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

Chapter: 6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism

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Suggested Citation:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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:"6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism." 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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6 Vascular Conditions and COVID-19 Vaccines: Myocardial Infarction, Stroke, Pulmonary Embolism, Deep Vein Thrombosis and Venous Thromboembolism This chapter describes the potential relationship between COVID-19 vaccines and potential vascular-related harms: myocardial infarction, ischemic stroke, hemorrhagic stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), and the composite venous thromboembolism (PE and/or DVT). Each outcome is addressed in a separate section in this chapter. Twelve scientific reports were selected for evaluation of the six clinical outcomes considered; these are summarized and referenced in Table 6-1. Many of these reports addressed more than one clinical outcome and more than one vaccine. Additionally, some of these reports included outcomes and vaccines that were addressed in other chapters of this report. The 12 reports in Table 6-1 generally represented large populations, with only one study from the United States, conducted on the Medicare populations (persons 65+), multiple studies from the United Kingdom, and Scandinavia, two from the French national health system (covering different age groups), and individual studies from Israel, Hong Kong, Japan, Spain, and Malaysia. These studies may in some sense represent broad global coverage, but many countries, cultures, and health systems were not covered, including most low- and middle-income countries. Although these studies applied standard epidemiological methods and analytical techniques overall, they did not appear to have followed a common or harmonized protocol. For example, they varied in how age groups were presented and the postimmunization exposure interval, although many centered on approximately 28 days. One study examined outcomes for weeks one and two separately, resulting in smaller sample sizes. None of the reports emphasized vaccine outcomes in children, which is unsurprising given the emphasis on the chronic vascular conditions of older persons. Only a minority of the studies adjusted their analytic models for a history of comorbid conditions. Several studies used patient self-controls, with a few employing case-control or cohort designs, including non-immunized comparator groups (Grosso et al., 2011). Further information can be found on the studies as part of the descriptions of the vaccine–disease outcomes in the respective sections of this chapter. Some other general methodological issues of potential import to the reports were discussed sparingly or not at all, such as the potential health impact of multiple vaccines at the same time of administration (e.g., COVID-19 and influenza). A particularly interesting and difficult issue is possible exposure to SARS-CoV-2 simultaneously with vaccination, although some reports provided separate comparator groups of patients with documented, possibly making it more difficult to distinguish harms caused by vaccination from those caused by COVID-19 infection. The studies also varied in whether sources of patient data included both inpatient and ambulatory care, although all studies reported information on hospitalized patients. These and PREPUBLICATION COPY—Uncorrected Proofs

158 VACCINE EVIDENCE REVIEW other issues should be the topic of more intensive research to better refine the evaluation of vaccine safety. The committee attempted to focus on the six thromboembolic outcomes from the first and/or second dose of the primary series. No studies of adverse outcomes from bivalent or monovalent updated booster vaccines were considered here, in part because few such studies were available, and a variety of important selective forces likely affected who received subsequent doses, such as variation in individual clinical circumstances. The studies had generally modest variations in analysis and presentation, such as differences in the post-immunization analytical intervals, age groups of the vaccinees, and clinical history of COVID-19 infection (see Table 6-1). All studies used in this chapter applied general administrative disease coding according to ICD-10 nosology. Importantly, some studies only included hospitalized patients, likely deterring identification of diseases and conditions that might be identified largely in ambulatory settings. Due to expected variation in cross-national medical care and coding practices, harmonization across disease rubrics and nosology could not be assured. Some studies reported diagnoses that could have been placed in alternative disease categories or classification codes. For example, “subarachnoid hemorrhage” may or may not be the same as “hemorrhagic stroke.” This was not unexpected, but it challenges the validity of disease classification. This is explained further in the subsections of this chapter. Studies were only included if the disease reports used identical terms to those requested in the Statement of Task. Only Shoaibi et al. (2023) provided a supplemental validation study of disease coding accuracy, using medical charts as the standard. For both MI and PE, the majority of diagnoses were consistent with this manual evaluation. No study reported an evaluation of the accuracy of population immunization registries used to link vaccine receipt data to the respective medical care systems. See Boxes 6-1 through 6-4 for all conclusions in this chapter. The following is a brief synopsis of the 12 studies contained in Table 6-1, in order to orient the reader to study characteristics and interpretation. They are presented in alphabetical order, as it appears also in the Table. Vaccines analyzed are identified throughout the table headings in this chapter’s subheadings. Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding any of the outcomes reviewed in this chapter and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Ab Rahman et al. (2021) explored adverse events of special interest among patients admitted to major urban hospitals in Malaysia, during Feb. through September 2021. The basic analyses were conducted using a self-controlled case series, and outcomes were represented as Incidence Rate Ratios. Three vaccine platforms were evaluated, although as noted elsewhere in this report only those vaccines used in the United States were presented in our evaluations. Several but not all adverse events of special interest were analyzed relevant to this chapter, but only those occurring within 21 days after immunization were included. More than one vaccine dose may have been administered during the study window. Barda et al. (2021) conducted an analysis of adverse events after the first dose of BNT162b2 vaccine, in the setting of the largest health care organization in Israel, starting among persons with no medical history of any of the adverse events of interest. One person with a history of vaccine receipt was matched with another with no vaccine history, and with adjustment for various sociodemographic variables. Adverse everts in both groups were monitored using medical records were followed for an observation interval of 42 days using system medical records. Study participants’ ages ranged from 16 years of age and above. Other PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 159 inclusion and exclusion were applied. In addition to the analysis of adverse events, a second, similarly matched analytical cohort was created using those with a history of COVID-19 infection, matched to similar persons with no history of infection at the same time; then, the clinical outcomes were followed in both groups to separately assess the role of general infection on these outcomes as a comparator. Other studies used in this chapter and in other chapters used similar methodology to contrast rates of adverse events following vaccination with similar rates of adverse events following infection. Botton et al. (2022) explored three adverse vascular effects, myocardial infarction, stroke, and pulmonary embolism, for three vaccines used also in the US: BNT162b2, mRNA1273 and Ad26.COV2.S, among persons ages 18–74 years. The study population included over 46 million adults using the French National Health System, using a self-controlled case series method adapted to the event-dependent exposure and overall high rate of general mortality characteristic of this large population size. The relative incidence of each clinical outcome of interest was determined for three, separately reported weeks after the recorded date of vaccine receipt, derived from separate population vaccine use files. Study data were separately reported for the first and second dose of the primary series for each of the vaccines. Of note, the same overall study methods were used for persons 75 years or older in the same geographic region but are reported separately by Jabagi et al. Burn et al (2022a) conducted a series of cohort studies from September 2020 through May 2021 in the United Kingdom, using a series of national clinical databases that included clinical characteristics of patients as well as vaccine receipt. Clinical outcomes included both vascular and hematological conditions, which also served to better understand pre-vaccination health status for a variety of comorbid conditions. Only data on the BNT162b2 were relevant to this chapter, and both first and second doses were considered, encompassing over 3 million doses distributed, who were 20 years of age and older. Additionally, a separate cohort of patients who sustained the COVID-19 infection was analyzed to use as a comparator to the vaccine receipt cohorts with regard to clinical outcomes. Adverse events were counted in the 28 days after vaccine receipt. Of note, this study used some of some of same clinical data resources as another study by Hippesley-Cox et al., but this was not deemed an important problem. Burn et al. (2022b) analyzed hospital and primary care data from the region of Catalonia, Spain, including the first and second dose of BNT162b2. Another vaccine was studied but not used in the United States. Over 3 million persons were reported to have used at least one dose of this vaccine and were available for study. The outcomes assessed relevant to this chapter were venous thromboembolism, myocardial infarction, and ischemic stroke, with results among vaccinated persons compared to an historical comparator group. However, several other comorbid conditions were studied as “pre-morbid” risk factors, or as potential harms assessed in other chapters of this report (e.g., immune thrombocytopenia). As in other reports utilized in this chapter and others, a separate cohort of persons with the viral COVID-19 infection was identified as a separate comparator outcome events relative to those receiving the study vaccines. Chui et al. (2022) conducted a series of studies on the potential harms of the BNT162b2 vaccine in 2.9 million vaccinees in the period between February and September 2021, Data were obtained from Hong Kong (China) territory-wide electronic health and vaccination records. The basic analytical design was a “modified” self-controlled case series using a variety of preselected vascular and thromboembolic events and hemorrhagic stroke. The period of adverse event risk assessment was 27 days after vaccination, and first and second doses of the vaccine were considered separately. An additional cohort of patients acquiring COVID-19 infection was also PREPUBLICATION COPY—Uncorrected Proofs

