# 63a14eb7-ec4a-4590-924b-fc604845aec8.pdf ## Metadata - PDFFormatVersion=1.4 - Language=en-US - IsLinearized=false - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Author=Husam Abdel-Qadir - CreationDate=D:20260316145850+05'30' - Creator=Adobe InDesign 15.1 (Windows) - Custom=[object Object] - ModDate=D:20260316145852+05'30' - Producer=Adobe PDF Library 15.0 - Title=Association between COVID-19 vaccination and sudden death in apparently healthy younger individuals: A population-based case-control study - Trapped=[object Object] - dc:identifier=10.1371/journal.pmed.1004924 - dc:format=application/pdf - dc:title=Association between COVID-19 vaccination and sudden death in apparently healthy younger individuals: A population-based case-control study - dc:creator=Husam Abdel-Qadir,Hardil Anup Bhatt,Sarah Swayze,Michael Paterson,Dennis T. Ko,David N. Juurlink,Jeffrey C. Kwong - xmp:createdate=2026-03-16T14:58:50+05:30 - xmp:metadatadate=2026-03-16T14:58:52+05:30 - xmp:modifydate=2026-03-16T14:58:52+05:30 - xmp:creatortool=Adobe InDesign 15.1 (Windows) - xmpmm:instanceid=uuid:8c91487f-73e1-4831-902d-d6316d571efe - xmpmm:originaldocumentid=xmp.did:253a3229-8a74-6d4f-a0a5-4027e6d46946 - xmpmm:documentid=xmp.id:d197abf4-d51a-c446-8039-d1c23c409017 - xmpmm:renditionclass=proof:pdf - xmpmm:history=convertedfrom application/x-indesign to application/pdfAdobe InDesign 15.1 (Windows)/2026-03-16T14:58:50+05:30 - xmpmm:derivedfrom=xmp.iid:3cf02683-bcd5-4447-9516-34e3d538a4d2xmp.did:0e95fe99-71cb-9748-9879-a58c763b771bxmp.did:253a3229-8a74-6d4f-a0a5-4027e6d46946default - crossmark:majorversiondate=2026-03-19 - crossmark:crossmarkdomainexclusive=false - crossmark:doi=10.1371/journal.pmed.1004924 - crossmark:crossmarkdomains=www.plosmedicine.org - pdfx:doi=10.1371/journal.pmed.1004924 - pdfx:crossmarkmajorversiondate=2026-03-19 - pdfx:crossmarkdomainexclusive=false - pdfx:epsprocessor=PStill version 1.84.42 - pdfx:crossmarkdomains=www.plosmedicine.org - prism:doi=10.1371/journal.pmed.1004924 - prism:url=https://doi.org/10.1371/journal.pmed.1004924 - pdf:producer=Adobe PDF Library 15.0 - pdf:trapped=False ## Contents ### Page 1 RESEARCH ARTICLE Association between COVID-19 vaccination andsudden death in apparently healthy youngerindividuals: A population-based case-controlstudy Husam Abdel-Qadir[](https://orcid.org/0000-0002-7105-7931)1,2,3☯4[](https://orcid.org/0000-0001-9798-914X),5☯3[](https://orcid.org/0009-0001-1284-9162),Michael Paterson[](https://orcid.org/0000-0001-5995-1714)3,6,7, Dennis T. Ko3,7,8,9, David N. Juurlink3,10, Jeffrey C. Kwong[](https://orcid.org/0000-0002-7820-2046)3,11,12,13,14,15 1 Women’s College Hospital, Toronto, Ontario, Canada, 2 Peter Munk Cardiac Centre, UniversityHealth Network, Toronto, Ontario, Canada, 3 ICES, Toronto, Ontario, Canada, 4 Temerty Faculty ofMedicine, University of Toronto, Toronto, Ontario, Canada, 5 Department of Medicine, University ofBritish Columbia, Vancouver, British Columbia, Canada, 6 Department of Family Medicine, McMasterUniversity, Hamilton, Ontario, Canada, 7 Institute of Health Policy, Management and Evaluation,University of Toronto, Toronto, Ontario, Canada, 8 Department of Medicine, University of Toronto,Toronto, Ontario, Canada, 9 Schulich Heart Centre, Sunnybrook Research Institute, SunnybrookHealth Sciences Centre, Toronto, Ontario, Canada, 10 Department of Medicine, Sunnybrook HealthSciences Centre, University of Toronto, Toronto, Ontario, Canada, 11 Dalla Lana School of PublicHealth, University of Toronto, Toronto, Ontario, Canada, 12 Public Health Ontario, Toronto, Ontario,Canada, 13 University Health Network, Toronto, Ontario, Canada, 14 Department of Family andCommunity Medicine, University of Toronto, Toronto, Ontario, Canada, 15 Centre for VaccinePreventable Diseases, University of Toronto, Toronto, Ontario, Canada ☯ These authors contributed equally to this work. *h.abdel.qadir@utoronto.ca Abstract Background COVID-19 vaccines can cause rare but serious adverse events such as myo-carditis and immune thrombotic thrombocytopenia. Despite a lack of strongevidence, concerns have been expressed that COVID-19 vaccination might leadto sudden death in younger healthy adults. We studied the association betweenCOVID-19 vaccination and sudden death in apparently healthy people aged12–50 years. Methods and findings We conducted a population-based case-control study using linked administrativedatasets of residents of Ontario, Canada who were alive as of April 1, 2021. Weexcluded individuals aged >50 years and those with documented cardiovascu-lar disease, mental illness, or diseases that predispose to adverse outcomesfrom COVID-19. We defined cases as those with out-of-hospital death, or deathwithin 24 hours of presentation to hospital with a final diagnosis of cardiac arrestbetween April 1, 2021 and June 30, 2023. We matched each case with five [](http://crossmark.crossref.org/dialog/?doi=10.1371/journal.pmed.1004924&domain=pdf&date_stamp=2026-03-19) OPEN ACCESS Citation: Abdel-Qadir H, Bhatt HA, Swayze S,Paterson M, Ko DT, Juurlink DN, et al. (2026)Association between COVID-19 vaccination andsudden death in apparently healthy youngerindividuals: A population-based case-controlstudy. PLoS Med 23(3): e1004924.