
K. Cupelli, V. S. Reddy, T. Stehle, M. K. Liszewski, J. P. Atkinson, and M. A. Barry. 2022. Ex
vivo and in vivo CD46 receptor utilization by Species D human adenovirus serotype 26
(HADV26). Journal of Virology 96(3):e0082621. https://doi.org/10.1128/JVI.00826-21.
Hwang, I., T. B. Calvit, B. D. Cash, and K. C. Holtzmuller. 2004. Bell’s palsy: A rare complication of
interferon therapy for hepatitis C. Digestive Diseases and Sciences 49(4):619–620.
https://doi.org/10.1023/b:ddas.0000026389.56819.0c.
International Headache Society. 2018. Headache classification committee of the international headache
society (IHS) the international classification of headache disorders, 3rd edition. Cephalalgia
38(1):1–211. https://doi.org/10.1177/0333102417738202.
Jacobs, B. C., M. P. Hazenberg, P. A. van Doorn, H. P. Endtz, and F. G. van der Meché. 1997. Cross-
reactive antibodies against gangliosides and campylobacter jejuni lipopolysaccharides in patients
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 105
PREPUBLICATION COPY—Uncorrected Proofs
with Guillain-Barré or Miller Fisher Syndrome. Journal of Infectious Diseases 175(3):729–733.
https://doi.org/10.1093/infdis/175.3.729.
Jain, S., A. Khormi, S. R. Sangle, and D. P. D’Cruz. 2023. Transverse myelitis associated with systemic
lupus erythematosus (SLE-TM): A review article. Lupus 32(9):1033–1042.
https://doi.org/10.1177/09612033231185612.
Jensen, R., and L. J. Stovner. 2008. Epidemiology and comorbidity of headache. Lancet Neurology
7(4):354–361. https://doi.org/10.1016/s1474-4422(08)70062-0.
Kadkhoda, K. 2022. Post-adenoviral-based vaccines Guillain-Barré syndrome: A proposed mechanism.
Medical Hypotheses 160:110792. https://doi.org/10.1016/j.mehy.2022.110792.
Kaplin, A. I., D. M. Deshpande, E. Scott, C. Krishnan, J. S. Carmen, I. Shats, T. Martinez, J. Drummond,
S. Dike, M. Pletnikov, S. C. Keswani, T. H. Moran, C. A. Pardo, P. A. Calabresi, and D. A. Kerr.
2005. IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory
disorder transverse myelitis. Journal of Clinical Investigation 115(10):2731–2741.
https://doi.org/10.1172/JCI25141.
Keddie, S., J. Pakpoor, C. Mousele, M. Pipis, P. M. Machado, M. Foster, C. J. Record, R. Y. S. Keh, J.
Fehmi, R. W. Paterson, V. Bharambe, L. M. Clayton, C. Allen, O. Price, J. Wall, A. Kiss-Csenki,
D. P. Rathnasabapathi, R. Geraldes, T. Yermakova, J. King-Robson, M. Zosmer, S.
Rajakulendran, S. Sumaria, S. F. Farmer, R. Nortley, C. R. Marshall, E. J. Newman, N.
Nirmalananthan, G. Kumar, A. A. Pinto, J. Holt, T. M. Lavin, K. M. Brennan, M. S. Zandi, D. L.
Jayaseelan, J. Pritchard, R. D. M. Hadden, H. Manji, H. J. Willison, S. Rinaldi, A. S. Carr, and
M. P. Lunn. 2021. Epidemiological and cohort study finds no association between COVID-19
and Guillain-Barré syndrome. Brain 144(2):682–693. https://doi.org/10.1093/brain/awaa433.
Keh, R. Y. S., S. Scanlon, P. Datta-Nemdharry, K. Donegan, S. Cavanagh, M. Foster, D. Skelland, J.
Palmer, P. M. Machado, S. Keddie, A. S. Carr, M. P. Lunn, and BPNS/ABN COVID-19 Study
Group. 2023. COVID-19 vaccination and guillain-barre syndrome: Analyses using the national
immunoglobulin database. Brain 146(2):739–748. https://doi.org/10.1093/brain/awac067.
Kharraziha, I., J. Axelsson, F. Ricci, G. Di Martino, M. Persson, R. Sutton, A. Fedorowski, and V.
Hamrefors. 2020. Serum activity against G protein–coupled receptors and severity of orthostatic
symptoms in postural orthostatic tachycardia syndrome. Journal of the American Heart
Association 9(15):e015989. https://doi.org/10.1161/jaha.120.015989.
Kim, M. H., and S. Y. Park. 2021. Population-based study and a scoping review for the epidemiology and
seasonality in and effect of weather on Bell’s palsy. Scientific Reports 11(1):16941.
https://doi.org/10.1038/s41598-021-96422-4.
Klein, N. P., N. Lewis, K. Goddard, B. Fireman, O. Zerbo, K. E. Hanson, J. G. Donahue, E. O.
Kharbanda, A. Naleway, J. C. Nelson, S. Xu, W. K. Yih, J. M. Glanz, J. T. B. Williams, S. J.
Hambidge, B. J. Lewin, T. T. Shimabukuro, F. DeStefano, and E. S. Weintraub. 2021.
Surveillance for adverse events after COVID-19 mRNA vaccination. JAMA 326(14):1390–1399.
https://doi.org/10.1001/jama.2021.15072.
Krishnan, C., A. I. Kaplin, D. M. Deshpande, C. A. Pardo, and D. A. Kerr. 2004. Transverse myelitis:
Pathogenesis, diagnosis and treatment. Frontiers in Bioscience 9:1483–1499.
https://doi.org/10.2741/1351.
Kwan, A. C., J. E. Ebinger, J. Wei, C. N. Le, J. R. Oft, R. Zabner, D. Teodorescu, P. G. Botting, J.
Navarrette, D. Ouyang, M. Driver, B. Claggett, B. N. Weber, P. S. Chen, and S. Cheng. 2022.
Apparent risks of postural orthostatic tachycardia syndrome diagnoses after COVID-19
vaccination and SARS-COV-2 infection. Nature Cardiovascular Research 1(12):1187–1194.
https://doi.org/10.1038/s44161-022-00177-8.
Laughlin, R., P. Dyck, L. R. Melton, C. Leibson, J. Ransom, and P. Dyck. 2009. Incidence and
prevalence of CIDP and the association of diabetes mellitus. Neurology 73(1):39–45.
Leibowitz, U. 1969. Epidemic incidence of Bell’s palsy. Brain 92(1):109–114.
https://doi.org/10.1093/brain/92.1.109.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
106 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
Leonhard, S. E., A. A. van der Eijk, H. Andersen, G. Antonini, S. Arends, S. Attarian, F. A. Barroso, K. J.
Bateman, M. R. Batstra, L. Benedetti, B. van den Berg, P. Van den Bergh, J. Bürmann, M.
