Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration (2024)

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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. PREPUBLICATION COPY—Uncorrected Proofs 

2 VACCINE EVIDENCE REVIEW 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 PREPUBLICATION COPY—Uncorrected Proofs 

SUMMARY 3 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. PREPUBLICATION COPY—Uncorrected Proofs 

4 VACCINE EVIDENCE REVIEW 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. PREPUBLICATION COPY—Uncorrected Proofs 

SUMMARY 5 ● 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. PREPUBLICATION COPY—Uncorrected Proofs 

6 VACCINE EVIDENCE REVIEW 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. PREPUBLICATION COPY—Uncorrected Proofs 

SUMMARY 7 TABLE S-1 Causal Conclusions Regarding COVID-19 Vaccines Causality Conclusions BNT162b2 mRNA-1273 Ad26.COV2.S NVX-CoV2373 Chapter Potential Harm (Pfizer-BioNTech) (Moderna) (Janssen) (Novavax) Favors rejection Favors rejection Favors acceptance Guillain-Barré of a causal of a causal of a causal I syndrome relationship relationship relationship Chronic inflammatory I I I I demyelinating polyneuropathy Favors rejection Favors rejection Bell’s palsy of a causal of a causal I I relationship relationship 3 Transverse myelitis I I I I Chronic headache I I I I Postural orthostatic tachycardia I I I I syndrome Sensorineural I I I I hearing loss 4 Tinnitus I I I I Thrombosis with Favors rejection Favors rejection Favors acceptance thrombocytopenia of a causal of a causal of a causal I syndrome relationship relationship relationship Immune 5 thrombocytopenic I I I I purpura Capillary leak I I I I syndrome PREPUBLICATION COPY—Uncorrected Proofs 

8 VACCINE EVIDENCE REVIEW TABLE S-1 Continued Causality Conclusions Potential Harm Chapter BNT162b2 mRNA-1273 Ad26.COV2.S NVX-CoV2373 (Pfizer-BioNTech) (Moderna) (Janssen) (Novavax) Favors rejection Favors rejection Myocardial of a causal of a causal I I infarction relationship relationship Favors rejection Ischemic stroke of a causal I I I relationship Hemorrhagic I I I I 6 stroke Deep vein thrombosis, pulmonary I I I I embolism, venous thromboembolism Establishes Establishes Myocarditis I I a causal relationship a causal relationship 7 Pericarditis without I I I I myocarditis 8 Sudden death I I I I Favors rejection Favors rejection 9 Female infertility of a causal of a causal I I relationship relationship *NOTE: “I” indicates that the evidence was inadequate to accept or reject a causal relationship. PREPUBLICATION COPY—Uncorrected Proofs 

SUMMARY 9 TABLE S-2 Conclusions Regarding Shoulder Injuries After Any Vaccination Specific Shoulder Injury (Chapter 10) Causality Conclusion Subacromial/subdeltoid bursitis caused by direct Establishes a causal relationship injection into the bursa Acute rotator cuff or acute biceps tendinopathy Establishes a causal relationship caused by direct injection into or adjacent to the tendon Chronic rotator cuff disease Favors rejection of a causal relationship Adhesive capsulitis I Septic arthritis I Bone injury caused by direct injection into or Establishes a causal relationship adjacent to the bone Axillary or radial nerve injury caused by direct Establishes a causal relationship injection into or adjacent to the nerve 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 PREPUBLICATION COPY—Uncorrected Proofs 

10 VACCINE EVIDENCE REVIEW 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. PREPUBLICATION COPY—Uncorrected Proofs 

SUMMARY 11 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. PREPUBLICATION COPY—Uncorrected Proofs 

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