[https://doi.org/10.1371/journal.pmed.1004924](https://doi.org/10.1371/journal.pmed.1004924) Academic Editor: Rebecca F. Grais, PasteurNetwork, FRANCE Received: March 17, 2025 Accepted: January 22, 2026 - Published: March 19, 2026 Peer Review History: PLOS recognizes thebenefits of transparency in the peer reviewprocess; therefore, we enable the publicationof all of the content of peer review andauthor responses alongside final, publishedarticles. The editorial history of this article isavailable here:[https://doi.org/10.1371/journal.pmed.1004924](https://doi.org/10.1371/journal.pmed.1004924) Copyright: © 2026 Abdel-Qadir et al. This is anopen access article distributed under the termsof the[Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/),which permits unrestricted use, distribution, ### Page 2 controls on age, sex, region of residence, and neighborhood income quintile. Weused conditional logistic regression to assess the association between suddendeath and previous COVID-19 vaccination after adjusting for multiple potentialconfounders (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 con-ducted with different definitions of the exposure and subsets of cases (with theirmatched controls). Another sensitivity analysis utilized a modified self-controlledcase series (SCCS) of vaccinated individuals meeting the case definition duringthe 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 ourdefinition of sudden death (median age 36 years, 74.4% male). In the primaryanalysis, COVID-19 vaccination was associated with a lower risk of suddendeath (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 weeksbefore death (aOR = 0.63; 95%CI [0.55,0.72]; p < 0.001) and in sensitivity analy-ses 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 significantdifference in the rate of sudden death in the 6 weeks following first (relative inci-dence (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 vac-cine. Study limitations include the inability to confirm the cause of out-of-hospitaldeaths and residual confounding due to differences in health-seeking behaviors forthe case-control analysis. Conclusions These findings do not support the hypothesis that COVID-19 vaccines increase therisk of sudden cardiac death in young healthy adults. Author summary Why was this study done? • COVID-19 vaccines were received by a large segment of the population as partof the public health response to the pandemic • There are emerging concerns that COVID-19 vaccines are responsible for sud-den death in younger healthy individuals despite a lack of evidence to supportthis claim and reproduction in any medium, provided theoriginal author and source are credited. Data availability statement: The dataset fromthis study is held securely in coded form atICES. While legal data sharing agreementsbetween ICES and data providers (e.g., health-care organizations and government) prohibitICES from making the dataset publicly available,access may be granted to those who meetpre-specified criteria for confidential access,available athttp://www.ices.on.ca/DAS (email:[das@ices.on.ca](http://www.ices.on.ca/DAS)). The full dataset creation planand underlying analytic code are availablefrom ICES upon request, understanding thatthe computer programs may rely upon codingtemplates or macros that are unique to ICESand are therefore either inaccessible or mayrequire modification. To view details on thetypes of data and datasets available, please visitthe ICES Data Dictionary (at[https://datadictio-nary.ices.on.ca/Applications/DataDictionary/Default.aspx](https://datadictionary.ices.on.ca/Applications/DataDictionary/Default.aspx)). Funding: This work was supported by fundingfrom the Canadian Immunization ResearchNetwork (CIRN, [[https://landing.cirnetwork.ca](https://datadictionary.ices.on.ca/Applications/DataDictionary/Default.aspx)])through a grant from the Public Health Agencyof Canada and the Canadian Institutes of HealthResearch (CNF 151944), and funding from thePublic Health Agency of Canada, through theVaccine Surveillance Working Party and theCOVID-19 Immunity Task Force (both grantsto JCK). This study was supported by PublicHealth Ontario and by ICES, which is fundedby an annual grant from the Ontario Ministryof Health (MOH) and Ministry of Long-TermCare (MLTC). This work was also supportedby the Ontario Health Data Platform (OHDP),a Province of Ontario initiative to supportOntario’s ongoing response to COVID-19 andits related impacts. HA-Q is supported by a Tier2 Canada Research Chair in CardiovascularDisease Epidemiology and Outcomes (fromthe Government of Canada), a Hold’em forLife Professorship in Cancer Research (fromthe University of Toronto) and was previous-ly