Busby, C. Casasnovas, D. R. Cornblath, A. Davidson, A. Y. Doets, P. A. van Doorn, C.
Dornonville de la Cour, T. E. Feasby, J. Fehmi, T. Garcia-Sobrino, J. M. Goldstein, K. C.
Gorson, V. Granit, R. D. M. Hadden, T. Harbo, H. P. Hartung, I. Hasan, J. V. Holbech, J. K. L.
Holt, I. Jahan, Z. Islam, S. Karafiath, H. D. Katzberg, R. P. Kleyweg, N. Kolb, K. Kuitwaard, M.
Kuwahara, S. Kusunoki, L. W. G. Luijten, S. Kuwabara, E. Lee Pan, H. C. Lehmann, M. Maas,
L. Martín-Aguilar, J. A. L. Miller, Q. D. Mohammad, S. Monges, V. Nedkova-Hristova, E.
Nobile-Orazio, J. Pardo, Y. Pereon, L. Querol, R. Reisin, W. Van Rijs, S. Rinaldi, R. C. Roberts,
J. Roodbol, N. Shahrizaila, S. H. Sindrup, B. Stein, T. Cheng-Yin, H. Tankisi, A. P. Tio-Gillen,
M. J. Sedano Tous, C. Verboon, F. H. Vermeij, L. H. Visser, R. Huizinga, H. J. Willison, and B.
C. Jacobs. 2022. An international perspective on preceding infections in Guillain-Barré
syndrome: The IGOS-1000 cohort. Neurology 99(12):e1299–e1313.
https://doi.org/10.1212/wnl.0000000000200885.
Li, H., X. Yu, C. Liles, M. Khan, M. Vanderlinde-Wood, A. Galloway, C. Zillner, A. Benbrook, S. Reim,
D. Collier, M. A. Hill, S. R. Raj, L. E. Okamoto, M. W. Cunningham, C. E. Aston, and D. C.
Kem. 2014. Autoimmune basis for postural tachycardia syndrome. Journal of the American Heart
Association 3(1):e000755. https://doi.org/10.1161/jaha.113.000755.
Li, X., B. Raventos, E. Roel, A. Pistillo, E. Martinez-Hernandez, A. Delmestri, C. Reyes, V. Strauss, D.
Prieto-Alhambra, E. Burn, and T. Duarte-Salles. 2022. Association between COVID-19
vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events:
Population-based cohort and self-controlled case series analysis. British Medical Journal
376:e068373. https://doi.org/10.1136/bmj-2021-068373.
Liston, S. L., and M. S. Kleid. 1989. Histopathology of Bell’s palsy. Laryngoscope 99(1):23–26.
https://doi.org/10.1288/00005537-198901000-00006.
Loo, L. K., O. Salim, D. Liang, A. Goel, S. Sumangala, A. S. Gowda, B. Davies, and Y. A. Rajabally.
2022. Acute-onset polyradiculoneuropathy after SARS-COV2 vaccine in the west and north
Midlands, United Kingdom. Muscle and Nerve 65(2):233–237.
https://doi.org/10.1002/mus.27461.
Lopez Chiriboga, S., and E. P. Flanagan. 2021. Myelitis and other autoimmune myelopathies. Continuum
(Minneap Minn) 27(1):62–92. https://doi.org/10.1212/CON.0000000000000900.
Low, P. A., P. Sandroni, M. Joyner, and W. K. Shen. 2009. Postural tachycardia syndrome (POTS).
Journal of Cardiovascular Electrophysiology 20(3):352–358. https://doi.org/10.1111/j.1540-
8167.2008.01407.x.
Marino Gammazza, A., S. Légaré, G. Lo Bosco, A. Fucarino, F. Angileri, E. Conway de Macario, A. J.
Macario, and F. Cappello. 2020. Human molecular chaperones share with SARS-CoV-2 antigenic
epitopes potentially capable of eliciting autoimmunity against endothelial cells: Possible role of
molecular mimicry in COVID-19. Cell Stress and Chaperones 25(5):737–741.
https://doi.org/10.1007/s12192-020-01148-3.
Masuki, S., J. H. Eisenach, W. G. Schrage, C. P. Johnson, N. M. Dietz, B. W. Wilkins, P. Sandroni, P. A.
Low, and M. J. Joyner. 2007. Reduced stroke volume during exercise in postural tachycardia
syndrome. Journal of Applied Physiology 103(4):1128–1135.
https://doi.org/10.1152/japplphysiol.00175.2007.
McCombe, P. A., J. G. McLeod, J. D. Pollard, Y. P. Guo, and T. J. Ingall. 1987. Peripheral sensorimotor
and autonomic neuropathy associated with systemic lupus erythematosus. Clinical, pathological
and immunological features. Brain 110 (Pt 2):533–549. https://doi.org/10.1093/brain/110.2.533.
Miglis, M. G., T. Prieto, R. Shaik, S. Muppidi, D. I. Sinn, and S. Jaradeh. 2020. A case report of postural
tachycardia syndrome after COVID-19. Clinical Autonomic Research 30(5):449–451.
https://doi.org/10.1007/s10286-020-00727-9.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 107
PREPUBLICATION COPY—Uncorrected Proofs
Morciano, C., S. Spila Alegiani, F. Menniti Ippoliti, V. Belleudi, G. Trifirò, G. Zanoni, A. Puccini, E.
Sapigni, N. Mores, O. Leoni, G. Monaco, E. Clagnan, C. Zappetti, E. Bovo, R. Da Cas, and M.
Massari. 2023. Post-marketing active surveillance of Guillan Barré syndrome following
vaccination with anti-COVID-19 vaccines in persons aged ≥12 years in Italy: A multi-database
self-controlled case series study. medRxiv:2023.2001.2017.23284585.
https://doi.org/10.1101/2023.01.17.23284585.
Morsy, S. 2020. NCAM protein and SARS-CoV-2 surface proteins: In-silico hypothetical evidence for
the immunopathogenesis of Guillain-Barre syndrome. Medical Hypotheses 145:110342.
https://doi.org/10.1016/j.mehy.2020.110342.
NORD (National Organization for Rare Disorders). 2022. Bell's palsy. https://rarediseases.org/rare-
diseases/bells-palsy (accessed February 20, 2024).
Oaklander, A. L., A. J. Mills, M. Kelley, L. S. Toran, B. Smith, M. C. Dalakas, and A. Nath. 2022.
Peripheral neuropathy evaluations of patients with prolonged long COVID. Neuroimmunology &
Neuroinflammation 9(3). https://doi.org/10.1212/nxi.0000000000001146.
Olshansky, B., D. Cannom, A. Fedorowski, J. Stewart, C. Gibbons, R. Sutton, W. K. Shen, J.
Muldowney, T. H. Chung, S. Feigofsky, H. Nayak, H. Calkins, and D. G. Benditt. 2020. Postural
orthostatic tachycardia syndrome (POTS): A critical assessment. Progress in Cardiovascular
Diseases 63(3):263–270. https://doi.org/10.1016/j.pcad.2020.03.010.