160 VACCINE EVIDENCE REVIEW analyzed as a separate comparator. Of note, this was one of the first studies to concede that citizens had the right to change the scheduling of the first and second primary series doses. Hippesley-Cox et al. (2021) conducted self-controlled case series analyses of thromboembolism and thrombocytopenia in over 9.5 million persons receiving the BNT162b2 vaccine in England, UK, between December 2020 and April 2021, among persons 16 years of age or older. All information was derived from national databases of mortality, hospitalization, and vaccinations. Only clinical outcomes after the first dose were considered by the authors. Important to this chapter, myocardial infarction, ischemic stroke, and venous thromboembolism outcomes were available, and were assessed in the 28 days after vaccination. Additionally, a separate cohort was analyzed using patients who were noted to be infected with COVID-19 virus, as a comparator for relevant clinical outcomes. As noted above, there may be a small amount of database overlap between this study and that of Burn et al. (2022a). Hviid et al. (2022) conducted a cohort study in Denmark of “frontline workers,” who were among the first priority groups to receive COVID-19 vaccines when available in that country. These workers, born after 1957, were the only study group of its type to be evaluated in this chapter (the remainder were all from the general community). They were largely health care and institutional workers (n ~101,000) although some others were not further classified occupationally. Analytical information was obtained from national health and immunization registers. Only the BNT162b2 vaccine was assessed in this chapter, and the most important outcomes here were pulmonary embolism and deep vein thrombosis. The study sample size was more modest than most of the other studies considered in this chapter, limiting the statistical power of the analysis. The window of observation extended from December 2020 to April 2021. Jabagi et al. (2022) conducted a self-controlled case series analysis of persons from the French National Health Service linked to the National COVID-19 vaccination database and can be considered an “extension” of the report by Botton et al. (2021) (see above), except that it included only persons 75 years and older. The paper by Botton et al. (2021) only considered persons only up to 74 years of age. The separate reporting emphasis was deemed useful because older persons were priority vaccinees in many global communities. Main outcomes included in this paper were myocardial infarction, stroke, and pulmonary embolism. In this paper over 3.9 million persons were included and only the BNT162b2 vaccine findings were reported, perhaps in part because of the limited sample availability for other vaccines during the study interval. Data on first and second doses were reported separately, but only a two-week post vaccination interval was reported. Patone et al. (2021) conducted a study in England, UK, that was mostly devoted to identifying potential neurological harms of two COVID-19 vaccines; Only BNT162b2 was considered in this chapter because of relevance to U.S. vaccine exposures, as noted above, and over 12 million persons received this vaccine between December 2020 and May 2021. The study was considered for assessment in this chapter because hemorrhagic stroke (HS) was one of the prespecified safety outcomes. The study analysis was a self-controlled case series, and 811 HS events were detected among those who received BNT162b2 vaccine. The follow-up interval was weekly for 28 days after immunization, and only the first dose of vaccine and the first detected adverse event were considered in the analysis. Additional cohorts were developed among patients from Scottish data to serve as validation of the findings from England, and among those who were found to have a positive COVID-19 test for infection, to be used as a comparator for the core findings. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 161 Shoaibi et al. (2023) studied two mRNA vaccines (BNT162b2 and mRNA-1273); this study differed in certain important ways from the other studies in this chapter. It was the only study reviewed in this section conducted on a U.S. population (the “Medicare” population consisting of nearly all Americans 65 years and older). Vascular, coagulation and certain neurological outcomes were evaluated, but only those related to this chapter (see Background information section to this chapter) were included. The study design was also different from some of the others. The two mRNA vaccines were considered separately and assessed using self- controlled case series methods. However, after a pre-vaccination data collection period, where demographic and general clinical information on the study cohorts were collected, the selected outcomes were assessed in both ambulatory and hospital settings for 90 days after the vaccines became available. Thus, it was not possible to separate out first and second dose effects of the individual vaccines. Shoaibi et al. also conducted secondary and exploratory analyses, including a validation study of outcome codes using medical case record reviews. These findings strengthened the understanding and challenges of medical record data, even if the findings may not be similar in other reports reviewed in this chapter. Whiteley et al. (2022) examined the adult population of England, UK, using hospitalization and primary care data, comprising a total population of approximately 46 million persons observed between December 2020 and March 2021. Extensive clinical and demographic information were noted in the pre-vaccine period; a 28-day period of observation was used following the first immunization was employed; only the first dose was considered in the authors’ analysis. Additionally, only the findings from the BNT162b2 vaccine were utilized in this chapter, as it was the only vaccine used in the United States. The clinical outcomes data in this report are specifically categorized two groups–those 69 years or younger and those 70 years and older. The authors noted two main limitations of their analyses: reliance on the accuracy of coded electronic health records and residual confounding within the adjusted models. Several of the hematological and coagulation findings from this report are contained in other chapters of this document. PREPUBLICATION COPY—Uncorrected Proofs

162 VACCINE EVIDENCE REVIEW TABLE 6-1 Epidemiological Studies in the Vascular Conditions Evidence Review Study Design and Comparison Age Total Author Group Location Data Source Vaccine(s) Range Sample Size Ab Rahman Self-controlled Malaysia Malaysia Vaccine BNT162b2 18–60+ years 20 million et al. (2022) case series Administration System (myVAS) Barda et al. Cohort, Israel Clalit Health BNT162b2 16+ years 1.7 million (2021) unvaccinated Services individuals Botton et al. Self-controlled France French National BNT162b2, 18–74 years 46.5 million (2022) case series Health Data System mRNA-1273, Ad26.COV2.S Burn et al. Cohort, UK Electronic health BNT162b2 20+ years 5.6 million (2022a) historical records comparator Burn et al. Cohort, Spain Electronic health BNT162b2 20+ years 4.6 million (2022b) historical records comparator Chui et al. Self-controlled China Electronic health BNT162b2 16+ years 2.9 million (2022) case series records (BNT162b2 vaccinees) PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 163 TABLE 6-1 Continued Study Design and Comparison Author Group Location Data Source Vaccine(s) Age Range Total Sample Size Hippisley-Cox Self-controlled England National BNT162b2 16+ years 29 million et al. (2021) Immunization Management System data Hviid et al. Nationwide Denmark Danish Civil BNT162b2 16–64 years 355,209 (2022) exploratory Registration System retrospective cohort, unvaccinated comparison group Jabagi et al. Self-controlled France French National BNT162b2 75+ years 3.9 million (2022) case series Health System Patone et al. Self-controlled Scotland English National BNT162b2 16–90+ years 12.1 million (2021) case series Immunization Database Shoaibi et al. Self-controlled US Medicare claims BNT162b2, 65+ years 3.3 million (2023) case series mRNA-1273 (Doses 1 and 2) Whiteley et al. Cohort England English NHS, BNT162b2 >18 years 46 million (2022) General Practice Extraction Service Data for Pandemic Planning and Research 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. SOURCES: Ab Rahman et al., 2022; Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Chui et al., 2022; Hippisley-Cox et al., 2021; Hviid et al., 2022; Jabagi et al., 2022; Patone et al., 2021; Shoaibi et al., 2023; Whiteley et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

164 VACCINE EVIDENCE REVIEW MYOCARDIAL INFARCTION BOX 6-1 Conclusions for Myocardial Infarction Conclusion 6-1: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and myocardial infarction. Conclusion 6-2: The evidence favors rejection of a causal relationship between the mRNA-1273 vaccine and myocardial infarction. Conclusion 6-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and myocardial infarction. Conclusion 6-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and myocardial infarction. Background A heart attack (myocardial infarction [MI]) usually occurs when a blood clot blocks blood flow to the heart. Tissues, particularly heart muscle, lose oxygen and may die. Symptoms include tightness or pain in the chest, neck, back, or arms and fatigue, lightheadedness, abnormal heartbeat, and anxiety (Thygesen et al., 2018). MI is important and common; with other cardiovascular diseases, it is the leading cause of death in many developed countries. MI rates will vary among regional and national populations because of differences in risk factor levels and their management or medical treatment access to and use of health care resources and vary worldwide in part because of these differences in populations and communities. Sometimes a definitive diagnosis is difficult to make because of timing of clinical events, variation in symptom rates, premature death, or therapeutic interventions; this is likely to be a worldwide finding. The global epidemiology and occurrence have been reasonably well characterized (Salari et al., 2023). SARS-CoV-2 is believed to cause both MI and other vascular conditions (Siddiqi et al., 2021), due to a variety of mechanisms, including infection and inflammation of atherosclerotic plaques and coagulation abnormalities. In the studies evaluated in this section, MI was substantially more common among COVID-19–infected persons than those who were uninfected but received any COVID-19 vaccine. Concordant exposure to both vaccine and infection during the pandemic can make it difficult to attribute MI to either potential cause. Mechanisms MI is primarily defined as the sudden ischemic death of myocardial tissue. This often occurs due to thrombotic blockage of a coronary vessel after a plaque ruptures. The lack of blood flow triggers significant metabolic and ionic disturbances in the myocardium, leading to rapid deterioration of systolic function (Prabhu and Frangogiannis, 2016). Prolonged lack of blood flow activates a “wavefront” of cardiomyocyte death, which progresses from the PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 165 subendocardium to the subepicardium. This process involves mitochondrial changes that are central to apoptosis and necrosis of cardiomyocytes (Davidson et al., 2020). Given the limited regenerative capacity of the adult mammalian heart, healing primarily occurs through scar formation. The immune system plays a significant role in both the homeostatic and perturbed conditions of the heart. Immune cells infiltrate the heart during gestation and persist in the myocardium throughout life, participating in essential housekeeping functions. After MI or in response to infection, large numbers of immune cells are recruited to the heart to remove dying tissue, scavenge pathogens, and promote healing (Prabhu and Frangogiannis, 2016). However, in some cases, these immune cells can cause irreversible damage, contributing to heart failure. Reports exist of vaccine-related MI cases, particularly after ChAdOx1-S, which were mostly characterized by ST-segment elevation and occurred after the first dose. However, no definitive mechanistic link is established in the literature between COVID-19 vaccination and MI. Furthermore, most cases occurred after the first dose, which suggests that the immune response elicited by the vaccine may play a minimal role in MI (Hana et al., 2022; Zafar et al., 2022); an overactive immune response would presumably lead to a higher incidence of MI after booster dose. The immune response to vaccination does not correlate with a single inflammatory biomarker associated with MI but shows a range of markers, including IL-6, C-reactive protein, and components of the interferon signaling pathway (Hervé et al., 2019). Epidemiological Evidence BNT162b2 and MI Table 6-2 presents eight studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