supported by a Chair in Women’s Heartand Brain Health (from the Heart and StrokeFoundation of Canada). JCK is supported by aClinician-Scientist Award from the University ofToronto Department of Family and CommunityMedicine. The funders had no role in studydesign, data collection and analysis, decision topublish, or preparation of the manuscript. ### Page 3 What did the researchers do and find? • A case-control study was conducted involving Ontario residents aged 12–50years without documented comorbidities predisposing to premature deathbetween April 1, 2021 and June 30, 2023 to examine the association betweenCOVID-19 vaccination and sudden death • The primary outcome was sudden death; the exposure of interest was anyCOVID-19 vaccination • Among 6,365,451 eligible individuals, 4,806 cases who experienced suddendeath were matched to 24,030 controls who were alive on the date of suddendeath for each corresponding case • Receipt of COVID-19 vaccination was not associated with increased odds ofsudden death What do these findings mean? • These findings do not support the hypothesis that COVID-19 vaccines increasethe risk of sudden cardiac death in younger healthy adults • A limitation of this study was the inability to confirm the cause of out-of-hospitaldeaths Introduction Messenger ribonucleic acid (mRNA) vaccines were an essential element of the strat-egy for curtailing the COVID-19 pandemic [1,2]. Emergency approval of the vaccineswas provided in an accelerated timeframe after large-scale clinical trials demon-strated robust efficacy and relatively benign adverse event profiles. With widespreaduse, however, it became clear that mRNA vaccines were associated with cases ofmyocarditis, most prominently in males aged <40 years [3]. The non-replicating viralvector vaccines were associated with vaccine-induced immune thrombotic thrombo-cytopenia (VITT), which led to rare cases of fatal thromboembolism [4]. Despite theseconcerns, the anticipated benefits of these vaccines were deemed to outweigh theirrisks at the time, and more than 75% of the adult population in high-income countrieshave been vaccinated [5]. Recently, concerns have been raised that healthy younger people were dying sud-denly because of COVID-19 vaccination, however, this notion is not supported by anyreliable scientific evidence [6–9]. Because most people living in the Western hemi-sphere have been vaccinated, most sudden deaths are expected to occur in previouslyvaccinated people. It is plausible that subclinical myocarditis after vaccination couldpredispose to arrhythmias if residual scar tissue served as an arrhythmogenic focus.In a prospective evaluation of 54 participants, we previously demonstrated that 1 in 8 Competing interests: The authors havedeclared that no competing interests exist. Abbreviations: aOR, adjusted odds ratio; CI,confidence interval; CIHI, Canadian Institute forHealth Information; COPD, chronic obstruc-tive pulmonary disease; CVD, cardiovasculardisease; DAD, Discharge Abstract Database;ED, emergency department; HIV, humanimmunodeficiency virus; mRNA, messengerribonucleic acid; NACRS, National AmbulatoryCare Reporting System; OHIP, Ontario HealthInsurance Plan; PCR, polymerase chainreaction; PHIPA, Personal Health InformationProtection Act; RECORD, Reporting of StudiesConducted using Observational Routinely-Collected Data; RI, relative incidence; SARS-CoV-2, severe acute respiratory syndromecoronavirus 2; SCCS, self-controlled caseseries; VITT, vaccine-induced immune throm-botic thrombocytopenia. ### Page 4 people with confirmed acute symptomatic myocarditis had evidence of focal myocardial inflammation by fluorodeoxyglucosepositron emission tomography/magnetic resonance imaging at two months follow-up [10]. A longer-term follow-up study in13 patients with symptomatic myocarditis using cardiac MRI demonstrated that myocardial edema had resolved in all partici-pants, although small areas of myocardial scar persisted in 2 (13%) patients [11]. There are limited data on the potential association of COVID-19 vaccination with sudden death in healthy people. Con-cerns about sudden death due to COVID-19 vaccination can deter future vaccination [12]. Accordingly, we conducted apopulation-based case-control study to explore the hypothesis that COVID-19 vaccination increases risk of sudden deathin apparently healthy people aged 12–50 years. Methods Study design, setting, and population We used a case-control design and linked databases in the Canadian province of Ontario, which provides universal healthcoverage to all residents through the Ontario Health Insurance Plan (OHIP). The datasets were linked using unique encodedidentifiers and analyzed at ICES (previously known as the Institute for Clinical Evaluative Sciences [www.ices.on.ca]) [[13](http://www.ices.on.ca/),14].ICES is an independent, non-profit research institute whose legal status under Ontario’s health information privacy law allows itto collect and analyze healthcare