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Suggested Citation:"8 Sudden Death and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"8 Sudden Death and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Suggested Citation:"8 Sudden Death and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Page 237
Suggested Citation:"8 Sudden Death and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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Page 238
Suggested Citation:"8 Sudden Death and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 239
Suggested Citation:"8 Sudden Death and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
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8 Sudden Death and COVID-19 Vaccines This chapter describes the potential relationship between COVID-19 vaccines and sudden death (see Box 8-1 for conclusions). BOX 8-1 Conclusions for Sudden Death Conclusion 8-1: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and sudden death. Conclusion 8-2: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and sudden death. Conclusion 8-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and sudden death. Conclusion 8-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and sudden death. BACKGROUND The conceptualization, definition, and clinical assignment of a “sudden death” or a “sudden unexpected death” (SUD) is complex and challenging despite useful attempts to define “sudden death” in the general case, and several public health applications have been advanced. This whole area will not be reviewed in detail, but some relevant dimensions will be addressed. Sudden death is subject to considerable definitional variation; most epidemiological studies have been limited to individual countries or subregions. One example of SUD is offered by the World Health Organization (WHO): “sudden, unexpected, natural deaths either witnessed, and within one hour of symptom onset or, if unwitnessed, within 24 hours of having been last seen alive and symptom-free” (Sefton et al., 2023). This definition highlights some of the definitional challenges. Whether a death is “witnessed” depends in part on social, geographic, and residential characteristics (Taylor et al., 2023). It also depends on the underlying medical conditions of the decedent and access to health care. In forensic and pathological studies and series, underlying causes of death can often be identified, but these studies (autopsies of certain types) are only variably performed, in part due to their substantial costs and whether certain PREPUBLICATION COPY—Uncorrected Proofs

240 VACCINE EVIDENCE REVIEW legal, regulatory, clinical, or public health issues are in play, such as possible homicide, suicide, environmental exposures, vehicular crashes, poisonings or other “suspicious” circumstances. The rates of designating SUDs in a given community will likely also depend on its health, social, and economic status, likely to vary among geographic areas. A central determinant of the accuracy of discovering SUD causes is the level of professional forensic skills and resources a community devotes to these services, including access to toxicologic, microbiologic, and other laboratory and technical services. Only about half of the U.S. population lives in a jurisdiction where coroner and medical examiner services are accredited by the National Association of Medical Examiners. Some U.S. communities, and others globally, have geographic sudden death registries. However, differences in definitions may occur when conducting SUD surveillance, such as time since apparent death or special topical areas of emphasis, including sudden cardiac death, acute drug poisonings, or a focus on adolescents and young adults. These registries may have other public health value, such as in assessing the efficacy of community-based cardiopulmonary resuscitation programs. However, estimates of community SUD incidence rates have been made. For example, in 2019, an estimate was published of 49 and 21.7 per 100,000 men and women aged 20–64, respectively (Mirzaei et al., 2019). In this same study, the years of life lost in this age group was estimated to be higher than all but combined cancer, heart disease, and unintentional injury deaths. This estimate may also reflect the lesser interest or greater complexity of assessing SUDs among older persons. In the past several years, there has been more emphasis on “sudden cardiac death,” due perhaps to increased attention to SUDs among younger people and to technical and scientific advances in understanding the mechanisms and treatments of SUDs. However, with the advent of COVID-19 vaccines, their distribution in public health programs often favored targeting older people, because of their greater mortality risks, and underlying causes of SUDs are at least somewhat different in this age group. With regard to COVID-19 distribution and overall population mortality trends, there was no difference in non-COVID-19 mortality between those who were or were not vaccinated as the pandemic worsened in 2020 and 2021 in the United States. For example, a report from the U.S. Vaccine Safety Datalink (Xu et al., 2021) found that vaccine recipients have lower mortality than those unvaccinated. Similarly, a report using data from the VAERS system found that in those receiving vaccine, death events within 7 and 42 days following vaccination occurred at lower rates than all-cause expected rates (Day et al., 2023). Despite limitations, this finding suggested lower mortality event rates among vaccinees. MECHANISMS AND CAUSES OF SUDS The WHO definition does not imply a particular cause or mechanism of death per se, and in many instances, evidence must often be gathered in multiple ways, including investigation of the death scene and the general environment, autopsies and related laboratory investigations, interviews with witnesses and other informants, and medical histories from informants and medical records. It has been estimated that about two-thirds of persons with SUDs have medical records from a visit to a health care provider in the 2 years prior to their unexpected death (Husain et al., 2021). However, identifying useful informants and accessing relevant medical records can be challenging, and cultural and legal impediments and other logistical or technical challenges may occur. For example, underreporting in patients with epilepsy has been suggested. PREPUBLICATION COPY—Uncorrected Proofs