166 VACCINE EVIDENCE REVIEW TABLE 6-2 Epidemiological Studies in the BNT162b2–Myocardial Infarction Evidence Review Number Results Author N of Events (95% CI) Ab Rahman et al. (2022) Dose 1: 8.7 million vaccinees 409 IRR 0.97 (0.87–1.08) Dose 2: 6.7 million vaccinees 387 IRR 1.08 (0.97–1.21) Barda et al. (2021) Dose 1: 884,828 vaccinees 59 RR 1.07 (0.74–1.60) Botton et al. (2022) Dose 1: 16,728 vaccinees Week 1: 543 RI 0.91 (0.83–1.00) Week 2: 492 RI 0.86 (0.78–0.94) Dose 1: 14,004 vaccinees Week 1: 408 RI 0.89 (0.80–1.00) Week 2: 404 RI 0.95 (0.85–1.06) Burn et al. (2022a) Dose 1: 1.8 million vaccinees 442 SIR 0.88 (0.80–0.97) Dose 2: 1.3 million vaccinees 283 SIR 0.80 (0.71–0.89) Burn et al. (2022b) Dose 1: 2.0 million vaccinees 280 SIR 1.05 (0.93–1.18) Dose 2: 1.3 million vaccinees 272 SIR 1.10 (0.98–1.24) Jabagi et al. (2022) Dose 1: 3.9 million vaccinees 6,510 RI 0.97 (0.88–1.06) Dose 2: 3.2 million vaccinees 4,843 RI 1.04 (0.93–1.16) Shoaibi et al. (2023) Doses 1 and 2: 3.4 million vaccinees 2,783 IRR 1.04 (0.91–1.18) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for BNT162b2 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IR: incidence rate; IRR: incidence rate ratio; RI: relative incidence; RR: risk ratio; SIR: standardized incidence ratio. SOURCES: Ab Rahman et al., 2022; Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 167 All studies have varying designs; the majority were self-controlled, and the remainder were cohort studies, except for a case-control study (Whiteley et al., 2022). The number of MI events after BNT162b2 1 was higher than the background rate, except for the Israeli study (n = 59) (Barda et al., 2021). Shoaibi et al. (2023) used the two-dose primary series as the “exposure,” without presenting the separate outcomes. This study was retained in the report, in part because it was the only U.S. study. The two studies from France are respectively the younger and older cohorts of patients from the same national health system (Botton et al., 2022; Jabagi et al., 2022); they reported MI outcomes only from a 2-week interval postimmunization. Whiteley et al. (2022) from England also presented data separately for two age categories (younger and older than 70). All the studies used a postimmunization analysis interval of 1 month or less, except Shoaibi et al. (2023), which used 90 days with appropriate adjustments. The findings were generally uniform across all eight studies. Seven of them showed no statistically significant increases in the risk of MI associated with BNT162b2. Shoaibi et al. (2023), in partially adjusted analyses, showed a modest increased risk: 1.17 (95% confidence interval [CI]: 1.08–1.28). However, these investigators included additional adjustments: current history of COVID-19 infection and seasonality. These factors were considered important; the latter was not explored in any other study contained in this chapter. After adjusting for these additional variables, the MI–BNT162b2 association was no longer significant: 1.04 (95% CI: 0.91–1.18). Shoaibi et al. (2023) also demonstrated that ICD codes for MI in their dataset were generally valid using medical chart reviews, with a positive predictive value of 80 percent. In summary, all the studies in Table 6-2 showed no significant association between immunization with BNT162b2 and MI. mRNA-1273 and MI Table 6-3 presents two studies that contributed to the causality assessment. TABLE 6-3 Epidemiological Studies in the mRNA-1273–Myocardial Infarction Evidence Review Number Author N Results (95% CI) of Events Week 1: 58 RI 0.78 (0.59–1.03) Dose 1: 2,435 vaccinees Botton et al. Week 2: 78 RI 1.06 (0.83–1.37) (2022) Week 1: 46 RI 0.85 (0.61–1.18) Dose 2: 1,831 vaccinees Week 2: 61 RI 1.21 (0.90–1.62) Shoaibi et al. Doses 1 and 2: 302 IRR 1.01 (0.82–1.26) (2023) 3.4 million vaccinees NOTES: mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for mRNA-1273 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval; N/A: not applicable; IRR: incidence rate ratio; RI: relative incidence. SOURCES: Botton et al., 2022; Shoaibi et al., 2023. 1 The COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. PREPUBLICATION COPY—Uncorrected Proofs

168 VACCINE EVIDENCE REVIEW Two studies evaluated the association between mRNA-1273 2 and MI, one using data from the French national health service (Botton et al., 2022) and one using data from the U.S. Medicare system (Shoaibi et al., 2023) (see Tables 6-1 and 6-3.) Botton et al. (2022) covered adults under 75, and the vaccine was one of four evaluated in this report. A French companion report (Jabagi et al., 2022) showed data from the same study in persons 75+ but did not include mRNA-1273. Botton et al. (2022) used standard epidemiological methods but reported only on outcomes over a 2-week postimmunization interval, and each week was reported separately. Another study explored the association of mRNA-1273 with MI risk with data from the U.S. Medicare health system, representing persons in the U.S. 65+ years (Shoaibi et al., 2023). They used a 90-day post- vaccination interval and assessed MI outcome risk of the two-dose primary series. Despite these variations, the study results aligned well with others. Botton et al. (2022) found no increase in risk of MI with mRNA-1273 in the first (RI 0.78, 95% CI: 0.59–1.03) or second (RI 1.06, 95% CI: 0.83–1.37) outcome week (Botton et al., 2022). Shoaibi et al. (2023) showed no increased risk of MI: IRR 1.01 (95% CI: 0.82–1.26), after full adjustment for selected study variables. Ad26.COV2.S and MI Table 6-4 summarizes one study that contributed to the causality assessment. TABLE 6-4 Epidemiological Study in the Ad26.COV2.S–Myocardial Infarction Evidence Review Results Author N Number of Events (95% CI) Botton et al. Dose 1: Week 1: 33 RI 1.57 (1.02–2.44) (2022) 282 vaccinees Week 2: 34 RI 1.75 (1.16–2.62) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; N/A: not applicable; RI: relative incidence. SOURCE: Botton et al., 2022. As noted, this study from the French national health system, covering adults 18–74 years, evaluated four vaccines (Table 6-1). Ad26.COV2.S 3 was received by about 30,000 persons overall, and of those receiving the first dose, 282 MIs were identified. Data were presented separately for the first and second postimmunization weeks only. Outcomes were RI 1.57 (95% CI: 1.02–2.44) for the first week and RI 1.75 (95% CI: 1.16–2.62) for the second week. From Evidence to Conclusions Eight studies assessed the relationship between BNT162b2 and MI across different demographic groups and national populations on three continents. Despite some variation in the types of observational epidemiological study designs, all of these studies showed no important overall statistical evidence of increased risk of MI associated with either dose of BNT162b2 (Ab 2 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. 3 The COVID-19 vaccine manufactured by Janssen. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 169 Rahman et al., 2022; Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022). Conclusion 6-1: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and myocardial infarction. Only two studies evaluated the association between mRNA-1273 and MI; neither showed evidence of increased risk (Botton et al., 2022; Shoaibi et al. 2023), but the findings aligned with those for BNT162b2. Conclusion 6-2: The evidence favors rejection of a causal relationship between the mRNA-1273 vaccine and myocardial infarction. Only one study evaluated the relation between Ad26.COV2.S and MI, and the number of MI events was modest (Botton et al., 2022). Conclusion 6-3: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and myocardial infarction. No studies examined the relationship between NVX-CoV2373 4 and MI. Conclusion 6-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and myocardial infarction. 4 The COVID-19 vaccine manufactured by Novavax. PREPUBLICATION COPY—Uncorrected Proofs

170 VACCINE EVIDENCE REVIEW ISCHEMIC STROKE BOX 6-2 Conclusions for Ischemic Stroke Conclusion 6-5: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and ischemic stroke. Conclusion 6-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and ischemic stroke. Conclusion 6-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and ischemic stroke. Conclusion 6-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and ischemic stroke. Background A stroke may occur due to either a blockage in blood flow to the brain or sudden bleeding within the brain. The primary form is known as an ischemic stroke, where the brain is deprived of necessary oxygen and nutrients due to a blockage in blood flow, leading to rapid cell death. The secondary type is termed a hemorrhagic stroke, characterized by blood leakage that applies pressure on brain cells, causing damage (NHLBI, 2023). Hemorrhagic strokes are discussed and evaluated in the next section. Ischemic strokes are usually caused by either atherosclerotic lesions in cerebral arteries or emboli, often blood clots, from the heart or other parts of the vascular tree. However, several other mechanisms are possible. Strokes can occur at any age but are most common in older people. In the United States, strokes are overall the fifth leading cause of death. Typically, strokes are acute and relatively sudden, often within hours or less, even though the lesions themselves may take a long time to develop. Sometimes, neurological manifestations occur intermittently and incompletely; these clinical events may be diagnosed as a “transient ischemic attack,” which is often considered diagnostically separate from “completed” strokes, which can be important in studies that assess stroke outcomes. The clinical presentation may also be modified by various medical interventions, leading to other diagnostic challenges. Stroke diagnoses may also vary by relative access to technology, such as imaging procedures, which can differ by country and within-country region. All of these factors can possibly affect apparent incidence rates across studies. To complicate matters further, persons with cardiovascular diseases are 2–4 times more likely to have a stroke (Robinson et al., 2023), raising issues of the underlying causes. These complex diagnostic challenges apply to all the thromboembolic outcomes assessed in this chapter, as discussed. However, in a comprehensive global review of ICD coding validity study, McCormick et al. (2015) found that the positive predictive value (PPV) was 82 and over 93 percent for ischemic and ICD-9 hemorrhagic stroke codes. For diagnosis, ischemic stroke is identified by the abrupt onset of focal neurologic deficits, with speech disturbance and weakness on one half of the body being the most common symptoms. Diagnostic studies are crucial to differentiate it from other conditions, such as PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 171 intracerebral hemorrhage, or entities mimicking it, such as seizures or hypoglycemia. Neuroimaging, particularly noncontrast computed tomography (CT) or magnetic resonance imaging (MRI), plays a vital role in this differentiation. Noncontrast CT is sensitive for detecting mass lesions and acute hemorrhage but less effective in detecting strokes within 3 hours of the event and has even lower sensitivity for small or posterior fossa strokes. In contrast, MRI, especially diffusion-weighted imaging, offers better resolution and greater sensitivity for detecting acute ischemic stroke and is as sensitive as noncontrast CT for intracerebral hemorrhagic stroke (Vymazal et al., 2012). Mechanisms A key aspect of ischemic stroke pathophysiology involves the immune system. In the acute phase, innate immune cells invade the brain and meninges, contributing to damage but also potentially offering protection. This phase is characterized by the damaged brain cells releasing danger signals, such as damage-associated molecular patterns (DAMPs), into the circulation, activating systemic immunity. In the chronic phase, antigen presentation triggers an adaptive immune response targeted at the brain, possibly underlying the neuropsychiatric sequelae that significantly contribute to morbidity (Chamorro et al., 2012; Nakamura and Shichita, 2019). A mechanism of ischemic stroke as a result of COVID-19 vaccination remains to be established. However, it can be hypothesized that temporary inflammation of the arterial wall could be a contributing factor in cerebral hemorrhage (de Mélo Silva and Lopes, 2021). The proposed immune response could also trigger a systemic prothrombotic state, characterized by endothelial dysfunction and activation, complement and platelet activation, and infiltration of inflammatory cells into atherosclerotic plaques. These processes lead to amplified inflammatory responses and potential thrombosis within these plaques (Bonaventura et al., 2021). This is in line with the concept that inflammatory conditions, especially in atherosclerosis, are precursors to thrombotic events, including cerebrovascular ones (Assiri et al., 2022). Some argue that COVID-19 vaccination could induce an inflammatory cascade similar to that in COVID-19 infection, leading to disseminated intravascular coagulation, vascular endothelial dysfunction, and large-vessel cerebral infarctions. Following messenger ribonucleic acid (mRNA) vaccination, the introduction of mRNA sequences coding for the SARS-CoV-2 spike protein into host cells leads to its synthesis and release, stimulating an inflammatory immune response (Assiri et al., 2022; Famularo, 2022). Epidemiological Evidence BNT162b2 and Ischemic Stroke Table 6-5 presents six studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