and demographic data, without consent, for health system evaluation and improvement. We used Ontario’s Registered Persons Database to identify all residents who were alive on April 1, 2021. This date waschosen to allow for accrual during a period with fewer restrictions on vaccine access for healthier people. We excludedresidents without OHIP eligibility on April 1, 2021, those with no recorded contact with the healthcare system in the prior10 years (to decrease the potential for undocumented disease), those missing key data (date of birth, sex, postal code),and those younger than 12 years (given lower vaccine coverage and weaker vaccination mandates). We then applied exclusion criteria to limit the study population to people who did not have diseases that would predis-pose them to sudden cardiovascular death or adverse outcomes from COVID-19, and those with documented mental illness(excluding mood/anxiety disorders) [15,16]. Exclusions included age 50 years or older, long-term care residence, schizo-phrenia [17], healthcare encounters for alcohol or illicit drug use in the 5 years preceding April 1, 2021 [18], cardiovasculardisease (CVD; including coronary artery disease, heart failure, and atrial fibrillation) [19], diabetes [20], cancer [21], dementia[22], chronic obstructive pulmonary disease (COPD) [23], chronic liver or kidney disease [24,25], inflammatory bowel disease[26], autoimmune rheumatologic disease [27,28], human immunodeficiency virus (HIV) infection [29], frailty (as per the JohnsHopkins ACG System Version 10 frailty indicator) [30], other forms of immunocompromised status/autoimmune diseases [31],or receipt of chronic home care in the 5 years before April 1, 2021. We did not exclude people with hypertension, asthma, ormood/anxiety disorders given the high prevalence of these diagnoses in otherwise healthy people. Application of these exclu-sions left us with a study population aged 12–50 years without documented illnesses that are expected to be strongly associ-ated with either the exposure (COVID-19 vaccination) or the outcome of interest (death). Definition of cases and controls Cases were required to fulfill one of three criteria between April 1, 2021 and June 30, 2023: 1. Death outside of hospital; OR 2. Death in an emergency department (ED), with a most responsible discharge diagnosis of cardiac arrest, sudden death,or significant ventricular arrhythmia, and where none of the other diagnostic codes indicated trauma, mental illness, orsubstance use (seeS1 Table); OR 3. In-hospital death within 24 hours of admission, with a most responsible discharge diagnosis of cardiac arrest, suddendeath, or ventricular arrhythmia, and where no other diagnostic code indicated trauma, mental illness, or substance use(seeS1 Table) ### Page 5 We ascertained hospitalization status and discharge diagnoses from the Canadian Institute for Health Information(CIHI) Discharge Abstract Database (DAD), and ED records from the CIHI National Ambulatory Care Reporting System(NACRS). We matched each case with up to 5 controls from the pool of eligible individuals who were alive on the index date,matching on age, sex, geographic area of residence (based upon the forward sortation area), and neighborhood incomequintile. The index date for controls was the date of death of their matched case. Definition of the exposure The exposure of interest was receipt of any COVID-19 vaccination, which was ascertained from the COVaxON database,a centralized registry that identifies all COVID-19 vaccination events in Ontario [32]. Statistical analysis The primary and secondary sensitivity case-control analyses were prospectively planned on January 5, 2023. The post-hoc analysis with modified self-controlled case series (SCCS) was performed after the peer-review process to addresspotential confounding associated with health-seeking behaviors of vaccine recipients. Baseline characteristics of case and controls were summarized using medians (with 25th–75th percentiles) for contin-uous variables and counts with percentages for categorical variables. Given the large sample size, we used standardizeddifferences rather than p-values to compare baseline differences between groups, with values greater than 0.1 indicatingmeaningful differences [33]. We used conditional logistic regression to determine the association between COVID-19 vaccination and the odds ofbeing a case or a control while accounting for the matched nature of the sample. The model included terms for a positiveSARS-CoV-2 test in the preceding 90 days (since SARS-CoV-2 infection can predispose to myocarditis [34]), a positiveSARS-CoV-2 test >90 days prior, influenza vaccination in the preceding 365 days, and the number of SARS-CoV-2 PCRtests in the preceding year (to adjust for health-seeking behaviors), as well as a history of asthma, hypertension, andmood or anxiety disorders. We conducted several sensitivity analyses to test the robustness of our conclusions. We