Patone, M., L. Handunnetthi, D. Saatci, J. Pan, S. V. Katikireddi, S. Razvi, D. Hunt, X. W. Mei, S. Dixon,
F. Zaccardi, K. Khunti, P. Watkinson, C. A. C. Coupland, J. Doidge, D. A. Harrison, R. Ravanan,
A. Sheikh, C. Robertson, and J. Hippisley-Cox. 2021. Neurological complications after first dose
of COVID-19 vaccines and SARS-CoV-2 infection. Nature Medicine 27(12):2144–2153.
https://doi.org/10.1038/s41591-021-01556-7.
Pegat, A., A. Vogrig, C. Khouri, K. Masmoudi, T. Vial, and E. Bernard. 2022. Adenovirus COVID-19
vaccines and Guillain-Barré syndrome with facial paralysis. Annals of Neurology 91(1):162–163.
https://doi.org/10.1002/ana.26258.
Polack, F. P., S. J. Thomas, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, G. Pérez Marc,
E. D. Moreira, C. Zerbini, R. Bailey, K. A. Swanson, S. Roychoudhury, K. Koury, P. Li, W. V.
Kalina, D. Cooper, R. W. Frenck, Jr., L. L. Hammitt, Ö. Türeci, H. Nell, A. Schaefer, S. Ünal, D.
B. Tresnan, S. Mather, P. R. Dormitzer, U. Şahin, K. U. Jansen, and W. C. Gruber. 2020. Safety
and efficacy of the BNT162b2 mRNA COVID-19 vaccine. New England Journal of Medicine
383(27):2603–2615. https://doi.org/10.1056/NEJMoa2034577.
Rafati, A., Y. Pasebani, M. Jameie, Y. Yang, M. Jameie, S. Ilkhani, M. Amanollahi, D. Sakhaei, M.
Rahimlou, and A. Kheradmand. 2023. Association of SARS-CoV-2 vaccination or infection with
Bell palsy: A systematic review and meta-analysis. JAMA Otolaryngology—Head & Neck
Surgery 149(6):493–504. https://doi.org/10.1001/jamaoto.2023.0160.
Raj, S. R., I. Biaggioni, P. C. Yamhure, B. K. Black, S. Y. Paranjape, D. W. Byrne, and D. Robertson.
2005. Renin-aldosterone paradox and perturbed blood volume regulation underlying postural
tachycardia syndrome. Circulation 111(13):1574–1582.
https://doi.org/10.1161/01.Cir.0000160356.97313.5d.
Rivers, T. M. 1932. Viruses. Science 75(1956):654–656. https://doi.org/10.1126/science.75.1956.654.
Rodriguez, B., R. Hoepner, A. Salmen, N. Kamber, and W. J. Z’Graggen. 2021. Immunomodulatory
treatment in postural tachycardia syndrome: A case series. European Journal of Neurology
28(5):1692–1697. https://doi.org/10.1111/ene.14711.
Rzymski, P. 2023. Guillain-Barré syndrome and COVID-19 vaccines: Focus on adenoviral vectors.
Frontiers in Immunology 14:1183258. https://doi.org/10.3389/fimmu.2023.1183258.
Sadoff, J., G. Gray, A. Vandebosch, V. Cárdenas, G. Shukarev, B. Grinsztejn, P. A. Goepfert, C. Truyers,
H. Fennema, B. Spiessens, K. Offergeld, G. Scheper, K. L. Taylor, M. L. Robb, J. Treanor, D. H.
Barouch, J. Stoddard, M. F. Ryser, M. A. Marovich, K. M. Neuzil, L. Corey, N. Cauwenberghs,
T. Tanner, K. Hardt, J. Ruiz-Guiñazú, M. Le Gars, H. Schuitemaker, J. Van Hoof, F. Struyf, and
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
108 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
M. Douoguih. 2021. Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-
19. New England Journal of Medicine 384(23):2187–2201.
https://doi.org/10.1056/NEJMoa2101544.
Sandroni, P., T. L. Opfer-Gehrking, B. R. McPhee, and P. A. Low. 1999. Postural tachycardia syndrome:
Clinical features and follow-up study. Mayo Clinic Proceedings 74(11):1106–1110.
https://doi.org/10.4065/74.11.1106.
See, I., J. R. Su, A. Lale, E. J. Woo, A. Y. Guh, T. T. Shimabukuro, M. B. Streiff, A. K. Rao, A. P.
Wheeler, S. F. Beavers, A. P. Durbin, K. Edwards, E. Miller, T. A. Harrington, A. Mba-Jonas, N.
Nair, D. T. Nguyen, K. R. Talaat, V. C. Urrutia, S. C. Walker, C. B. Creech, T. A. Clark, F.
DeStefano, and K. R. Broder. 2021. U.S. case reports of cerebral venous sinus thrombosis with
thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA
325(24):2448–2456. https://doi.org/10.1001/jama.2021.7517.
Sejvar, J. J., K. S. Kohl, J. Gidudu, A. Amato, N. Bakshi, R. Baxter, D. R. Burwen, D. R. Cornblath, J.
Cleerbout, K. M. Edwards, U. Heininger, R. Hughes, N. Khuri-Bulos, R. Korinthenberg, B. J.
Law, U. Munro, H. C. Maltezou, P. Nell, J. Oleske, R. Sparks, P. Velentgas, P. Vermeer, and M.
Wiznitzer. 2011. Guillain-Barré Syndrome and Fisher Syndrome: Case definitions and guidelines
for collection, analysis, and presentation of immunization safety data. Vaccine 29(3):599–612.
https://doi.org/10.1016/j.vaccine.2010.06.003.
Sekiguchi, K., N. Watanabe, N. Miyazaki, K. Ishizuchi, C. Iba, Y. Tagashira, S. Uno, M. Shibata, N.
Hasegawa, R. Takemura, J. Nakahara, and T. Takizawa. 2022. Incidence of headache after
COVID-19 vaccination in patients with history of headache: A cross-sectional study. Cephalalgia
42(3):266–272. https://doi.org/10.1177/03331024211038654.
Shahrizaila, N., H. C. Lehmann, and S. Kuwabara. 2021. Guillain-Barré Syndrome. Lancet
397(10280):1214–1228. https://doi.org/10.1016/S0140-6736(21)00517-1.
Shasha, D., R. Bareket, F. H. Sikron, O. Gertel, J. Tsamir, D. Dvir, D. Mossinson, A. D. Heymann, and
G. Zacay. 2022. Real-world safety data for the Pfizer BNT162b2 SARS-CoV-2 vaccine:
Historical cohort study. Clinical Microbiology and Infection 28(1):130–134.
https://doi.org/10.1016/j.cmi.2021.09.018.