172 VACCINE EVIDENCE REVIEW TABLE 6-5 Epidemiological Studies in the BNT162b2–Ischemic Stroke Evidence Review Number Author N of Events Results (95% CI) Ab Rahman et Dose 1: 8.7 million vaccinees Dose 1: 535 IRR 1.05 (0.95–1.15) al. (2022) Dose 2: 6.7 million vaccinees Dose 2: 471 IRR 1.11 (1.00–1.23) Botton et al. Dose 1: 11,282 vaccinees Week 1: 329 RI 0.84 (0.74–0.94) (2022) Week 2: 366 RI 0.95 (0.85–1.06) Dose 2: 9,344 vaccinees Week 1: 279 RI 0.93 (0.81–1.06) Week 2: 307 RI 1.09 (0.96–1.23) Burn et al. Dose 1: 1.8 million vaccinees 146 SIR 1.10 (0.93–1.29) (2022a) Dose 2: 1.3 million vaccinees 68 SIR 0.68 (0.54–0.86) Burn et al. Dose 1: 2.0 million vaccinees 521 SIR 0.98 (0.90–1.07) (2022b) Dose 2: 1.3 million vaccinees 515 SIR 1.01 (0.92–1.10) Jabagi et al. Dose 1: 3.9 million vaccinees 9,162 RI 0.90 (0.84–0.98) (2022) Dose 2: 3.2 million vaccinees 6,531 RI 1.04 (0.93–1.16) Whiteley et al. Dose 1: 8.7 million vaccinees 4,143 <70 years: HR 0.90 (0.83–0.97) (2022) >70 years: HR 0.71 (0.68–0.75) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IRR: incidence rate ratio; RI: relative incidence; SIR: standardized incidence ratio. SOURCES: Ab Rahman et al., 2022; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Whiteley et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 173 The two papers from France report on one study, addressing adults younger than and over 75, respectively (Botton et al., 2022; Jabagi et al., 2022). This study, as noted, reported only two separate weeks of postimmunization outcomes. Botton et al. showed no increased risk of stroke after either week (Botton et al., 2022), and Jabagi et al. (2022) studied the oldest population (over 74) and found similar results. The UK study (Burn et al., 2022a) and the Catalonia, Spain study (Burn et al., 2022b) also found no increased stroke risk with this vaccine. The Malaysian study, with a different design, had the same findings (Ab Rahman et al., 2022). Whiteley et al. (2022) from England had one of the largest immunized populations, over 8 million, but presented findings separately for those over and under 70. Hazard ratios were reported for two separate age groups: younger than 70 and 70+. All studies showed no increased risk of ischemic stroke with the BNT162b2 vaccine in all major analytical groups. mRNA-1273 and Ischemic Stroke Table 6-6 summarizes one study that contributed to the causality assessment. TABLE 6-6 Epidemiological Study in the mRNA-1273–Ischemic Stroke Evidence Review Number of Results Author N Events (95% CI) Botton et al. Dose 1: 1,491 vaccinees Week 1: 42 RI 0.76 (0.55–1.07) (2022) Week 2: 40 RI 0.76 (0.54–1.07) Dose 1: 1,200 vaccinees Week 1: 45 RI 1.15 (0.82–1.62) Week 2: 41 RI 1.12 (0.77–1.62) NOTES: mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Only one relevant scientific report attempted to link mRNA-1273 with ischemic stroke risk. As seen in other sections, Botton et al. (2022), covering adults 18–74 years, reported ischemic stroke risk in the 2 weeks after immunization. Some weaknesses included inability to fully assess the risk association on the day of immunization, the reporting of each outcome week risk separately, and that, as in many of the other reports, outpatient-only clinical events were not surveyed. The risk was not significantly increased in either postimmunization week. The companion paper (Jabagi et al., 2022) on persons 75+ in this study did not include this vaccine. Ad26.COV2.S and Ischemic Stroke Table 6-7 summarizes one study that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

174 VACCINE EVIDENCE REVIEW TABLE 6-7 Epidemiological Study in the Ad26.COV2.S–Ischemic Stroke Evidence Review Number of Author N Events Results (95% CI) Botton et al. Dose 1: 196 vaccinees Week 1: 14 RI 0.78 (0.43–1.41) (2022) Week 2: 19 RI 1.09 (0.66–1.81) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series of Ad26.COV2.S is one dose. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Botton et al. (2022), as mentioned in the discussion on BNT162b2 and mRNA-1273, other vaccines, was the only available report on the association of Ad26.COV2.S with ischemic stroke. Its strengths and limitations are similar. One additional limitation for this vaccine is that the number of outcome events was modest, which should be considered in statistical evaluation of the findings. However, within these limitations, no significantly increased risk of ischemic stroke was found. From Evidence to Conclusions All six studies that assessed the association between BNT162b2 and ischemic stroke, comprising five robust studies from multiple countries and exploring younger and older adults, found no evidence of increased risk, despite modest difference in the study designs Ab Rahman et al., 2022; Botton et al., 2022; Burn et al., 2022a, 2022b; Jabagi et al., 2022; Whiteley et al., 2022). Conclusion 6-5: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and ischemic stroke. A single study assessed the relationship between mRNA-1273 and Ad26.COV2.S and ischemic stroke (Botton et al., 2022). Although it was generally well designed, it had limitations: a lack of representation of older persons (over 75), separate presentation of outcome rates for each postimmunization week, a group with high ischemic stroke risk, and a modest number of stroke outcomes. No studies evaluated the relationship between NVX-CoV2373 and ischemic stroke. Conclusion 6-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and ischemic stroke. Conclusion 6-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and ischemic stroke. Conclusion 6-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and ischemic stroke. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 175 HEMORRHAGIC STROKE BOX 6-3 Conclusions for Hemorrhagic Stroke Conclusion 6-9: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and hemorrhagic stroke. Conclusion 6-10: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and hemorrhagic stroke. Conclusion 6-11: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and hemorrhagic stroke. Conclusion 6-12: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and hemorrhagic stroke. Background As with other strokes, hemorrhagic stroke (HS) is usually an acute event that occurs after bleeding within the cerebrum or more specifically within the brain, usually caused by a ruptured blood vessel. It has been estimated that about 750,000 persons in the United States die of stroke each year. About 20 percent of incident strokes are due to hemorrhage. Often, the bleeding that comes with HS can damage the brain and impair neurological function by many mechanisms, such as due to physical pressure or inflammation. HS has many causes, such as ruptured aneurysms, head trauma, vascular malformations, and anticoagulants (Caplan, 2023). Some of the risk factors are similar to those of other important vascular conditions, such as MI or ischemic stroke (e.g., smoking, hypertension, diabetes), so prevention is an important part of the management of this condition. HS may occur in several areas of the brain, such as epidural, intraparenchymal, subdural, and subarachnoid locations. The extent of diagnostic specificity depends, as with other vascular conditions, on regional and national diagnostic and therapeutic practices and health care resources, such as advanced imaging and other neuroradiological techniques. This is particularly important because in studies of vaccine use and clinical outcomes, the latter will depend on these resources and diagnostic nomenclature. For example, an HS may be primarily called a “ruptured aneurysm” or a “subarachnoid hemorrhage,” which may have causal implications. As COVID-19 infection may be a cause of HS, this complicates assessing vaccine causation due to interacting comorbid conditions and treatments (Wang et al., 2020). Research has advanced the use of artificial intelligence to help identify anatomic locations of hemorrhage and its classification (Neves et al., 2023), but how this is being applied to causal studies, such as those related to vaccines, is uncertain. Yet, as noted, validation studies of ICD coding of HS have been positive and useful (Kirkman et al., 2009). PREPUBLICATION COPY—Uncorrected Proofs

176 VACCINE EVIDENCE REVIEW Mechanisms HS occurs when a blood vessel within the brain ruptures, leading to bleeding in or around the brain, and can result from various etiologies, including hypertension, aneurysms, and arteriovenous malformations. Chronic hypertension may lead to Charcot-Bouchard microaneurysms in small penetrating arterioles, which are prone to rupture under sustained high pressure. Subarachnoid hemorrhage is often due to the rupture of a saccular aneurysm, and arteriovenous malformations, which are tangles of blood vessels with abnormal connections between arteries and veins, can also rupture (Montano et al., 2021; Smith and Eskey, 2011). The secondary injury mechanisms include the mass effect and increase intracranial pressure, where blood accumulation causes compression of brain tissue, leading to blocked blood flow and the toxic effects of blood breakdown products (Serrone et al., 2015). Hemoglobin degradation products can be toxic to brain tissue and contribute to vasospasm, particularly in subarachnoid hemorrhage (Gross et al., 2019). An immune response after hemorrhage is characterized by the activation of microglia and infiltration of macrophages and lymphocytes, which can exacerbate neuronal damage. Proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, are elevated, contributing to secondary injury and brain edema (Li and Chen, 2023). Some vaccines, notably those associated with a risk of thrombocytopenia, could theoretically lead to HS, although this is exceedingly rare; an autoimmune response leading to platelet destruction and severe thrombocytopenia might predispose individuals to hemorrhage. The proposed mechanism of HS is similar to that of ischemic stroke, as mentioned. Epidemiological Evidence BNT162b2 and HS Table 6-8 presents six studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 177 TABLE 6-8 Epidemiological Studies in the BNT162b2–Hemorrhagic Stroke Evidence Review Number Author N of Events Results (95% CI) Ab Rahman et al. Dose 1: 8.7 million vaccinees 119 IRR 1.29 (1.05–1.59) (2022) Dose 2: 6.7 million vaccinees 80 IRR 1.05 (0.82–1.34) Botton et al. (2022) Dose 1: 3,141 vaccinees Week 1: 112 RI 0.97 (0.80–1.19) Week 2: 119 RI 1.07 (0.88–1.30) Dose 2: 2,372 vaccinees Week 1: 86 RI 0.98 (0.77–1.25) Week 2: 71 RI 0.86 (0.67–1.11) Chui et al. (2022) Dose 1: 2.9 million vaccinees 31 IRR 1.67 (1.04–2.69) Dose 2: 2.7 million vaccinees 26 IRR 1.68 (0.99–2.84) Jabagi et al. (2022) Dose 1: 3.9 million vaccinees 2,050 RI 0.90 (0.78–1.04) Dose 2: 3.2 million vaccinees 1,366 RI 0.97 (0.81–1.15) Patone et al. (2021) Dose 1: 12.1 million vaccinees 151 RI 1.24 (1.07–1.43) Whiteley et al. Dose 1: 8.7 million vaccinees 440 <70 years: HR 0.77 0.62–0.96) (2022) >70 years: HR 0.65 (0.57–0.74) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IRR: incidence rate ratio; RI: relative incidence; RR: risk ratio. SOURCES: Ab Rahman et al., 2022; Botton et al., 2022; Chui et al., 2022; Jabagi et al., 2022; Patone et al., 2021; Whiteley et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