SUDDEN DEATH 241 Acute myocardial infarction, pulmonary embolism, stroke, and myocarditis can all cause SUD, as discussed in Chapters 6 and 7. The role of various COVID-19 vaccines in causing SUD is complex as well. The extent to which vaccines may cause particular medical conditions that may lead to an SUD is discussed in other chapters in this report. For example, it would seem that acute allergic vaccine reactions, such as anaphylaxis, would be immediate and likely detected at the time of vaccination, although some delays are possible. Such delays could conceivably relate to unattended deaths. SUDs may also occur in the context of COVID-19 vaccines in other ways. First and probably most important is that vaccinees may have various underlying conditions that could coincidentally lead to an SUD. Under most circumstances, it would seem possible to identify such situations using informants, autopsy, and other forensic procedures and medical records; most persons with SUDs are likely to have a notable medical history. Another circumstance that is likely to lead to SUDs is infection with various strains of SARS-CoV-2 itself. This virus, and possibly other viruses circulating in the community, may cause cardiomyopathies of various types, which are known to cause SUDs (Kyuno et al., 2023). The possibility of SUDs in association with post-COVID-19 syndrome has also been raised (Spartalis et al., 2024). In this situation, many cases may be suspected or identified using conventional virus detection techniques, and incumbent pathological findings may be seen at autopsy. However, if viral testing was not performed in the community, and the infected cases had asymptomatic or presymptomatic infections, the infection may never have been identified. Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding sudden death and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Table 8-1 presents one study that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

242 VACCINE EVIDENCE REVIEW TABLE 8-1 Epidemiological Study in the Sudden Death Evidence Review Study Design and Comparison Data Age Number Author Group Location Source Vaccine(s) Range N of Events Results Paratz, Ecological, Australia Out-of- BNT162b2, 5–50 4.2 38 “No difference was et al. previously hospital mRNA- million seen in underlying (2023) published cardiac 1273 eligible causes of sudden death age-matched arrest for compared with data registry vaccinati previously published on age-matched data (p = 0.235)” 8.8 million doses SOURCE: Paratz et al., 2023. PREPUBLICATION COPY—Uncorrected Proofs

SUDDEN DEATH 243 The committee explored Paratz et al. (2023), who used an Australian population study of one type of sudden unexpected death, out-of-hospital cardiac arrest (OHCA), obtained from a registry of about 4.49 million persons, 4.2 million of whom were 5–50 years old and eligible for vaccination. The authors report unexplained deaths by month, April 2019–March 2022. Deaths when vaccines (BNT162b2, mRNA-1273, and ChAdOx1-S 1) were available were compared to immediate earlier time periods. The vaccines available and used during the period of analysis varied, and the data do not identify which vaccines were given to any specific individual. During the study period, 2,242 people experienced OHCA; the authors noted no variation in median monthly rates during the three time periods. Within 30 days of their COVID-19 vaccination (type not documented), 38 people died and were referred for forensic assessment: “No differences were seen in underlying causes of death compared with previously published age-matched data” (Paratz et al., 2023). The authors only assessed sudden cardiac arrest, unascertained sudden cardiac arrest, and myocarditis, and it was not clear how many deaths resulted from each type of OHCA. They used a clear definition of OHCA, and in one analysis, they linked the history of COVID-19 vaccination within 30 days. The number of deaths was modest, and it was not clear which vaccines were associated with those deaths. The report showed no evidence of an association between the SUD syndrome and vaccination. Paratz et al. (2023) also included an analysis of sudden death within 30 days of vaccination in “young people” without specifying the age. They reported that causes of death in that population “were consistent with pre-pandemic causative profiles,” but specific data were not included in the paper. FROM EVIDENCE TO CONCLUSIONS The informative literature that critically assessed the association of the SUD with COVID-19 immunizations was sparse, with many methodological limitations. Only one paper, which included BNT162b2 and mRNA-1273, was relevant. The authors found a modest number of sudden unexpected deaths and noted no difference from the comparators. No studies assessed the relationship between Ad26.COV2.S and NVX-CoV2373 and sudden death. Conclusion 8-1: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and sudden death. Conclusion 8-2: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and sudden death. Conclusion 8-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and sudden death. Conclusion 8-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and sudden death. 1 The COVID-19 vaccine manufactured by Oxford-AstraZeneca. PREPUBLICATION COPY—Uncorrected Proofs