first limited the exposureto mRNA vaccines, given their association with myocarditis, and then the AstraZeneca vaccine, given its associationwith thromboembolic events. We next examined COVID-19 vaccination in the six weeks preceding the index date(the period when myocarditis is most likely). We then limited cases to deaths in hospital or the ED where the causeof death was documented to be due to sudden cardiac death, with exclusion of diagnostic codes indicating trauma,mental illness, or substance use. Furthermore, we restricted the analysis to people aged 40 years or younger, a pop-ulation with a lower likelihood of undiagnosed cardiac disease and a higher risk of vaccine-associated myocarditis.In addition, we repeated the analysis with a secondary case definition that excluded opioid-related deaths using theDrug and Drug/Alcohol Related Death (DDARD) database. This analysis was limited to deaths before June 30, 2022due to data availability. In an additional post-hoc sensitivity analysis, we utilized a modified SCCS method [35,36]. This was restricted to vacci-nated residents meeting the case definition during the study period who had up to three doses of any COVID-19 vaccine.For this analysis, the observation period remained the same (April 1, 2021 to June 30, 2023). We used a 6-week riskinterval beginning on the vaccination date (day 0) for each dose received, with person-time for each interval included inthe model as an offset. The control period was the remainder of the observation period after exclusion of the 6-week riskintervals if applicable. Vaccine exposures were modeled as first dose, second dose, or third dose. Relative incidence (RI)was estimated using conditional Poisson regression with a pseudo-likelihood approach and sandwich variance estimatorsto calculate Wald confidence intervals. Models were adjusted for age as a time-varying covariate and for quarterly rate ofsudden death among unvaccinated individuals derived from our case-control analysis. ### Page 6 All analyses were conducted using SAS Version 9.4 (SAS Institute). Statistical significance for comparisons of out-comes was defined as a two-tailed p-value <0.05. This study is reported as per the Reporting of Studies Conducted usingObservational Routinely-Collected Data (RECORD) guideline (S1 Checklist). Ethics approval The use of most data in this project is authorized under section 45 of Ontario’s Personal Health Information ProtectionAct (PHIPA) and does not require review by a Research Ethics Board [37]. Ethics approval was required for the analysesexcluding opioid-related deaths, which was part of our secondary case definition; this was obtained from the Women’sCollege Hospital Research Ethics Board (REB # 2024-0002-E). Results We identified 14,664,193 Ontario residents who were alive as of April 1st, 2021. After applying exclusion criteria (Fig 1),we were left with 6,365,451 eligible individuals. During the accrual period, 4,963 (0.08%) individuals died and met criteriato be cases. Of these, 4,448 (89.6%) died in the prehospital setting and 515 (10.4%) died within 24 hours of presenting toa hospital or ED with a discharge diagnosis of cardiac arrest. From this pool of 4,963 cases, 4,806 (96.8%) were includedin the primary case-control analysis after each was matched to 5 controls (for a total of 24,030 controls). Prior to matching, cases were older and were more likely to be male compared to controls. They were also more likelyto reside in northern Ontario, and less likely to reside in Toronto or the neighboring regions of Peel and York (S2 Table).Cases were more likely to live in neighborhoods with lower income, fewer people per household, lower proportions of vis-ible minorities, and higher proportions of people employed in sales, trades, manufacturing, or agriculture (industries morelikely to stay open during pandemic-related lockdowns). There was a higher prevalence of hypertension and mood/anxietydisorders, but a lower prevalence of documented influenza vaccination among cases. There were no relevant differencesin the percentage receiving COVID-19 vaccination. A total of 4,806 cases were matched with 5 controls on age, sex, andforward sortation area (Table 1). Most differences between cases and controls were nullified after matching, but thereremained a higher prevalence of hypertension and mood/anxiety disorders and lower documented COVID-19 and influ-enza vaccinations among cases. A total of 3,237 (67.4%) of cases had prior COVID-19 vaccination, compared with 18,520 (77.1%) of controls. Two ormore COVID-19 vaccines had been received before the index date in 2,912 (60.6%) cases and 17,097 (71.1%) controls.When limiting the exposure to mRNA vaccines, at least one dose was documented in 3,212 (66.8%) cases compared to18,374 (76.5%) controls. These observations were mostly driven by the Pfizer/BioNTech Comirnaty vaccine, which wasreceived by 2,482 (51.6%) cases and 14,801 (61.6%) controls. The standardized differences