178 VACCINE EVIDENCE REVIEW Six reports represent five studies addressing the association of HS with this vaccine, and several reports were used in other sections of this chapter. One was a cohort study; the remainder were self-controlled designs. The committee examined the data on the first dose of the primary series. All but Patone et al. (2021) and Chui et al. (2022) have been discussed. Patone et al. (2021) was conducted using the English National Immunization Database, using a self-controlled design. Only first-dose outcomes and hospitalized patients were evaluated. The study showed a modestly increased risk of (RI 1.24, 95% CI: 1.07–1.43). However, this group also conducted a validation study using similar methods on Scottish data and found no increased risk of HS, using a somewhat smaller sample size. An important issue with this report is that subarachnoid hemorrhage was considered as a separate outcome from HS; as discussed in the background of this section, these two diseases may have some amount of overlap and/or misclassification, although no further information was offered. Chui et al. (2022) was conducted in Hong Kong, China, and used geography-wide medical care and immunization databases, a “modified” self-control design with seasonal adjustment, and a 28-day postimmunization outcomes interval. They found an increased risk of HS associated with BNT162b2 (IRR 1.67, 95% CI: 1.04–2.69). In addition, Ab Rahman et al. (2022) from Malaysia showed a marginally increased risk of HS (IRR 1.29, 95% CI: 1.05–1.59). The remaining studies showed no increased risk, including two analyses that separated the findings into older and younger adults (Botton et al., 2022; Jabagi et al., 2022). mRNA-1273 and HS Table 6-9 summarizes the one study that contributed to the causality assessment. TABLE 6-9 Epidemiological Study in the mRNA-1273–Hemorrhagic Stroke Evidence Review Number of Author N Events Results (95% CI) Botton et al. Dose 1: 414 vaccinees Week 1: 12 RI 0.73 (0.39–1.37) (2022) Week 2: 14 RI 0.91 (0.51–1.61) Dose 2: 299 vaccinees Week 1: 10 RI 1.06 (0.56–2.00) Week 2: 4 RI 0.45 (0.16–1.23) NOTES: mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Botton et al. (2022) used the French national health system to explore the association between mRNA-1273 and HS. This was a study of HS outcomes after the first dose of the primary series. As in the other applications of this study, only 2 weeks of the postimmunization interval were presented, and the risks for each week were presented separately. This study included adults up to 74, but the number of HS case outcomes in the first 2 weeks was only 26. The portion of the study describing outcomes in persons 75+ showed no findings on mRNA- 1273 and HS (Jabagi et al., 2022), likely because of an inadequate number of case outcomes. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 179 Ad26.COV2.S and HS Table 6-10 summarizes one study that contributed to the causality assessment. TABLE 6-10 Epidemiological Study in the Ad26.COV2.S–Hemorrhagic Stroke Evidence Review Number Author N of Events Results (95% CI) Botton et al. Dose 1: 38 vaccinees Week 1: 6 RI 1.28 (0.46–3.61) (2022) Week 2: 6 RI 1.59 (0.60–4.21) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. As with mRNA-1273, only one study evaluated Ad26.COV2.S described for adults aged 18–74 (Botton et al., 2022). The same limitations apply here, and only 12 HS cases occurred in the 2-week postimmunization interval. The outcomes for the older patient set (75+ years) were not available (Jabagi et al., 2022). From Evidence to Conclusions The findings from the studies evaluating BNT162b2 and HS were mixed, with some finding an increased risk. Additionally, evidence of possible disease misclassification of HS with other sources of intracranial hemorrhage could not be resolved, as suggested by the general medical literature. Only two of the five studies showed an increased signal of HS risk, and an additional study showed a marginally increased risk (Ab Rahman et al., 2022; Chui et al., 2022; Patone et al., 2021). Conclusion 6-9: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and hemorrhagic stroke. Only one study evaluated the relationship between mRNA-1273 and HS; it had only 2 weeks of postimmunization follow-up (Botton et al., 2022). Only 26 HS cases occurred in those who received mRNA-1273. Conclusion 6-10: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and hemorrhagic stroke. Only one study evaluated the relationship between Ad26.COV2.S and HS, which showed no evidence of increased risk; it had only 2 weeks of postimmunization follow-up with only 12 cases (Botton et al., 2022). No studies evaluated the association between NVX-CoV2373 and HS. Conclusion 6-11: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and hemorrhagic stroke. PREPUBLICATION COPY—Uncorrected Proofs

180 VACCINE EVIDENCE REVIEW Conclusion 6-12: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and hemorrhagic stroke. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 181 DEEP VEIN THROMBOSIS, PULMONARY EMBOLISM, AND VENOUS THROMBOEMBOLISM BOX 6-4 Conclusions for Deep Vein Thrombosis, Pulmonary Embolism, and Venous Thromboembolism Conclusion 6-13: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-14: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-15: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-16: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Background Deep vein thrombosis (DVT), pulmonary embolism (PE), and venous thromboembolism (VTE) are related conditions, often with common risk factors, clinical manifestations, pathogenetic mechanisms, treatments, and preventive interventions. “ VTE” mostly or entirely may represent a category including PE and DVT. Occurrence rates can depend on the chronicity, comorbidity, and prevalent risk factors. The mortality risk among adults ≥65 with VTE is 3.1 percent at 30 days and 19.6 percent at 1 year (Giorgio et al., 2023). Other vascular and related immunologic outcomes, such as immune thrombotic purpura (ITP) and immune thrombocytopenic purpura (ITP), are considered separately in Chapter 5. The evidence regarding association of each of the three conditions with COVID-19 vaccines will be discussed separately, but conclusions and the relevant justifications appear together at the end of this section. DVT, PE and VTE, in part because of these overlapping characteristics, present a dilemma in research and clinical outcome studies because regional and national variation in diagnostic practices and medical terminology may lead to misclassification, which can be substantial. For example, in an important report cited in this chapter (Shoaibi et al., 2023), a medical chart review of PE from the U.S. Medicare system found that the PPV for accuracy of 101 cases was only 45 percent. Other, similar validation studies show varying results. In a study of over 4,000 VTE cases, also from the United States, Fang et al. (2017) found a PPV of 64.6 percent in patients who were hospitalized or seen in an emergency department but only 30.9 percent for outpatients. In a systematic review of matching medical records to claim codes. On the other hand, Tamariz et al. (2012) found the highest PPV values among ICD-9 codes for combined PE and DVT to range from 65–95 percent accuracy, with the highest among those at PREPUBLICATION COPY—Uncorrected Proofs

182 VACCINE EVIDENCE REVIEW greatest risk of VTE. These studies overall found important variation in accuracy according to patient risk, location seen in the health care system, whether the diagnosis was primary or secondary and anatomic site, highlighting factors related to variation accuracy. Pathophysiology The pathophysiology of DVT is often explained by Virchow’s triad: venous stasis, endothelial injury, and hypercoagulability. PE involves not only the mechanical obstruction of the pulmonary artery but also the release of vasoactive substances that cause pulmonary vasoconstriction, leading to an increase in pulmonary vascular resistance and right ventricular strain. Immune responses, particularly those involving inflammatory mediators, can exacerbate this by increasing vascular permeability and promoting further thrombosis. VTE occurs at higher frequency in the context of inflammation, such as during infections, in autoimmune conditions, and postoperatively. In an immune-mediated context, inflammation plays a critical role. Proinflammatory cytokines can alter the coagulation cascade, leading to a prothrombotic state. For instance, elevated levels of IL-6 have been implicated in increased thrombin generation (Tang et al., 2015). COVID-19 vaccines have been shown to increase IL-6 production both in situ (Zhu et al., 2023) and ex vivo (Langgartner et al., 2023). Other ways that the immune system can lead to a hypercoagulable state include monocytes and neutrophil release of tissue factor, a potent activator of the coagulation cascade, and the formation of neutrophil extracellular traps, which can provide a scaffold for thrombus formation. Deep Vein Thrombosis DVT occurs when blood clots develop and persist in a larger vein, such as in the thighs, pelvis, arms, splanchnic vasculature, and cerebrum. Most of these clots, however, form in the legs, with varying signs and symptoms, altered persistence, and uncertain clinical consequences (Mithoowani, 2022). Signs and symptoms may include edema, redness, pain, and disability. The diagnosis can be challenging, made by a combination of clinical signs and symptoms, biomarkers, imaging studies, and physiological measures. DVT may occur acutely or chronically, the latter supporting the importance of having a history of DVT. This is important because prior DVT and its underlying conditions may be central to understanding the pathogenetic underpinnings during acute exposures, such as vaccines. Various studies, some reviewed here, may or may not have included prior comorbidity occurrence in DVT risk models. DVT (and VTE in general) may have different rates across countries and global regions. Epidemiological Evidence BNT162b2 and DVT Table 6-11 lists five studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 183 TABLE 6-11 Epidemiological Studies in the BNT162b2–Deep Vein Thrombosis Evidence Review Number of Author N Events Results (95% CI) Barda et al. (2021) Dose 1: 884,828 vaccinees 39 RR 0.87 (0.55–1.40) Burn et al. (2022a) Dose 1: 1.8 million vaccinees 303 SIR 1.00 (0.89–1.12) Dose 2: 1.3 million vaccinees 182 SIR 0.85 (0.74 to 0.99) Burn et al. (2022b) Dose 1: 2.0 million vaccinees 182 SIR 1.03 (0.89–1.19) Dose 2: 1.3 million vaccinees 130 SIR 0.80 (0.67–0.95) Hviid et al. (2022) Dose 1: 101,212 vaccinees 13 RD 2.05 (-2.49–6.59) Whiteley et al. Dose 1: 8.7 million vaccinees 555 Age <70: HR 0.82 (0.71–0.95) (2022) Age <70: HR 0.61 (0.53–0.70) NOTES: Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. Number of events refers to events in vaccinees only. CI: confidence interval; IR: incidence rate; RD: risk difference; RR: rate ratio; SIR: standardized incidence rate. SOURCES: Barda et al., 2021; Burn et al., 2022a, 2022b; Hviid et al., 2022; Whiteley et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