Sheerin, D., C. Dold, D. O’Connor, A. J. Pollard, and C. S. Rollier. 2021. Distinct patterns of whole
blood transcriptional responses are induced in mice following immunisation with adenoviral and
poxviral vector vaccines encoding the same antigen. BMC Genomics 22(1):777.
https://doi.org/10.1186/s12864-021-08061-8.
Sheikh, K. A., I. Nachamkin, T. W. Ho, H. J. Willison, J. Veitch, H. Ung, M. Nicholson, C. Y. Li, H. S.
Wu, B. Q. Shen, D. R. Cornblath, A. K. Asbury, G. M. McKhann, and J. W. Griffin. 1998.
Campylobacter jejuni lipopolysaccharides in Guillain-Barré syndrome: Molecular mimicry and
host susceptibility. Neurology 51(2):371–378. https://doi.org/10.1212/wnl.51.2.371.
Shemer, A., E. Pras, A. Einan-Lifshitz, B. Dubinsky-Pertzov, and I. Hecht. 2021. Association of COVID-
19 vaccination and facial nerve palsy: A case-control study. JAMA Otolaryngology—Head &
Neck Surgery 147(8):739–743. https://doi.org/10.1001/jamaoto.2021.1259.
Shibao, C., C. Arzubiaga, L. J. Roberts, II, S. Raj, B. Black, P. Harris, and I. Biaggioni. 2005.
Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension
45(3):385–390. https://doi.org/10.1161/01.Hyp.0000158259.68614.40.
Shibli, R., O. Barnett, Z. Abu-Full, N. Gronich, R. Najjar-Debbiny, I. Doweck, G. Rennert, and W.
Saliba. 2021. Association between vaccination with the BNT162b2 mRNA COVID-19 vaccine
and Bell’s palsy: A population-based study. Lancet Regional Health—Europe 11:100236.
https://doi.org/10.1016/j.lanepe.2021.100236.
Shoaibi, A., P. C. Lloyd, H. L. Wong, T. C. Clarke, Y. Chillarige, R. Do, M. Hu, Y. Jiao, A. Kwist, A.
Lindaas, K. Matuska, R. McEvoy, M. Ondari, S. Parulekar, X. Shi, J. Wang, Y. Lu, J. Obidi, C.
K. Zhou, J. A. Kelman, R. A. Forshee, and S. A. Anderson. 2023. Evaluation of potential adverse
events following COVID-19 mRNA vaccination among adults aged 65 years and older: Two self-
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 109
PREPUBLICATION COPY—Uncorrected Proofs
controlled studies in the U.S. Vaccine 41(32):4666–4678.
https://doi.org/10.1016/j.vaccine.2023.06.014.
Shouman, K., G. Vanichkachorn, W. P. Cheshire, M. D. Suarez, S. Shelly, G. J. Lamotte, P. Sandroni, E.
E. Benarroch, S. E. Berini, J. K. Cutsforth-Gregory, E. A. Coon, M. L. Mauermann, P. A. Low,
and W. Singer. 2021. Autonomic dysfunction following COVID-19 infection: An early
experience. Clinical Autonomic Research 31(3):385–394. https://doi.org/10.1007/s10286-021-
00803-8.
Silvestro, M., A. Tessitore, I. Orologio, P. Sozio, G. Napolitano, M. Siciliano, G. Tedeschi, and A. Russo.
2021. Headache worsening after COVID-19 vaccination: An online questionnaire-based study on
841 patients with migraine. Journal of Clinical Medicine 10(24).
https://doi.org/10.3390/jcm10245914.
Soeiro, A. M., and P. M. Pego-Fernandes. 2021. Post-COVID-19 cardiological alterations. Sao Paulo
Medical Journal 139(6):543–544. https://doi.org/10.1590/1516-3180.2021.139628062021.
Steiner, I., and Y. Mattan. 1999. Bell’s palsy and herpes viruses: To (acyclo)vir or not to (acyclo)vir?
Journal of the Neurological Sciences 170(1):19–23. https://doi.org/10.1016/s0022-
510x(99)00187-2.
Stewart, J. M., A. J. Ocon, D. Clarke, I. Taneja, and M. S. Medow. 2009. Defects in cutaneous
angiotensin-converting enzyme 2 and angiotensin-(1-7) production in postural tachycardia
syndrome. Hypertension 53(5):767–774. https://doi.org/10.1161/hypertensionaha.108.127357.
Stovner, L., K. Hagen, R. Jensen, Z. Katsarava, R. Lipton, A. Scher, T. Steiner, and J. A. Zwart. 2007.
The global burden of headache: A documentation of headache prevalence and disability
worldwide. Cephalalgia 27(3):193–210. https://doi.org/10.1111/j.1468-2982.2007.01288.x.
Sturkenboom, M., D. Messina, O. Paoletti, A. de Burgos-Gonzalez, R. Zabner, P. García-Poza, C. Huerta,
A. Llorente García, M. Martin-Perez, M. Martinez, I. Martin, J. Overbeek, M. Padros-Goossens,
P. Souverein, K. Swart, O. Klungel, and R. Gini. 2022. Cohort monitoring of 29 adverse events of
special interest prior to and after COVID-19 vaccination in four large European electronic health
care data sources. medRxiv:2022.2008.2017.22278894.
https://doi.org/10.1101/2022.08.17.22278894.
Sullivan, F. M., I. R. Swan, P. T. Donnan, J. M. Morrison, B. H. Smith, B. McKinstry, R. J. Davenport, L.
D. Vale, J. E. Clarkson, V. Hammersley, S. Hayavi, A. McAteer, K. Stewart, and F. Daly. 2007.
Early treatment with prednisolone or acyclovir in Bell’s palsy. New England Journal of Medicine
357(16):1598–1607. https://doi.org/10.1056/NEJMoa072006.
Suvas, S. 2017. Role of substance P neuropeptide in inflammation, wound healing, and tissue
homeostasis. Journal of Immunology 199(5):1543–1552.
https://doi.org/10.4049/jimmunol.1601751.
Takeuchi, Y., M. Iwagami, S. Ono, N. Michihata, K. Uemura, and H. Yasunaga. 2022. A post-marketing
safety assessment of COVID-19 mRNA vaccination for serious adverse outcomes using
administrative claims data linked with vaccination registry in a city of Japan. Vaccine
40(52):7622–7630. https://doi.org/10.1016/j.vaccine.2022.10.088.
Takuva, S., A. Takalani, I. Seocharan, N. Yende-Zuma, T. Reddy, I. Engelbrecht, M. Faesen, K. Khuto,
C. Whyte, V. Bailey, V. Trivella, J. Peter, J. Opie, V. Louw, P. Rowji, B. Jacobson, P.
Groenewald, R. E. Dorrington, R. Laubscher, D. Bradshaw, H. Moultrie, L. Fairall, I. Sanne, L.
Gail-Bekker, G. Gray, A. Goga, and N. Garrett. 2022. Safety evaluation of the single-dose
Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase
3b implementation trial. PLoS Medicine 19(6):e1004024.
https://doi.org/10.1371/journal.pmed.1004024.