for all these comparisonswere ≥0.1. For vaccines that were administered in lower numbers, such as Moderna’s Spikevax and AstraZeneca’s Vax-zevria vaccines, the prevalence of vaccination was low in both groups. There were fewer than 6 cases who died with priorexposure to Janssen’s Jcoyden vaccine and none with exposure to Novavax’s Nuvaxovid vaccine. When we specificallyfocused on COVID-19 vaccination in the preceding six weeks, vaccination was documented for 317 (6.6%) of cases com-pared with 2,246 (9.3%) of controls (standardized difference = 0.1). In the primary analysis, COVID-19 vaccination was associated with lower odds of sudden death (adjusted odds ratio[aOR] = 0.57; 95%CI [0.53,0.61]]; p < 0.001;Fig 2). Documented influenza vaccination was also associated with lowerodds of death (aOR = 0.72; 95%CI [0.66,0.80]; p < 0.001). A documented positive SARS-CoV-2 PCR test within 90 daysof the index date was associated with higher odds of death (aOR = 2.36; 95%CI [1.84,3.02]; p < 0.001), while a positiveSARS-CoV-2 PCR test greater than 90 days before the index date was associated with lower odds of death (aOR = 0.83;95%CI [0.72,0.95]; p = 0.006). The odds of death were also increased by the presence of asthma (aOR = 1.26; 95%CI[1.16,1.36]; p < 0.001), hypertension (aOR = 1.70; 95%CI [1.50,1.92]; p < 0.001), and a mood or anxiety disorder (aOR =3.46; 95%CI [2.94,4.07]; p < 0.001). ### Page 7 Fig 1. Selection criteria of the study cohort. CHF, Congestive Heart Failure; COPD, Chronic Obstructive Pulmonary Disease; CVD, cardiovasculardisease; Dementia, Ontario Dementia Database; HIV, Ontario HIV Database; IKN, ICES key number; LTC, long term care; OCCC, Ontario Crohn’s andColitis Cohort dataset; ODD, Ontario Diabetes Dataset; OHIP, Ontario Health Insurance Plan Claims Database; ORAD, Ontario Rheumatoid ArthritisDatabase; RPDB, Registered Persons Database. https://doi.org/10.1371/journal.pmed.1004924.g001 | | | - | ### Page 8 Table 1. Baseline characteristics of residents of Ontario, Canada who were included in the case-control analysis. | Variable | Cases | Controls | Std. Diff* | | - | - | - | - | | | (Continued) ### Page 9 | Variable | Cases | Controls | Std. Diff*https://doi.org/10.1371/journal.pmed.1004924.t001 | | - | - | - | - | Fig 2. The adjusted odds ratio (with 95% confidence interval) for death and COVID-19 vaccination among the matched cohort (n = 28,836)assessed using conditional logistic regression modeling. [https://doi.org/10.1371/journal.pmed.1004924.g002](https://doi.org/10.1371/journal.pmed.1004924.t001) Table 1. (Continued) ### Page 10 The inverse association of COVID-19 vaccination with death was consistent for most other definitions of vaccineexposure. Receipt of mRNA COVID-19 vaccination was associated with an aOR of 0.57 (95%CI [0.53,0.62]; p < 0.001)for death. Recent COVID-19 vaccination within six weeks prior to the index date was also associated with lower odds ofdeath (aOR = 0.63; 95%CI [0.55,0.72]; p < 0.001). Individuals who received two doses of COVID-19 vaccination displayeda stronger negative association with death (aOR = 0.53; 95%CI [0.49,0.57]; p < 0.001), while receipt of only one dose wasassociated with lower risk of death that did not reach statistical significance (aOR = 0.88; 95%CI [0.76,1.01]; p = 0.071). People aged <40 years The baseline characteristics of matched cases and controls in the subgroup aged <40 years are described inS3 Table.They demonstrated similar patterns to the overall cohort, wherein COVID-19 vaccination was less prevalent among cases(1,832 [64.3%]) compared to controls (10,778 [75.7%]). After adjusting for differences between cases and controls, therewas an inverse association between any COVID-19 vaccination and sudden death (aOR = 0.53; 95%CI [0.48,0.58];p < 0.001). The aORs for other definitions of COVID-19 vaccination are summarized inS1 Fig. Analyses excluding opioid-related deaths The baseline characteristics of matched cases that excluded opioid-related deaths, along with matched controls, aredescribed inS4 Table. Once again, COVID-19 vaccination was less prevalent among cases who died (1,232 [61.1%])compared to living controls (7,159 [71.0%]). This pattern was observed in other definitions of the vaccination exposure,with standardized differences for all the comparisons being ≥0.1. After adjustment, we continued to observe an inverseassociation between any COVID-19 vaccination and sudden death (aOR = 0.57; 95%CI [0.51,0.64]; p < 0.001). The aORsfor other definitions of COVID-19 vaccination are summarized inS2 Fig. Deaths in hospital or an emergency department S5 Table lists the baseline characteristics of people who died within 24 hours of presenting to hospital or ED witha discharge diagnosis indicating cardiac arrest, with comparison to their matched controls. We observed a lowerprevalence of COVID-19 vaccination among cases (365 [73.6%]) compared to controls (1,952 [78.7%]). Cases hadlower proportions of people vaccinated with