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). The Institute of Medicine (IOM, 1991, 1994) focused on assessing the causal relationship of the Centers for Disease Control and Prevention (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 severe acute respiratory syndrome coronavirus-2 (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. 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 to 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, 2023a), 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.

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 (NASEM, 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 injury related to vaccine administration (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, 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

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¹ The sentence was updated after the report was shared with the sponsor to clarify the EUA process.

² Public Access File materials can be requested by contacting the Public Access Records Office via the link on this project’s webpage: www.nationalacademies.org/our-work/review-of-relevant-literature-regarding-adverse-events-associated-with-vaccines.

TABLE 1-1 COVID-19 Vaccines Used in the United States

NOTES: *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; LNP: lipid nanoparticle; mRNA: messenger ribonucleic acid.

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 that is 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., 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

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³ Public Access File materials can be requested by contacting the Public Access Records Office via the link on this project’s webpage: www.nationalacademies.org/our-work/review-of-relevant-literature-regarding-adverse-events-associated-with-vaccines.

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 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

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-19 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., magnetic resonance imaging) provided in case reports and case series.

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 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) (see Table 1-2).

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 percent, and 68 percent in children aged 6 months to 4 years, 5–11, and 12–17, respectively, according to the CDC (AAP, 2023). For these reasons, considerably less data exist on possible harms in children, especially in those under 11, compared to adults. Ad26. COV2.S⁵ 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

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⁴ Public Access File materials can be requested by contacting the Public Access Records Office via the link on this project’s webpage: www.nationalacademies.org/our-work/review-of-relevant-literature-regarding-adverse-events-associated-with-vaccines.

⁵ Refers to the COVID-19 vaccine manufactured by Janssen.

⁶ Refers to the COVID-19 vaccine manufactured by Novavax.

TABLE 1-2 COVID-19 Vaccine Food and Drug Administration Emergency Use Authorization Dates, Adults and Children

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.

children, which consisted of data from BNT162b2⁷ 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 were 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.

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 it felt the observational epidemiological literature was sufficient to support a conclusion or if it felt evidence of those uncontrolled designs was unlikely to contribute to a causal conclusion. The committee notes that uncontrolled studies would likely have been excluded from consideration if it 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.

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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^®.

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.

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 (see 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, 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 thrombosis with thrombocytopenia syndrome 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 outcome but not for every outcome 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 that all outcomes under study were evaluated similarly to ensure that a consistent approach to the causal conclusions was maintained.

The committee adopted the wording of the causality conclusions developed by National Academies/IOM 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 that limitations exist for 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 evidence is portrayed in detail in tables within each section and described briefly in the text. Each section includes a summary of the most compelling argument in support of the conclusion and ends with the causal conclusion. Chapter 10 reviews 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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