244 VACCINE EVIDENCE REVIEW REFERENCES Day, B., Menschik, D., Thompson, D., Jankosky, C., Su, J., Moro, P., Zinderman, C., Welsh, K., Dimova, R.B., and Nair, N. 2023. Reporting rates for VAERS death reports following COVID-19 vaccination, December 14, 2020 November 17, 2021. Pharmacoepidemiology and Drug Safety 32(7):763-772. 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). 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). Husain, A., E. A. Masoudi, M. Mirzaei, G. Joodi, M. I. Sadaf, F.-C. Lin, and R. J. Simpson, Jr. 2021. Missed opportunities for prevention of sudden death. North Carolina Medical Journal 82(2):95– 99. https://doi.org/10.18043/ncm.82.2.95. Kyuno, D., M. Tateno, Y. Ono, K. Magara, K. Takasawa, A. Takasawa, and M. Osanai. 2023. Common pathological findings in the heart in COVID-19-related sudden death cases: An autopsy case series. Heliyon 9(10):e20564. https://doi.org/10.1016/j.heliyon.2023.e20564. Mirzaei, M., G. Joodi, B. Bogle, S. Chen, and R. J. Simpson, Jr. 2019. Years of life and productivity loss due to adult sudden unexpected death in the United States. Medical Care 57(7):498–502. https://doi.org/10.1097/mlr.0000000000001129. Paratz, E. D., Z. Nehme, D. Stub, and A. La Gerche. 2023. No association between out-of-hospital cardiac arrest and COVID-19 vaccination. Circulation 147(17):1309–1311. https://doi.org/10.1161/circulationaha.122.063753. Sefton, C., S. Keen, C. Tybout, F. C. Lin, H. Jiang, G. Joodi, J. G. Williams, and R. J. Simpson, Jr. 2023. Characteristics of sudden death by clinical criteria. Medicine (Baltimore) 102(16):e33029. https://doi.org/10.1097/md.0000000000033029. Spartalis, M., D. Zweiker, E. Spartalis, D. C. Iliopoulos, and G. Siasos. 2024. Long COVID-19 syndrome and sudden cardiac death: The phantom menace. Current Medicinal Chemistry 31(1):2–6. https://doi.org/10.2174/0929867330666230515145041. Taylor, C. T., L. Campbell-Sills, R. C. Kessler, X. Sun, M. K. Nock, R. J. Ursano, S. Jain, and M. B. Stein. 2023. Social network size and personality traits independently and prospectively predict distress disorders and suicidal behavior in U.S. Army soldiers. Psychological Medicine 53(11):5081–5090. https://doi.org/10.1017/s0033291722002082. Xu, S., R. Huang, L. S. Sy, S. C. Glenn, D. S. Ryan, K. Morrissette, D. K. Shay, G. Vazquez-Benitez, J. M. Glanz, N. P. Klein, D. McClure, E. G. Liles, E. S. Weintraub, H. F. Tseng, and L. Qian. 2021. COVID-19 vaccination and non-COVID-19 mortality risk - seven integrated health care organizations, United States, December 14, 2020-July 31, 2021. MMWR: Morbidity and Mortality Weekly Report 70(43):1520-1524. https://doi.org/10.15585/mmwr.mm7043e2. PREPUBLICATION COPY—Uncorrected Proofs

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

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

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