184 VACCINE EVIDENCE REVIEW Five scientific reports from Europe and Israel explored the association of relevant COVID-19 vaccines to DVT. Of the four vaccines that are the focus of the committee’s review, only BNT162b2 was included in these analyses. The five studies included three cohort designs and one each with a self-controlled design and a matched case-control design. The sample sizes were generally robust, except for the Danish study (Hviid et al., 2022), where these were more modest. This study was also the only one that presented its outcome statistics as risk differences. Whiteley et al. (2022) presented its findings separately for persons under and over 70. Burn et al. (2022a) from the United Kingdom included VTE and DVT outcomes. Hviid et al. (2022) had many fewer cases, and the confidence interval (CI) was wide but not significant in this relative difference analysis. All the studies showed no significantly increased risk. Pulmonary Embolism PE is the obstruction of a pulmonary artery by a physical entity, the embolus, that travels to the heart, lodging in the lungs. This “obstruction” may often be from blood clots forming elsewhere, usually due to some form of DVT, but in it could be a tumor, air, or fat globule. This could be quite traumatic and acute or chronic, and it may be fatal, depending on the extent and cause of the embolus. According to the American Lung Association, about 900,000 people have a PE each year (ALA, 2023). Because these may be symptomatic or asymptomatic and have varying degrees of clinical severity, difficulties may arise in making a definitive diagnosis. Due to the challenges and variations in PE diagnostic practices and technology and in coding and classification systems, apparent PE rates may vary across populations and countries, and this variation may lead to variations in community and regional study findings and in identifying risk factors and outcomes, as is the case for DVT (see above). As is with DVT, the nomenclature for diagnostic coding varies, leading to some of these thromboembolic events being designated under different rubrics, such as DVT, PE or VTE. This complicates the interpretation of vaccine-related population studies, and only a few of them address these issues in detail or with validation studies. Epidemiological Evidence BNT162b2 and PE Table 6-12 presents eight studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 185 TABLE 6-12 Epidemiological Studies in the BNT162b2–Pulmonary Embolism Evidence Review Number of Author N Events Results (95% CI) Barda et al. (2021) Dose 1: 884,828 vaccinees 10 RR 0.56 (0.21–1.15) Botton et al. (2022) Dose 1: 7,242 vaccinees Week 1: 203 RI 0.81 (0.70–0.94) Week 2: 200 RI 0.83 (0.71–0.96) Dose 2: 5,665 vaccinees Week 1: 156 RI 0.83 (0.70–0.99) Week 2: 178 RI 1.00 (0.85–1.17) Burn et al. (2022a) Dose 1: 1.8 million vaccinees 324 SIR 1.25 (1.12–1.40) Dose 2: 1.3 million vaccinees 153 SIR 0.84 (0.71–0.98) Burn et al. (2022b) Dose 1: 2.0 million vaccinees 154 SIR 1.25 (1.07–1.46) Dose 2: 1.3 million vaccinees 116 SIR 1.00 (0.84–1.20) Hviid et al. (2022) Dose 1: 101,212 vaccinees 8 RD 1.32 (-2.55–5.19) Jabagi et al. (2022) Dose 1: 3.9 million vaccinees 3,993 RI 0.85 (0.75–0.96) Dose 2: 3.2 million vaccinees 2,889 RI 1.10 (0.95–1.26) Shoaibi et al. (2023) Doses 1 and 2: 1,684 IRR 1.19 (1.03–1.38) 3.4 million vaccinees Whiteley et al. (2022) Dose 1: 8.7 million vaccinees 928 Age <70: HR 0.78 (0.69–0.88) Age >70: HR 0.54 (0.49–0.69) NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for BNT162b2 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval; HR: hazard ratio; IR: incidence rate; IRR: incidence rate ratio; RD: risk difference; RI: relative incidence; RR: risk ratio. SOURCES: Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Hviid et al., 2022; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

186 VACCINE EVIDENCE REVIEW PE outcomes were explored in nine scientific reports, including eight separate studies and three vaccines (BNT162b2, mRNA-1273, and Ad26.COV2.S). Eight represented findings from the first dose of the primary COVID-19 vaccination series; Shoaibi et al. (2023) reflected the combined effects of doses 1 and 2. The eight studies represented countries in Europe, and one was in the United States. Two studies in three reports presented older and younger vaccines separately (see Table 6-1 for more detail) (Botton et al., 2022; Jabagi et al., 2022; Whiteley et al., 2022). All the outcomes shown were listed only as derived from the outcome rubric “PE.” As described for certain reports, some of the statistical models were adjusted for demographic characteristics, length of postimmunization follow-up interval, prevalent comorbidity at baseline, and other features, such as season. Study designs included self-controls, cohort studies and matched case-control, all noted in Table 6-1. Hviid et al. (2022) from Denmark had the smallest number of follow-up patients. Six reports from five studies showed no evidence of increased risk of PE, but three studies showed increased risk (Burn et al., 2022a, 2022b; Shoaibi et al., 2023). Hviid et al. (2022), despite not showing an increased risk, had a very wide CI of the estimate, likely due to a smaller sample size in the base population and number of cases (RD 1.32, 95% CI: -2.55–5.19). mRNA-1273 and PE Table 6-13 presents two studies that contributed to the causality assessment. TABLE 6-13 Epidemiological Studies in the mRNA-1273–Pulmonary Embolism Evidence Review Number Author N of Events Results (95% CI) Botton et al. (2022) Dose 1: 1,003 vaccinees Week 1: 18 RI 0.43 (0.26–0.71) Week 2: 26 RI 0.72 (0.48–1.09) Dose 2: 769 vaccinees Week 1: 36 RI 1.31 (0.90–1.91) Week 2: 23 RI 0.88 (0.56–1.40) Shoaibi et al. (2023) Doses 1 and 2: 786 IRR 1.15 (0.94–1.41) 3.4 million vaccinees NOTES: Shoaibi et al. (2023) combined the number of BNT162b2 and mRNA-1273 vaccinees. The primary series for mRNA-1273 is two doses. Number of events refers to events in vaccinees only. CI: confidence interval, IRR: incidence rate ratio; RI: relative incidence SOURCES: Botton et al., 2022; Shoaibi et al., 2023. The mRNA-1273 association with PE was explored in two reports (Botton et al., 2022; Shoaibi et al., 2023). These studies are summarized in this section and Tables 6-1 and 6-13. The findings from Botton et al. (2022), representing persons 18–74 years of age, showed no increased risk of PE, but only 44 cases were noted. Shoaibi et al. (2023) also showed no increased risk. However, uniquely among all the reports assessed in this chapter, Shoaibi et al. (2023) conducted a medical record review of PE validated against the ICD codes. For the 101 cases identified by code, over half of the diagnoses were inaccurate or could not be determined. This suggests that case misclassification could be an important problem. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 187 Ad26.COV2.S and PE Table 6-14 summarizes one study that contributed to the causality assessment. TABLE 6-14 Epidemiological Study in the Ad26.COV2.S–Pulmonary Embolism Evidence Review Number of Author N Events Results (95% CI) Botton et al. (2022) Dose 1: 77 vaccinees Week 1: 7 RI 0.94 (0.40–2.21) Week 2: 3 RI 0.42 (0.13–1.32) NOTES: Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; RI: relative incidence. SOURCE: Botton et al., 2022. Only one scientific report related Ad26.COV2.S to PE: Botton et al. (2022), an assessment from the French national health system, covering persons aged 18–74. The findings showed no increased association of this vaccine with PE, but only 10 cases of PE recorded in the 2 postimmunization weeks were available for analysis. Venous Thromboembolism Although VTE is used throughout the literature on vascular and coagulation-related diseases, it appears to be used differently in different literature reports, as noted. For example, it often appears to include both thrombotic conditions (deep and superficial) in various anatomic sites and for embolic phenomena. A few studies have been done on validation of the rubric as used in ICD coding. One study of VTE using ICD-9 coding concluded that it was not an effective code for determining underlying conditions (Fang et al., 2017). Another study of VTE coding in the emergency department setting concluded that the ICD-10 code was only moderately effective in identifying DVT and PE (Al-Ani et al., 2015). Shoaibi et al. (2023) found validation problems with these entities, and this calls into question the potential validity of VTE outcomes in certain population studies that apply institutional coding systems, where validation studies have not been performed. Epidemiological Evidence BNT162b2 and VTE Table 6-15 presents four studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