Thieben, M. J., P. Sandroni, D. M. Sletten, L. M. Benrud-Larson, R. D. Fealey, S. Vernino, V. A.
Lennon, W. K. Shen, and P. A. Low. 2007. Postural orthostatic tachycardia syndrome: The Mayo
Clinic experience. Mayo Clinic Proceedings 82(3):308–313. https://doi.org/10.4065/82.3.308.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
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Thomas, P. K., R. W. Walker, P. Rudge, J. A. Morgan-Hughes, R. H. King, J. M. Jacobs, K. R. Mills, I.
E. Ormerod, N. M. Murray, and W. I. McDonald. 1987. Chronic demyelinating peripheral
neuropathy associated with multifocal central nervous system demyelination. Brain 110 (Pt
1):53–76. https://doi.org/10.1093/brain/110.1.53.
Togha, M., S. M. Hashemi, N. Yamani, F. Martami, and Z. Salami. 2022. A review on headaches due to
COVID-19 infection. Frontiers in Neurology 13:942956.
https://doi.org/10.3389/fneur.2022.942956.
Transverse Myelitis Consortium Working Group. 2002. Proposed diagnostic criteria and nosology of
acute transverse myelitis. Neurology 59(4):499–505. https://doi.org/10.1212/wnl.59.4.499.
Van den Bergh, P. Y., R. D. Hadden, P. Bouche, D. R. Cornblath, A. Hahn, I. Illa, C. L. Koski, J. M.
Léger, E. Nobile‐Orazio, and J. Pollard. 2010. European Federation of Neurological
Societies/Peripheral Nerve Society guideline on management of chronic inflammatory
demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of
Neurological Societies and the Peripheral Nerve Society—first revision. European Journal of
Neurology 17(3):356–363.
Van den Bergh, P. Y. K., P. A. van Doorn, R. D. M. Hadden, B. Avau, P. Vankrunkelsven, J. A. Allen, S.
Attarian, P. H. Blomkwist-Markens, D. R. Cornblath, F. Eftimov, H. S. Goedee, T. Harbo, S.
Kuwabara, R. A. Lewis, M. P. Lunn, E. Nobile-Orazio, L. Querol, Y. A. Rajabally, C. Sommer,
and H. A. Topaloglu. 2021. European Academy of Neurology/Peripheral Nerve Society guideline
on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy:
Report of a joint task force—second revision. Journal of the Peripheral Nervous System
26(3):242–268. https://doi.org/10.1111/jns.12455.
Vellozzi, C., S. Iqbal, and K. Broder. 2014. Guillain-Barré syndrome, influenza, and influenza
vaccination: The epidemiologic evidence. Clinical Infectious Diseases 58(8):1149–1155.
https://doi.org/10.1093/cid/ciu005.
Vernino, S., K. M. Bourne, L. E. Stiles, B. P. Grubb, A. Fedorowski, J. M. Stewart, A. C. Arnold, L. A.
Pace, J. Axelsson, J. R. Boris, J. P. Moak, B. P. Goodman, K. R. Chémali, T. H. Chung, D. S.
Goldstein, A. Diedrich, M. G. Miglis, M. M. Cortez, A. J. Miller, R. Freeman, I. Biaggioni, P. C.
Rowe, R. S. Sheldon, C. A. Shibao, D. M. Systrom, G. A. Cook, T. A. Doherty, H. I. Abdallah,
A. Darbari, and S. R. Raj. 2021. Postural orthostatic tachycardia syndrome (POTS): State of the
science and clinical care from a 2019 national institutes of health expert consensus meeting—part
1. Autonomic Neuroscience 235:102828. https://doi.org/10.1016/j.autneu.2021.102828.
Vernino, S., Hopkins, S., Bryarly, M., Hernandez, R., Salter, A. 2023. Randomized controlled trial of
intravenous immunoglobulin for autoimmune postural tachycardia syndrome (ISTAND). Clinical
Autonomic Research.
Walker, J. L., A. Schultze, J. Tazare, A. Tamborska, B. Singh, K. Donegan, J. Stowe, C. E. Morton, W. J.
Hulme, H. J. Curtis, E. J. Williamson, A. Mehrkar, R. M. Eggo, C. T. Rentsch, R. Mathur, S.
Bacon, A. J. Walker, S. Davy, D. Evans, P. Inglesby, G. Hickman, B. MacKenna, L. Tomlinson,
A. Ca Green, L. Fisher, J. Cockburn, J. Parry, F. Hester, S. Harper, C. Bates, S. J. Evans, T.
Solomon, N. J. Andrews, I. J. Douglas, B. Goldacre, L. Smeeth, and H. I. McDonald. 2022.
Safety of COVID-19 vaccination and acute neurological events: A self-controlled case series in
England using the OpenSafely platform. Vaccine 40(32):4479–4487.
https://doi.org/10.1016/j.vaccine.2022.06.010.
Wanschitz, J., H. Maier, H. Lassmann, H. Budka, and T. Berger. 2003. Distinct time pattern of
complement activation and cytotoxic T cell response in Guillain-Barré syndrome. Brain 126(Pt
9):2034–2042. https://doi.org/10.1093/brain/awg207.
Weinstock, L. B., J. B. Brook, T. L. Myers, and B. Goodman. 2018. Successful treatment of postural
orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and
antibiotic treatment. BMJ Case Reports. https://doi.org/10.1136/bcr-2017-221405.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
NEUROLOGIC CONDITIONS 111
PREPUBLICATION COPY—Uncorrected Proofs
Wratten, S. J., D. J. Faulkner, K. Hirotsu, and J. Clardy. 1977. Trimethylenemethane. A reversible,
temperature dependent transformation from higher to lower symmetry as observed by electron
spin resonance spectroscopy. Journal of the American Chemical Society 99(8):2824-2825.
https://doi.org/10.1021/ja00450a083.
Yılmaz, M., M. Tarakcioglu, N. Bayazit, Y. A. Bayazit, M. Namiduru, and M. Kanlikama. 2002. Serum
cytokine levels in Bell’s palsy. Journal of the Neurological Sciences 197(1–2):69–72.
https://doi.org/10.1016/s0022-510x(02)00049-7.
Yuki, N., T. Taki, F. Inagaki, T. Kasama, M. Takahashi, K. Saito, S. Handa, and T. Miyatake. 1993. A
bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1 ganglioside-like
structure. Journal of Experimental Medicine 178(5):1771–1775.
https://doi.org/10.1084/jem.178.5.1771.
Yuki, N., K. Susuki, M. Koga, Y. Nishimoto, M. Odaka, K. Hirata, K. Taguchi, T. Miyatake, K.
Furukawa, T. Kobata, and M. Yamada. 2004. Carbohydrate mimicry between human ganglioside
GM1 and campylobacter jejuni lipooligosaccharide causes Guillain-Barré syndrome. Proceedings
of the National Academy of Sciences of the United States of America 101(31):11404–11409.
https://doi.org/10.1073/pnas.0402391101.