mRNA vaccines than controls (73.2% versus 78.1%) and a lower propor-tion vaccinated within 6 weeks prior to the index date (8.3% versus 11.4%). The standardized differences for all thecomparisons described were ≥0.1. After adjustment, there continued to be an inverse association between COVID-19vaccination and sudden death (aOR = 0.71; 95%CI [0.55,0.91]; p = 0.006). The aORs for other definitions of COVID-19vaccination are summarized inS3 Fig. Modified SCCS analysis The SCCS sensitivity analysis demonstrated that there was no significant difference in the rate of sudden death in the 6weeks following first (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 later doses(RI 0.87; 95%CI [0.37, 2.05]; p = 0.10) of a COVID-19 vaccine (S6 Table). Discussion In this population-based study, vaccination against COVID-19 was not associated with an increased risk of sudden deathin people younger than 50 years who had no documented evidence of cardiovascular disease. This finding persistedthrough sensitivity analyses limited to people aged <40 years, those who died in-hospital with a diagnosis of suddencardiac arrest within 24 hours of presentation, after exclusion of admissions associated with trauma, mental illness, andsubstance use, after exclusion of opioid-related deaths, and another sensitivity analysis utilizing a modified SCCS. While ### Page 11 most Ontarians received the Pfizer/BioNTech mRNA vaccine, we did not observe a higher prevalence of exposure to anyHealth Canada-approved vaccine among people who died. Collectively, these observations refute the claim that COVID-19 vaccination increases the risk of sudden death. Our data align with recent publications which report that COVID-19 vaccination is not associated with higher risk ofsudden death. Previous studies from the United States and England utilized a modified SCCS design to demonstrate nosignificant increase in cardiac or all-cause mortality in the 4 weeks and 12 weeks after COVID-19 vaccination, respectively[38,39]. A case-control study from India suggested a decreased likelihood of sudden death in younger individuals whohad received 2 or more doses of COVID-19 vaccines (odds ratio 0.58; 95%CI [0.37, 0.92]) compared to those who hadreceived only 1 dose (odds ratio = 1.00; 95%CI [0.73,1.36]) [40]. Our primary case-control analyses similarly demonstrateda dose-dependent protective effect, while the SCCS sensitivity analysis showed no protective effect associated with anydose of COVID-19 vaccination. It is possible that the apparent protective effective of increasing doses of COVID-19 vac-cination in the case-control analyses may reflect confounding due to greater health-seeking behaviors among vaccinatedindividuals. While some studies have suggested dose-dependent safety concerns due to higher risks of myocarditis after the sec-ond dose [41,42], this does not align with our data and that from other large, epidemiologic analyses. Further supportingthe absence of an increased risk of sudden death following COVID-19 vaccines, an analysis of mortality records of resi-dents in Italy aged 1–40 years showed no increase in sudden cardiac death after the introduction of COVID-19 vaccines[43]. Indeed, rates of sudden death have decreased among athletes between the years 2002–2022, including the yearswhen COVID-19 vaccines were introduced [44]. Furthermore, a study examining death certificates of younger individualsbetween the years 2021–2022 found no evidence directly attributing COVID-19 vaccination to cardiac death [45]. WhilemRNA vaccines have demonstrated an increased risk of myocarditis in younger men, mortality rates following the devel-opment of postvaccine myocarditis are lower than mortality rates following COVID-19-related myocarditis or conventionalmyocarditis [46]. Postmortem histopathologic analyses have raised potential causal relations between unexpected deathand VITT following COVID-19 vaccination [47–49], but this may be less relevant for mRNA vaccines which comprise mostCOVID-19 vaccines in use today. The strengths of our study include its large, population-based cohort of residents covered by a universal single-payerhealthcare system. The combination of case-control and SCCS methods provides more confidence in our conclusions.A major limitation of this study is that we could not confirm the underlying cause of death out of hospital, so could notexclude deaths out of hospital that were due to motor vehicle collisions, violence, or suicides. However, we consistentlyfound that COVID-19 vaccination was not associated with increased odds of deaths due to cardiac arrest diagnosed inhospital or the ED within 24 hours of presentation after exclusion of alternative causes of death. We could only utilizeneighborhood-level data rather than individual data for income, proportion of visible minorities, and occupations. ForSARS-CoV-2 testing, we accounted for PCR tests but could not capture results of rapid antigen tests. Moreover, theregistries