Association between COVID-19 vaccination and sudden death in apparently healthy younger individuals: a population-based case-control study

Background — COVID-19 vaccines can cause rare but serious adverse events such as myocarditis and immune thrombotic thrombocytopenia. Despite a lack of strong evidence, concerns have been expressed that COVID-19 vaccination might lead to sudden death in younger healthy adults. We studied the association between COVID-19 vaccination and sudden death in apparently healthy people aged 12–50 years.

Methods and findings — We conducted a population-based case-control study using linked administrative datasets of residents of Ontario, Canada who were alive as of April 1, 2021. We excluded individuals aged >50 years and those with documented cardiovascular disease, mental illness, or diseases that predispose to adverse outcomes from COVID-19. We defined cases as those with out-of-hospital death, or death within 24 hours of presentation to hospital with a final diagnosis of cardiac arrest between April 1, 2021 and June 30, 2023. We matched each case with five controls on age, sex, region of residence, and neighborhood income quintile. We used conditional logistic regression to assess the association between sudden death and previous COVID-19 vaccination after adjusting for multiple potential confounders (positive severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] tests, number of SARS-CoV-2 polymerase chain reaction (PCR) tests, influenza vaccination, common comorbidities). Sensitivity analyses were conducted with different definitions of the exposure and subsets of cases (with their matched controls). Another sensitivity analysis utilized a modified self-controlled case series (SCCS) of vaccinated individuals meeting the case definition during the study period with up to three doses of any COVID-19 vaccine.

Of 6,365,451 eligible individuals, we identified 4,963 (0.08%) cases meeting our definition of sudden death (median age 36 years, 74.4% male). In the primary analysis, COVID-19 vaccination was associated with a lower risk of sudden death (adjusted odds ratio [aOR] = 0.57; 95% confidence interval (CI) [0.53,0.61]; p < 0.001). The findings were consistent for COVID-19 vaccination within six weeks before death (aOR = 0.63; 95%CI [0.55,0.72]; p < 0.001) and in sensitivity analyses limited to people aged <40 years (aOR = 0.53; 95%CI [0.48,0.58]; p < 0.001), those who died in hospital or in the emergency department (aOR = 0.71; 95%CI [0.55,0.91]; p = 0.006), and after exclusion of opioid-related deaths (aOR = 0.57; 95%CI [0.51,0.64]; p < 0.001). The SCCS sensitivity analysis showed no significant difference in the rate of sudden death in the 6 weeks following first (relative incidence (RI) 0.87; 95%CI [0.54,1.40]; p = 0.57), second (RI 0.94; 95%CI [0.57,1.57]; p = 0.82), or third (RI 0.87; 95%CI [0.37,2.05]; p = 0.10) dose of the COVID-19 vaccine. Study limitations include the inability to confirm the cause of out-of-hospital deaths and residual confounding due to differences in health-seeking behaviors for the case-control analysis.

Conclusions — These findings do not support the hypothesis that COVID-19 vaccines increase the risk of sudden cardiac death in young healthy adults.