Zalewski, N. L., A. A. Rabinstein, K. N. Krecke, R. D. Brown, Jr., E. F. M. Wijdicks, B. G. Weinshenker,
T. J. Kaufmann, J. M. Morris, A. J. Aksamit, J. D. Bartleson, G. Lanzino, M. M. Blessing, and E.
P. Flanagan. 2019. Characteristics of spontaneous spinal cord infarction and proposed diagnostic
criteria. JAMA Neurology 76(1):56–63. https://doi.org/10.1001/jamaneurol.2018.2734.
Zhang, W., L. Xu, T. Luo, F. Wu, B. Zhao, and X. Li. 2020. The etiology of Bell’s palsy: A review.
Journal of Neurology 267(7):1896–1905. https://doi.org/10.1007/s00415-019-09282-4.
Zussy, C., F. Loustalot, F. Junyent, F. Gardoni, C. Bories, J. Valero, M. G. Desarmenien, F. Bernex, D.
Henaff, N. Bayo-Puxan, J. W. Chen, N. Lonjon, Y. de Koninck, J. O. Malva, J. M. Bergelson, M.
di Luca, G. Schiavo, S. Salinas, and E. J. Kremer. 2016. Coxsackievirus adenovirus receptor loss
impairs adult neurogenesis, synapse content, and hippocampus plasticity. Journal of
Neuroscience 36(37):9558–9571. https://doi.org/10.1523/JNEUROSCI.0132-16.2016.
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4
Sensorineural Hearing Loss, Tinnitus,
and COVID-19 Vaccines
This chapter describes the potential relationship between COVID-19 vaccines and sudden
sensorineural hearing loss (SSNHL) and tinnitus (see Boxes 4-1 and 4-2 for all conclusions in
this chapter).
SENSORINEURAL HEARING LOSS
BOX 4-1
Conclusions for Sensorineural Hearing Loss
Conclusion 4-1: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and sensorineural hearing loss.
Conclusion 4-2: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and sensorineural hearing loss.
Conclusion 4-3: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and sensorineural hearing loss.
Conclusion 4-4: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and sensorineural hearing loss.
Background
The whole auditory system is how humans’ access and make sense of environmental
sounds. It is a multistage system characterized by encoding of environmental auditory stimuli by
peripheral structures and decoding of the stimuli by central structures in the brainstem and
cerebral cortex (Pickles, 2013). Peripherally, auditory energy is funneled into the pinna toward
the tympanic membrane (eardrum), where it is converted to mechanical energy and moves along
the ossicles in the middle ear to the cochlea, which contains the organ of Corti, which acts to
encode auditory signals as neuroelectric signals (e.g., action potentials) that are transmitted to the
temporal lobe via the eighth nerve and brainstem for decoding and processing (Pickles, 2013).
Damage can occur at any step in this process, resulting in different types of hearing loss.
Conductive hearing loss is characterized by an inability for the outer and middle ear to transmit
signals to the inner ear (e.g., rupture in the tympanic membrane, fluid in the middle ear) and is
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often transient (e.g., fluid drains from the ear) or can be addressed via medical or surgical
interventions (Lee, 2013; Pickles, 2013). Sensorineural hearing loss is distinguished by
disruption in encoding auditory information in the cochlea or along the eighth nerve and is
usually permanent. Central hearing loss or auditory processing disorders (Martin and Jerger,
2005; Task Force on Central Auditory Processing Consensus Development, 1996), although
more poorly understood and considered rare, especially among adults, occur when sound is
encoded normally in the peripheral ear (e.g., no sign of sensorineural or conductive loss but
deficits in the neural processing of auditory information mean that individuals struggle with
understanding it despite functioning peripheral hearing (Katz, 2015).
Audiologists and otolaryngologists diagnose hearing loss using a comprehensive
assessment battery, including various measures assessing different processes of the auditory
system (Katz, 2015). The criterion standard for peripheral hearing is pure-tone audiometry,
which identifies the softest volume at which tones at different frequencies can be detected. A
combination of methods of presenting the tone via air conduction (e.g., traditional headphones
that stimulate the entire outer, middle, and inner ears) and bone conduction (e.g., oscillator that
directly stimulates the cochlea) distinguish different types of hearing loss (Katz, 2015).
Self-reported hearing has relatively poor agreement with the criterion standard, with
sensitivity and specificity reported as 41–65 percent and 81–88 percent among U.S. adults over
20 years old, respectively (Agrawal et al., 2008). Moreover, accuracy and the direction of
misclassification (e.g., directional difference between self-report and criterion measured degree
of hearing loss) differs by key demographic variables, including age, race, and sex; older White
men are more likely to underestimate their level of hearing loss relative to younger Black women
(Kamil et al., 2015). The relatively poor accuracy of self-reported hearing can be attributed to the
insidious onset of age-related hearing loss masking the change, perceived normalcy for a given
age group, stigma, or projection (believing that others are mumbling or speaking poorly).
Moreover, understanding speech requires both an auditory (e.g., accessing sound) and cognitive
(e.g., making sense of the information) component, and listening with hearing loss can contribute
to fatigue from cognitive load placed on the brain when decoding poor peripheral signals
(Hornsby et al., 2016; Wingfield et al., 2005). Some may misattribute hearing loss to cognitive
processes and vice versa when considering their own hearing levels.
Although the procedures are standardized, the actual clinical cut points vary by
professional organizations and are at the discretion of the provider. Population estimates vary by
the definition and whether hearing loss estimates are limited to bilateral or unilateral (estimates
increase when including unilateral loss) (Lin et al., 2011). Using the commonly cited World
Health Organization (WHO) cutoffs from before 2021, estimates suggest that 23 percent of U.S.
individuals over age 12 have bilateral hearing loss and that prevalence increases with age, from
less than 1 percent at 20–29 years to more than 80 percent over 80 years (Goman and Lin, 2016).
WHO suggests approximately 20 percent of the global population has hearing loss (WHO).
Among the types of hearing loss, specific reliable national estimates are not reported. Permanent
conductive hearing loss is relatively rare (Cruickshanks et al., 1998), and sensorineural hearing
loss is the overwhelmingly most common permanent form, with the majority of cases being
attributed to age (Reed et al., 2023; Yamasoba et al., 2013). However, estimates vary by
definition of hearing loss and global region and are limited due to the often-transient nature of
conductive hearing loss, relatively low uptake of hearing assessment within health systems, and
lack of feasibility for comprehensive hearing assessment in epidemiological studies (Chadha et
al., 2021; Katz, 2015; Powell et al., 2021).