used to derive a cohort free of cardiac and other chronic diseases would not capture people with undiagnoseddiseases. Lastly, differences in healthcare seeking behaviors may have led to residual confounding; this is expected to beless applicable for the SCCS analysis. This population-based case-control study did not show a positive association between COVID-19 vaccination anddeath in apparently healthy individuals aged <50 years. We did not observe higher odds of death in people who receivedany of the Health Canada-approved COVID-19 vaccines. These data do not support the hypothesis that COVID-19 vac-cines increase the risk of sudden cardiac death. Supporting information Reporting of Studies Conducted using Observational Routinely-Collected Data (RECORD) checklist. (DOCX) ### Page 12 ICD-10 diagnostic codes used for defining a case. (DOCX) Baseline characteristics of the residents of Ontario, Canada who met criteria for inclusion in the study.The data are presented after dividing the cohort into two groups—people who met the definition for being a case, andthose who were eligible for being selected as controls. Please note that the cases are not matched to controls in this table. (DOCX) Baseline characteristics of matched cases and controls aged <40 years. (DOCX) Baseline characteristics of matched cases and controls excluding opioid-related deaths. (S4_Table.DOCX) Baseline characteristics of matched cases and controls only including deaths within 24-hours of pre-senting to the hospital. (DOCX) The relative incidence (with 95% confidence interval) of sudden death in vaccinated individualswithin the post COVID-19 vaccination risk period (6-weeks after the vaccination date for each dose received)compared to the control period. The analysis adjusted for age and quarterly rate of sudden death among unvacci-nated individuals. (DOCX) The adjusted odds ratio (with 95% confidence interval) for death and COVID-19 vaccination in individualsyounger than 40 years of age among the matched cohort (n = 17,094), assessed using conditional logistic regres-sion modeling. (TIFF) The adjusted odds ratio (with 95% confidence interval) for death and COVID-19 vaccination excludingopioid-related deaths among the matched cohort (n = 12,096), assessed using conditional logistic regressionmodeling. (TIFF) The adjusted odds ratio (with 95% confidence interval) for death and COVID-19 vaccination only involvingdeaths within 24-hours of arriving to the hospital among the matched cohort (n = 2,976), assessed using condi-tional logistic regression modeling. (TIFF) Acknowledgments We would like to acknowledge Public Health Ontario for access to vaccination data from COVaxON. This document useddata adapted from the Statistics Canada Postal Code Conversion File, which is based on data licensed from Canada PostCorporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains datacopied under license from Canada Post Corporation and Statistics Canada. Parts of this material are based on data and/or information compiled and provided by: the Ontario Ministry of Health, Ontario Health (OH), and CIHI. The analyses,conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of thefunding or data sources. We thank IQVIA Solutions Canada for use of their Drug Information File. Importantly, we thankthe Ontario residents, without whom this research would be impossible. ### Page 13 Author contributions Conceptualization: Husam Abdel-Qadir, Jeffrey C. Kwong. Data curation: Husam Abdel-Qadir, Sarah Swayze, Michael Paterson, Dennis T. Ko, David N. Juurlink, Jeffrey C. Kwong. Formal analysis: Husam Abdel-Qadir, Sarah Swayze, Michael Paterson, Dennis T. Ko, David N. Juurlink, Jeffrey C.Kwong. Funding acquisition: Husam Abdel-Qadir, Jeffrey C. Kwong. Investigation: Husam Abdel-Qadir, Hardil Anup Bhatt, Sarah Swayze, Michael Paterson, Dennis T. Ko, David N. Juurlink,Jeffrey C. Kwong. Methodology: Husam Abdel-Qadir, Sarah Swayze, Michael Paterson, Dennis T. Ko, David N. Juurlink, Jeffrey C. Kwong. Project administration: Husam Abdel-Qadir, Sarah Swayze, Michael Paterson, Dennis T. Ko, David N. Juurlink, JeffreyC. Kwong. Resources: Husam Abdel-Qadir, Sarah Swayze, Michael Paterson, Dennis T. Ko, David N. Juurlink, Jeffrey C. Kwong. Supervision: Husam Abdel-Qadir. Visualization: Husam Abdel-Qadir, Hardil Anup Bhatt. Writing – original draft: Husam Abdel-Qadir, Hardil Anup Bhatt. Writing – review & editing: Husam Abdel-Qadir, Hardil Anup Bhatt, Sarah Swayze, Michael Paterson, Dennis T. Ko,David N. Juurlink, Jeffrey C. Kwong. References Tuite AR, Ng V, Ximenes R, Diener A, Rafferty E, Ogden NH, et al. Quantifying the economic gains associated with COVID-19 vaccination in theCanadian population: a cost-benefit analysis. Can Commun Dis Rep. 2023;49(6):263–73.https://doi.org/10.14745/ccdr.v49i06a03 PMID:[38440772](https://doi.org/10.14745/ccdr.v49i06a03) Watson OJ, Barnsley G, Toor J, Hogan AB, Winskill P, Ghani AC. 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