188 VACCINE EVIDENCE REVIEW TABLE 6-15 Epidemiological Studies in the BNT162b2–Venous Thromboembolism Evidence Review Number of Author N Events Results (95% CI) Ab Rahman et al. Dose 1: 103 IRR 1.34 (1.07–1.26) (2022) 8.7 million vaccinees Dose 2: 63 IRR 1.09 (0.83–1.44) 6.7 million vaccinees Burn et al. (2022a) Dose 1: 595 SIR 1.12 (1.03–1.21) 1.8 million vaccinees Dose 2: 324 SIR 0.86 (0.77–0.96) 1.3 million vaccinees Burn et al. (2022b) Dose 1: 313 SIR 1.18 (1.06–1.32) 2.0 million vaccinees Dose 2: 227 SIR 0.92 (0.81–1.05) 1.3 million vaccinees Hippisley-Cox et Dose 1: Total: 2,054 Days 8–14: al. (2021) 9.5 million vaccinees Days 8–14: 555 IRR 0.99 (0.90–1.08) NOTES: Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. Number of events refers to events in vaccinees only. CI: confidence interval; IRR: incidence rate ratio; SIR: standardized incidence ratio. SOURCES: Ab Rahman et al., 2022; Burn et al., 2022a, 2022b; Hippisley-Cox et al., 2021. Despite issues of outcome identification and the possibility of case misclassification, the committee assessed the three studies that used the VTE outcome rubric. The four reports presented VTE outcomes, available for BNT162b2 only. Hippisley-Cox et al. (2021) presented VTE outcomes for four separate 1-week postimmunization outcomes, without any further summarization; the week with the highest risk outcome (days 8–14) is included in Table 6-15. Burn et al. (2022a, 2022b) showed a very slight increased risk after dose 1. Given the limitations noted, three of the four studies showed an increased risk of VTE associated with this vaccine, albeit modest increases. From Evidence to Conclusions Five population studies from Europe and Israel evaluated the association between BNT162b2 and the risk of DVT. None showed any significant increased risk. However, Hviid et al. (2022) had a much smaller number of patient outcomes and a wide CI. The dilemma for these five studies is that some had other clinical rubrics or outcome categories denoting coagulation disorders or “VTE.” This and the general problem of uncertainty in disease classification raised the issue that some of these patients may not have had DVT, leading to some possible loss of sample size and disease misclassification. Eight reports from seven studies addressed the association between BNT162b2 and risk of PE (Barda et al., 2021; Botton et al., 2022; Burn et al., 2022a, 2022b; Hviid et al., 2022; Jabagi et al., 2022; Shoaibi et al., 2023; Whiteley et al., 2022). All studies were informative for the committee’s analysis, but they varied to some extent in epidemiological design. All but one study had suitably robust sample sizes. Some concern arose based on a validation study whether PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 189 all diagnoses of PE could be confirmed on further review. Four studies showed no evidence of increased risk of PE, but three found a statistically significant increased risk. The number of studies addressing VTE was limited (four) and addressed only BNT126b2, three pointed in the direction of increased risk, albeit modest (Ab Rahman et al., 2022; Burn et al., 2022a, 2022b; Hippisley-Cox et al., 2021). A composite outcome, VTE could have been analyzed in the other studies that reported only PE and DVT as the outcomes, so the results might be at greater risk of reporting bias compared with other outcomes. The remaining issue is potential validation problems for VTE, and its constituent DVT and PE diagnoses, based on some of the quality assessment literature consulted. Conclusion 6-13: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. No studies evaluated the relationship between mRNA-1273 and DVT or VTE. Only two studies provided evidence for PE outcomes (Botton et al., 2022; Shoaibi et al., 2023); both showed no evidence of increased risk. The sample sizes were generally more modest than with BNT162b2. The results are complicated by the problem noted with diagnostic validation. Conclusion 6-14: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Only one study was available to assess the evidence between Ad26.COV2.S and PE (Botton et al., 2022). The number of cases was very small in the 2-week postimmunization follow-up period, although no increased risk was found. The committee notes the case validation issue. No studies evaluated the relationship between NVX-CoV2373 and DVT, PE, or VTE. Conclusion 6-15: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. Conclusion 6-16: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and deep vein thrombosis, pulmonary embolism, and venous thromboembolism. PREPUBLICATION COPY—Uncorrected Proofs

190 VACCINE EVIDENCE REVIEW 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. ALA (American Lung Association). 2023. Learn about pulmonary embolism. https://www.lung.org/lung- health-diseases/lung-disease-lookup/pulmonary-embolism/learn-about-pulmonary-embolism (accessed December 12, 2023). Al-Ani, F., S. Shariff, L. Siqueira, A. Seyam, and A. Lazo-Langner. 2015. Identifying venous thromboembolism and major bleeding in emergency room discharges using administrative data. Thrombosis Research 136(6):1195–1198. https://doi.org/10.1016/j.thromres.2015.10.035. Assiri, S. A., R. M. M. Althaqafi, K. Alswat, A. A. Alghamdi, N. E. Alomairi, D. M. Nemenqani, Z. S. Ibrahim, and A. Elkady. 2022. Post COVID-19 vaccination-associated neurological complications. Neuropsychiatric Disease and Treatment 18:137–154. https://doi.org/10.2147/ndt.S343438. Barda, N., N. Dagan, Y. Ben-Shlomo, E. Kepten, J. Waxman, R. Ohana, M. A. Hernán, M. Lipsitch, I. Kohane, D. Netzer, B. Y. Reis, and R. D. Balicer. 2021. Safety of the BNT162b2 mRNA COVID-19 vaccine in a nationwide setting. New England Journal of Medicine 385(12):1078– 1090. https://doi.org/10.1056/NEJMoa2110475. Bonaventura, A., A. Vecchié, L. Dagna, K. Martinod, D. L. Dixon, B. W. Van Tassell, F. Dentali, F. Montecucco, S. Massberg, M. Levi, and A. Abbate. 2021. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nature Reviews: Immunology 21(5):319–329. https://doi.org/10.1038/s41577-021-00536-9. Botton, J., M. J. Jabagi, M. Bertrand, B. Baricault, J. Drouin, S. Le Vu, A. Weill, P. Farrington, M. Zureik, and R. Dray-Spira. 2022. Risk for myocardial infarction, stroke, and pulmonary embolism following COVID-19 vaccines in adults younger than 75 years in France. Annals of Internal Medicine 175(9):1250–1257. https://doi.org/10.7326/m22-0988. Burn, E., X. Li, A. Delmestri, N. Jones, T. Duarte-Salles, C. Reyes, E. Martinez-Hernandez, E. Marti, K. M. C. Verhamme, P. R. Rijnbeek, V. Y. Strauss, and D. Prieto-Alhambra. 2022a. Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom. Nature Communications 13(1):7167. https://doi.org/10.1038/s41467-022-34668-w. Burn, E., E. Roel, A. Pistillo, S. Fernández-Bertolín, M. Aragón, B. Raventós, C. Reyes, K. Verhamme, P. Rijnbeek, X. Li, V. Y. Strauss, D. Prieto-Alhambra, and T. Duarte-Salles. 2022b. Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in Catalonia, Spain. Nature Communications 13(1):7169. https://doi.org/10.1038/s41467-022-34669-9. Caplan, L. R. 2023. Patient education: Hemorrhagic stroke treatment (beyond the basics). https://www.uptodate.com/contents/hemorrhagic-stroke-treatment-beyond-the-basics (accessed November 6, 2023). Chamorro, A., A. Meisel, A. M. Planas, X. Urra, D. van de Beek, and R. Veltkamp. 2012. The immunology of acute stroke. Nature Reviews: Neurology 8(7):401–410. https://doi.org/10.1038/nrneurol.2012.98. Chui, C. S. L., M. Fan, E. Y. F. Wan, M. T. Y. Leung, E. Cheung, V. K. C. Yan, L. Gao, Y. Ghebremichael-Weldeselassie, K. K. C. Man, K. K. Lau, I. C. H. Lam, F. T. T. Lai, X. Li, C. K. H. Wong, E. W. Chan, C. L. Cheung, C. W. Sing, C. K. Lee, I. F. N. Hung, C. S. Lau, J. Y. S. Chan, M. K. Lee, V. C. T. Mok, C. W. Siu, L. S. T. Chan, T. Cheung, F. L. F. Chan, A. Y. Leung, B. J. Cowling, G. M. Leung, and I. C. K. Wong. 2022. Thromboembolic events and hemorrhagic stroke after mRNA (BNT162b2) and inactivated (CoronaVac) COVID-19 vaccination: A self- PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 191 controlled case series study. EClinicalMedicine 50:101504. https://doi.org/10.1016/j.eclinm.2022.101504. Davidson, S. M., A. Adameova, L. Barile, H. A. Cabrera-Fuentes, A. Lazou, P. Pagliaro, K. O. Stenslokken, D. Garcia-Dorado, and E.-C. C. Action. 2020. Mitochondrial and mitochondrial- independent pathways of myocardial cell death during ischaemia and reperfusion injury. Journal of Cellular and Molecular Medicine 24(7):3795–3806. https://doi.org/10.1111/jcmm.15127. de Mélo Silva, M. L., Jr., and D. P. Lopes. 2021. Large hemorrhagic stroke after ChAdOx1 NCOV-19 vaccination: A case report. Acta Neurologica Scandinavica 144(6):717–718. https://doi.org/10.1111/ane.13505. Famularo, G. 2022. Stroke after COVID-19 vaccination. Acta Neurologica Scandinavica 145(6):787–788. https://doi.org/10.1111/ane.13608. Fang, M. C., D. Fan, S. H. Sung, D. M. Witt, J. R. Schmelzer, S. R. Steinhubl, S. H. Yale, and A. S. Go. 2017. Validity of using inpatient and outpatient administrative codes to identify acute venous thromboembolism: The CVRN VTE study. Medical Care 55(12):e137–e143. https://doi.org/10.1097/MLR.0000000000000524. Faura, J., A. Bustamante, F. Miro-Mur, and J. Montaner. 2021. Stroke-induced immunosuppression: Implications for the prevention and prediction of post-stroke infections. Journal of Neuroinflammation 18(1):127. https://doi.org/10.1186/s12974-021-02177-0. 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). Fischbein, N. J., and C. A. Wijman. 2010. Nontraumatic intracranial hemorrhage. Neuroimaging Clinics of North America 20(4):469–492. https://doi.org/10.1016/j.nic.2010.07.003. Giorgio, K., R. F. Walker, R. F. MacLehose, D. Adrianzen-Herrera, W. Wang, A. Alonso, N. A. Zakai, and P. L. Lutsey. 2023. Venous thromboembolism mortality and trends in older U.S. adults, 2011–2019. American Journal of Hematology 98(9):1364–1373. https://doi.org/10.1002/ajh.26996. Gonçalves de Andrade, E., E. Šimončičová, M. Carrier, H. A. Vecchiarelli, M. Robert, and M. Tremblay. 2021. Microglia fighting for neurological and mental health: On the central nervous system frontline of COVID-19 pandemic. Frontiers in Cellular Neuroscience 15:647378. https://doi.org/10.3389/fncel.2021.647378. Gross, B. A., B. T. Jankowitz, and R. M. Friedlander. 2019. Cerebral intraparenchymal hemorrhage: A review. JAMA 321(13):1295–1303. https://doi.org/10.1001/jama.2019.2413. Grosso, A., I. Douglas, R. MacAllister, I. Petersen, L. Smeeth, and A. D. Hingorani. 2011. Use of the self-controlled case series method in drug safety assessment. Expert Opinion on Drug Safety 10(3):337–340. https://doi.org/10.1517/14740338.2011.562187. Hana, D., K. Patel, S. Roman, B. Gattas, and S. Sofka. 2022. Clinical cardiovascular adverse events reported post-COVID-19 vaccination: Are they a real risk? Current Problems in Cardiology 47(3):101077. https://doi.org/10.1016/j.cpcardiol.2021.101077. Hervé, C., B. Laupèze, G. Del Giudice, A. M. Didierlaurent, and F. Tavares Da Silva. 2019. The how’s and what’s of vaccine reactogenicity. NPJ Vaccines 4:39. https://doi.org/10.1038/s41541-019- 0132-6. Hippisley-Cox, J., M. Patone, X. W. Mei, D. Saatci, S. Dixon, K. Khunti, F. Zaccardi, P. Watkinson, M. Shankar-Hari, J. Doidge, D. A. Harrison, S. J. Griffin, A. Sheikh, and C. A. C. Coupland. 2021. PREPUBLICATION COPY—Uncorrected Proofs