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Known individual risk factors for sensorineural hearing loss include congenital and
progressive genetic conditions, excessive noise, certain medications and chemicals, health
behaviors (e.g., smoking), chronic cardiovascular conditions, viral infections, and age-related
cellular degeneration (Agrawal et al., 2008; Eggermont, 2017; Van Eyken et al., 2007). The
majority of adult hearing loss is often labeled as “age-related” and attributed to a combination of
exposures that insidiously degrades hearing acuity such that changes are so subtle they often go
unnoticed until they are more pronounced (Lin et al., 2011; Yamasoba et al., 2013).
SSNHL is characterized as an acute change (e.g., within a 72-hour period). The specific
mechanisms are poorly characterized as several risk factors and potential causes have been
reported including infection, trauma, autoimmune disease, certain medications (e.g.,
aminoglycosides), and certain disorders of the inner ear (e.g., Meniere’s) (Kuhn et al., 2011;
Schreiber et al., 2010; Stachler et al., 2012). It is relatively rare (approximately 5–20 of 100,000
people yearly), but estimates are mostly reliant on high-income countries (Stachler et al., 2012).
Estimates suggest that approximately 40–60 percent of cases will recover to normal levels in a
few weeks of follow-up (Kuhn et al., 2011; Mattox and Simmons, 1977; Wilson et al., 1980).
However, the incidence and recovery rate are not well documented in low- and middle-income
countries. Moreover, there is variation in the literature of the different definitions for risk-
windows and specific change in audiometric thresholds.
Mechanisms
The mechanistic evidence for a biologically plausible association between hearing loss
and COVID-19 vaccination is limited; a paucity of work offers direct evidence. Similarly, there
is little mechanistic evidence whether COVID-19 infection causes hearing loss. Much of the
relevant literature is theoretical or postulated based on adjacent research. Moreover, no literature
offers substantive discussion of the potential for increased risk of an association by comorbid
conditions, genetic predisposition, concurrent pharmacologic agent, or environmental exposures.
The initial consideration is the possible direct viral involvement of the inner ear or the
vestibulocochlear nerve (Kaliyappan et al., 2022). The inflammatory response, possibly
cochleitis or neuritis, could be an effect of the immune activation by the vaccine. The
hyperproduction of proinflammatory cytokines in response to the vaccine could inadvertently
affect the audio vestibular system, leading to symptoms such as vertigo, tinnitus, and hearing
loss. Such a hyperinflammatory state is known to cause tissue damage and could be particularly
detrimental to the sensitive structures of the ear (Kamogashira et al., 2022). Specifically, the
response to BNT162b2 1 provides a hypothetical framework. Studies demonstrate that this
vaccine elicits a strong immune response, characterized by high levels of neutralizing antibodies
and robust T cell responses, including antigen-specific CD8+ and Th1-type CD4+ T cells
(Sadarangani et al., 2021). Although this is crucial for protective immunity, it also raises the
potential for unintended auditory effects. The inflammatory environment can indirectly inflict
damage on the intricate anatomy of the ear, affecting or occluding small areas within it. The
vigorous immune response, especially the aspects involving cell-mediated immunity and
cytokine production, could inadvertently affect the ear through either direct inflammatory
damage or secondary effects, such as vascular complications.
1 The COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®.
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Others have postulated about molecular mimicry and immunological considerations, such
as an autoimmune-like response, where antibodies or T cells, activated by the vaccine, might
erroneously recognize inner ear antigens as viral epitopes and trigger an immune attack (Ahmed
et al., 2022). Given the specificity and sensitivity of the immune response, particularly the
adaptive immunity involving antigen-specific T cell and B cell responses, this cross-reactivity
could be a plausible mechanism for vaccine-induced auditory damage.
Last, the unique anatomical and physiological characteristics of the cochlea and
semicircular canals, notably their isolated blood supply, make them particularly vulnerable to
ischemic events (Tabuchi et al., 2010). Vaccine-induced alterations in the cardiovascular system,
either directly or through an immune-mediated pathway, could lead to thrombosis or hypoxia in
these areas, resulting in auditory dysfunction.
Epidemiological Evidence
Clinical trial results submitted to FDA for Emergency Use Authorization and/or full
approval do not indicate a signal regarding sensorineural hearing loss and any of the vaccines
under study (FDA, 2021, 2023a, 2023b, 2023c). Table 4-1 presents five studies that contributed
to the causality assessment.
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Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
HEARING LOSS AND TINNITUS 119
PREPUBLICATION COPY: Uncorrected Proofs
Nieminen et al. (2023) compared the incidence rate of SSNHL in the 30-day window
preceding vaccination and 0–54 days and more than 54 days after vaccination to that between
January 1, 2019, and March 1, 2020, using a national Finnish electronic health database (n = 5.5
million people); excluding those with pre-existing recent diagnosis of SSNHL from the period
immediately before the study (2015–2018). Finland’s national vaccination register provided the
vaccination dates and product names. SSNHL was identified using an ICD-10 diagnostic code
for specialized care visits and from hospital wards. Comorbid conditions were identified from
multiple sources. Models were adjusted for calendar time, SARS-CoV-2 infection, demographic,
cardiovascular, chronic comorbidities, and health care use covariates. Relative to the incidence
before March 2020, adjusted models suggest no increased risk in the initial 0–54-day risk period
after the first dose or second dose with BNT162b2 (Dose 1: IR 0.8, 95% CI: 0.6–1.0; Dose 2:
IRR 0.8, 95% CI: 0.6–1.2), or mRNA-1273 2 (Dose 1: IR 0.8, 95% CI: 0.5–1.4; Dose 2: IRR 1.2,
95% CI: 0.7–1.9). Secondary models examining risk after 54 days postvaccination and after a
third dose likewise yielded no associations.
Yanir et al. (2022) used the Clalit Health Services database in Israel to estimate the
incidence of SSNHL after first and second doses of BNT162b2 from December 20, 2020, to
April 30, 2021. Subsequent analysis compared estimates to the incidence of SSNHL from the
same database in 2018 and 2019 and developed age- and sex- standardized incidence ratios.
SSNHL was identified using a broad array of ICD-9 codes for hearing loss (388.2, 389.1,
389.10–389.13, 389.15–389.18, 389.8, and 389.9) and concurrent prednisone use within 30 days
of diagnosis. The authors reported that 2.6 million people (mean [SD] age, 46.8 [19.6] years;
51.5 percent female) received the first dose, with 91 cases of SSNHL reported. Of these, 2.4
million (93.8 percent) received the second dose, with 79 cases of SSNHL reported. The age- and
sex-weighted standardized incidence ratios (SIR) were 1.35 (95% CI: 1.09–1.65) after the first
dose and 1.23 (95% CI: 0.98–1.53) after the second dose when using 2018 data as a reference
(the sensitivity analysis was similar when using 2019 data).