192 VACCINE EVIDENCE REVIEW Risk of thrombocytopenia and thromboembolism after COVID-19 vaccination and SARS-CoV-2 positive testing: Self-controlled case series study. British Journal of Medicine 374:n1931. https://doi.org/10.1136/bmj.n1931. Hviid, A., J. V. Hansen, E. M. Thiesson, and J. Wohlfahrt. 2022. Association of AZD1222 and BNT162b2 COVID-19 vaccination with thromboembolic and thrombocytopenic events in frontline personnel: A retrospective cohort study. Annals of Internal Medicine 175(4):541–546. https://doi.org/10.7326/m21-2452. Jabagi, M. J., J. Botton, M. Bertrand, A. Weill, P. Farrington, M. Zureik, and R. Dray-Spira. 2022. Myocardial infarction, stroke, and pulmonary embolism after BNT162b2 mRNA COVID-19 vaccine in people aged 75 years or older. JAMA 327(1):80–82. https://doi.org/10.1001/jama.2021.21699. Kirkman, M. A., W. Mahattanakul, B. A. Gregson, and A. D. Mendelow. 2009. The accuracy of hospital discharge coding for hemorrhagic stroke. Acta Neurologica Belgica 109(2):114–119. Langgartner, D., R. Winkler, J. Brunner-Weisser, N. Rohleder, M. N. Jarczok, H. Gündel, K. Weimer, and S. O. Reber. 2023. COVID-19 vaccination exacerbates ex vivo IL-6 release from isolated PBMCS. Scientific Reports 13(1):9496. https://doi.org/10.1038/s41598-023-35731-2. Li, X., and G. Chen. 2023. CNS-peripheral immune interactions in hemorrhagic stroke. Journal of Cerebral Blood Flow and Metabolism 43(2):185–197. https://doi.org/10.1177/0271678x221145089. McCormick, N., V. Bhole, D. Lacaille, and J. A. Avina-Zubieta. 2015. Validity of diagnostic codes for acute stroke in administrative databases: A systematic review. PLoS One 10(8):e0135834. https://doi.org/10.1371/journal.pone.0135834. Mithoowani, S. 2022. Deep vein thrombosis (DVT) (beyond the basics). www.uptodate.com/contents/deep-vein-thrombosis-dvt-beyond-the-basics (accessed November 16, 2023). Montano, A., D. F. Hanley, and J. C. Hemphill, III. 2021. Hemorrhagic stroke. Handbook of Clinical Neurology 176:229–248. https://doi.org/10.1016/B978-0-444-64034-5.00019-5. Nakamura, K., and T. Shichita. 2019. Cellular and molecular mechanisms of sterile inflammation in ischaemic stroke. Journal of Biochemistry 165(6):459–464. https://doi.org/10.1093/jb/mvz017. Neves, G., P. I. Warman, A. Warman, R. Warman, T. Bueso, J. D. Vadhan, and T. Windisch. 2023. External validation of an artificial intelligence device for intracranial hemorrhage detection. World Neurosurgery 173:e800–e807. https://doi.org/10.1016/j.wneu.2023.03.019. NHLBI (National Heart, Lung, and Blood Institute). 2023. What is a stroke? https://www.nhlbi.nih.gov/health/stroke (accessed November 16, 2023). 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. Prabhu, S. D., and N. G. Frangogiannis. 2016. The biological basis for cardiac repair after myocardial infarction: From inflammation to fibrosis. Circulation Research 119(1):91–112. https://doi.org/10.1161/CIRCRESAHA.116.303577. Robinson, K., J. M. Katzenellenbogen, T. J. Kleinig, J. Kim, C. A. Budgeon, A. G. Thrift, and L. Nedkoff. 2023. Large burden of stroke incidence in people with cardiac disease: A linked data cohort study. Clinical Epidemiology 15:203–211. https://doi.org/10.2147/CLEP.S390146. Salari, N., F. Morddarvanjoghi, A. Abdolmaleki, S. Rasoulpoor, A. A. Khaleghi, L. A. Hezarkhani, S. Shohaimi, and M. Mohammadi. 2023. The global prevalence of myocardial infarction: A systematic review and meta-analysis. BMC Cardiovascular Disorders 23(1):206. https://doi.org/10.1186/s12872-023-03231-w. PREPUBLICATION COPY—Uncorrected Proofs

VASCULAR CONDITIONS 193 Serrone, J. C., H. Maekawa, M. Tjahjadi, and J. Hernesniemi. 2015. Aneurysmal subarachnoid hemorrhage: Pathobiology, current treatment and future directions. Expert Review of Neurotherapeutics 15(4):367–380. https://doi.org/10.1586/14737175.2015.1018892. 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- controlled studies in the U.S. Vaccine 41(32):4666–4678. https://doi.org/10.1016/j.vaccine.2023.06.014. Siddiqi, H. K., P. Libby, and P. M. Ridker. 2021. COVID-19 - a vascular disease. Trends in Cardiovascular Medicine 31(1):1–5. https://doi.org/10.1016/j.tcm.2020.10.005. Smith, S. D., and C. J. Eskey. 2011. Hemorrhagic stroke. Radiologic Clinics of North America 49(1):27– 45. https://doi.org/10.1016/j.rcl.2010.07.011. Tamariz, L., T. Harkins, and V. Nair. 2012. A systematic review of validated methods for identifying venous thromboembolism using administrative and claims data. Pharmacoepidemiology and Drug Safety 21(Suppl 1):154–162. https://doi.org/10.1002/pds.2341. Tang, Y. H., S. Vital, J. Russell, H. Seifert, and D. N. Granger. 2015. Interleukin-6 mediates enhanced thrombus development in cerebral arterioles following a brief period of focal brain ischemia. Experimental Neurology 271:351–357. https://doi.org/10.1016/j.expneurol.2015.06.004. Thygesen, K., J. S. Alpert, A. S. Jaffe, B. R. Chaitman, J. J. Bax, D. A. Morrow, and H. D. White. 2018. Fourth universal definition of myocardial infarction (2018). Journal of the American College of Cardiology 72(18):2231–2264. https://doi.org/doi:10.1016/j.jacc.2018.08.1038. Vymazal, J., A. M. Rulseh, J. Keller, and L. Janouskova. 2012. Comparison of CT and MR imaging in ischemic stroke. Insights Imaging 3(6):619–627. https://doi.org/10.1007/s13244-012-0185-9. Wang, H., X. Tang, H. Fan, Y. Luo, Y. Song, Y. Xu, and Y. Chen. 2020. Potential mechanisms of hemorrhagic stroke in elderly COVID-19 patients. Aging 12(11):10022–10034. https://doi.org/10.18632/aging.103335. Whiteley, W. N., S. Ip, J. A. Cooper, T. Bolton, S. Keene, V. Walker, R. Denholm, A. Akbari, E. Omigie, S. Hollings, E. Di Angelantonio, S. Denaxas, A. Wood, J. A. C. Sterne, and C. Sudlow. 2022. Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England. PLoS Medicine 19(2):e1003926. https://doi.org/10.1371/journal.pmed.1003926. Zafar, U., H. Zafar, M. S. Ahmed, and M. Khattak. 2022. Link between COVID-19 vaccines and myocardial infarction. World Journal of Clinical Cases 10(28):10109–10119. https://doi.org/10.12998/wjcc.v10.i28.10109. Zhu, X., K. A. Gebo, A. G. Abraham, F. Habtehyimer, E. U. Patel, O. Laeyendecker, T. J. Gniadek, R. E. Fernandez, O. R. Baker, M. Ram, E. R. Cachay, J. S. Currier, Y. Fukuta, J. M. Gerber, S. L. Heath, B. Meisenberg, M. A. Huaman, A. C. Levine, A. Shenoy, S. Anjan, J. E. Blair, D. Cruser, D. N. Forthal, L. L. Hammitt, S. Kassaye, G. S. Mosnaim, B. Patel, J. H. Paxton, J. S. Raval, C. G. Sutcliffe, M. Abinante, P. Broderick, V. Cluzet, M. E. Cordisco, B. Greenblatt, J. Petrini, W. Rausch, D. Shade, K. Lane, A. L. Gawad, S. L. Klein, A. Pekosz, S. Shoham, A. Casadevall, E. M. Bloch, D. Hanley, D. J. Sullivan, and A. A. R. Tobian. 2023. Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: A prospective cohort study. The Lancet Microbe 4(9):e692–e703. https://doi.org/https://doi.org/10.1016/S2666- 5247(23)00171-4. PREPUBLICATION COPY—Uncorrected Proofs

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