Leong et al. (2023) leveraged a clinical convenience sample from an otology clinic
(NYC, NY) (rather than prospective outreach) from May to July 2021 to characterize the
incidence of hearing loss after COVID-19 vaccination. Among 500 individuals who completed
screening (median age 56.6 years; 59.4 percent female), 420 reported being vaccinated (58.4
percent BNT162b2, 29.1 percent mRNA-1273, 3.3 percent Ad26.COV2.S); 21 (5 percent)
reported hearing loss within 4 weeks of vaccination. However, after comprehensive audiologic
and otologic evaluation, only seven cases (1.7 percent of vaccinated individuals) were deemed to
be SSNHL; the rest represented new or exacerbated symptoms of known pathologies of hearing
loss that did not represent SSNHL definition or were unrelated to vaccination. The study did not
compare vaccinated to unvaccinated individuals. Despite concerns with selection bias, recall bias
and confounding, a key finding from this paper was that self-reported declines in hearing after
vaccination may be unreliable, as a majority of cases were attributable to other etiologies.
Inaccurate reporting of tinnitus may lead to overestimation of observed associations.
Two included studies used data from the U.S. Vaccine Adverse Events Reporting System
(VAERS). For denominators, each of these studies utilized publicly available data from the CDC
on the total number of individuals vaccinated with COVID-19 vaccines and the total number of
doses administered in the United States during the time frames of interest. As part of a larger
analysis of neurologic events after COVID-19 vaccination, Frontera et al. (2022) reported an
2 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®.
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
120 VACCINE EVIDENCE REVIEW
PREPUBLICATION COPY—Uncorrected Proofs
incidence rate (IR) of 3.26 cases of hearing loss identified by free text or automated coding per
1,000,000 vaccines (IR per 1,000,000 by vaccine type: 3.20 BNT162b2, 3.08 mRNA-1273, 6.29
Ad26.COV2.S) between January 1, 2021, and June 14, 2021 (306.9 million COVID-19 vaccine
doses; 314,610 total adverse events). The number of hearing loss events are not specifically
reported (Frontera et al., 2022). Formeister et al. (2022) described the incidence rate of SSNHL
in the initial 7-month period of the U.S. vaccination campaign (December 14, 2020, to July 16,
2021). The authors identified 2,170 reports of hearing loss after vaccination in VAERS (search
terms: sudden hearing loss, deafness, deafness neurosensory, deafness unilateral, deafness
bilateral, and hypoacusis). Of those, the authors deemed 555 events as credible because they
occurred within 21 days of vaccination and had one of the following: reference to an audiologic
assessment, evaluation by an otolaryngologist, audiologist, or other physician resulting in
diagnosis of SSNHL, or evaluation by an otolaryngologist resulting in magnetic resonance
imaging and/or treatment with systemic or intratympanic steroid medication. The resultant
estimates of annual incidence of SSNHL after COVID-19 vaccination in VAERS data were
between 0.6 (probable; minimum estimate) and 28.0 (maximum estimate) cases per 100,000
people per year. The authors note that this is lower than or similar to the estimated annual U.S.
incidence (11–77 per 100,000 people per year) (Formeister et al., 2022). In a secondary analysis,
the authors note that the reports per 100,000 doses in VAERS decreased from 1.10 in December
2020 to 0.01 in June 2021, despite large increases in the absolute number of vaccines
administered.
From Evidence to Conclusions
The broader academic literature includes a handful of published articles reporting sudden
sensorineural hearing loss (SSNHL) in individuals receiving COVID-19 vaccination; however,
this level of evidence does not support an association between vaccination and SSNHL
(Formeister et al., 2022; Jeong and Choi, 2021; Tsetsos et al., 2021). However, the committee
found that the majority of the literature was limited to single case reports, unadjusted descriptive
reports lacking a comparison or without thoughtful adjudication of hearing loss, or publications
with potential bias and these did not meet our inclusion criteria during screening. Only one of the
studies included in this review suggested an association between COVID-19 vaccination and
SSNHL. However, the magnitude of the effect was small, with potential for confounding from
unmeasured variables. In contrast, the most methodologically rigorous analysis that included
potential confounders (e.g., infection status, comorbidities, and health care use patterns) in
models found no association. Using pharmacovigilance data without comparators offers low-
level evidence to support a conclusion. Nonetheless, one article used VAERS data and offered
compelling evidence that incidence of SSNHL were similar to expected rates and much lower
after an adjudication procedure to assess the credibility of the reported hearing loss. Moreover,
the same report showed that the weekly number of reports of SSNHL did not change over time
despite large increases in the number of vaccines administered.
An emergent theme is heterogeneity in identification of SSNHL and potential for
misclassification. First, self-reported data may be unreliable. Insights from the reviewed
literature may reflect this. Formeister et al. (2022) offered insights that many reports of SSNHL
in the VAERS data may not be true cases, and Leong et al. (2023) found that the majority of self-
reported new cases from vaccination were attributable to exacerbating known etiologies of
hearing loss. Another consideration may be that hearing includes peripheral encoding and central
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Copyright National Academy of Sciences. All rights reserved.
HEARING LOSS AND TINNITUS 121
PREPUBLICATION COPY: Uncorrected Proofs
processing of information in the brain, and cognitive processes play a key role in how individuals
understand speech. The role of cognition in the potential association between self-reported
hearing and COVID-19 infection or vaccination may be highly overlooked, as it is plausible that
existing age-related hearing loss, which is highly prevalent, could be perceived as “new” due to
fatigue or “brain fog.” Second, studies varied in definitions of SSNHL, including using different
risk-windows. Moreover, different and unverified approaches to diagnosis codes were used. Two
studies used diagnosis codes. Yanir et al. (2022) took a wide approach by looking for many
different ICD codes for hearing loss with concurrent prednisone usage; Nieminen et al. (2023)
used a single SSNHL code. Given the acute nature of SSNHL, diagnosis codes may be accurate
and reliable with some suggestion that an audiological test battery occurred. However, it is
unknown if concurrent ICD codes for more general hearing loss paired with prednisone use is
reliable. No studies examined the relationship between NVX-CoV2373 3 and SSNHL.
Overall, we found that the literature on vaccination and sensorineural hearing loss
focused almost exclusively on SSNHL. Our review of said literature resulted in weak evidence
and concerns about the measurement of SSNHL. Although the combination of the more
methodologically rigorous evidence suggesting no association and lack of identified potential
mechanisms beyond hypotheses may hint at no relationship between vaccination and SSNHL,
the literature is inadequate to offer a decision on the acceptance or rejection of a causal
relationship. Future epidemiological evidence is required.
Conclusion 4-1: The evidence is inadequate to accept or reject a causal relationship
between the BNT162b2 vaccine and sensorineural hearing loss.
Conclusion 4-2: The evidence is inadequate to accept or reject a causal relationship
between the mRNA-1273 vaccine and sensorineural hearing loss.
Conclusion 4-3: The evidence is inadequate to accept or reject a causal relationship
between the Ad26.COV2.S vaccine and sensorineural hearing loss.
Conclusion 4-4: The evidence is inadequate to accept or reject a causal relationship
between the NVX-CoV2373 vaccine and sensorineural hearing loss.
3 Refers to the COVID-19 vaccine manufactured by Novavax.