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SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Is SARS-CoV-2 messenger RNA (mRNA) vaccination associated with risk of myocarditis?

Findings  In a cohort study of 23.1 million residents across 4 Nordic countries, risk of myocarditis after the first and second doses of SARS-CoV-2 mRNA vaccines was highest in young males aged 16 to 24 years after the second dose. For young males receiving 2 doses of the same vaccine, data were compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after second-dose BNT162b2, and between 9 and 28 per 100 000 vaccinees after second-dose mRNA-1273.

Meaning  The risk of myocarditis in this large cohort study was highest in young males after the second SARS-CoV-2 vaccine dose, and this risk should be balanced against the benefits of protecting against severe COVID-19 disease.

Abstract

Importance  Reports of myocarditis after SARS-CoV-2 messenger RNA (mRNA) vaccination have emerged.

Objective  To evaluate the risks of myocarditis and pericarditis following SARS-CoV-2 vaccination by vaccine product, vaccination dose number, sex, and age.

Design, Setting, and Participants  Four cohort studies were conducted according to a common protocol, and the results were combined using meta-analysis. Participants were 23 122 522 residents aged 12 years or older. They were followed up from December 27, 2020, until incident myocarditis or pericarditis, censoring, or study end (October 5, 2021). Data on SARS-CoV-2 vaccinations, hospital diagnoses of myocarditis or pericarditis, and covariates for the participants were obtained from linked nationwide health registers in Denmark, Finland, Norway, and Sweden.

Exposures  The 28-day risk periods after administration date of the first and second doses of a SARS-CoV-2 vaccine, including BNT162b2, mRNA-1273, and AZD1222 or combinations thereof. A homologous schedule was defined as receiving the same vaccine type for doses 1 and 2.

Main Outcomes and Measures  Incident outcome events were defined as the date of first inpatient hospital admission based on primary or secondary discharge diagnosis for myocarditis or pericarditis from December 27, 2020, onward. Secondary outcome was myocarditis or pericarditis combined from either inpatient or outpatient hospital care. Poisson regression yielded adjusted incidence rate ratios (IRRs) and excess rates with 95% CIs, comparing rates of myocarditis or pericarditis in the 28-day period following vaccination with rates among unvaccinated individuals.

Results  Among 23 122 522 Nordic residents (81% vaccinated by study end; 50.2% female), 1077 incident myocarditis events and 1149 incident pericarditis events were identified. Within the 28-day period, for males and females 12 years or older combined who received a homologous schedule, the second dose was associated with higher risk of myocarditis, with adjusted IRRs of 1.75 (95% CI, 1.43-2.14) for BNT162b2 and 6.57 (95% CI, 4.64-9.28) for mRNA-1273. Among males 16 to 24 years of age, adjusted IRRs were 5.31 (95% CI, 3.68-7.68) for a second dose of BNT162b2 and 13.83 (95% CI, 8.08-23.68) for a second dose of mRNA-1273, and numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100 000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100 000 vaccinees after the second dose of mRNA-1273. Estimates for pericarditis were similar.

Conclusions and Relevance  Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

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Article Information

Accepted for Publication: February 23, 2022.

Published Online: April 20, 2022. doi:10.1001/jamacardio.2022.0583

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Karlstad Ø et al. JAMA Cardiology.

Corresponding Author: Rickard Ljung, MD, PhD, MPH, Division of Use and Information, Swedish Medical Products Agency, PO Box 26, SE-751 03 Uppsala, Sweden (rickard.ljung@lakemedelsverket.se).

Author Contributions: Drs Karlstad and Ljung had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Karlstad, Hovi, and Husby contributed equally to this study and are considered co–first authors; Drs Hviid and Ljung contributed equally and are considered co–senior authors.

Concept and design: Karlstad, Hovi, Husby, Selmer, Nohynek, Sundström, Grünewald, Gulseth, Hviid, Ljung.

Acquisition, analysis, or interpretation of data: Karlstad, Hovi, Husby, Härkänen, Selmer, Pihlström, Hansen, Gunnes, Sundström, Wohlfahrt, Nieminen, Grünewald, Gulseth, Hviid, Ljung.

Drafting of the manuscript: Karlstad, Husby, Härkänen, Nohynek, Ljung.

Critical revision of the manuscript for important intellectual content: Karlstad, Hovi, Husby, Härkänen, Selmer, Pihlström, Hansen, Nohynek, Gunnes, Sundström, Wohlfahrt, Nieminen, Grünewald, Gulseth, Hviid.

Statistical analysis: Karlstad, Härkänen, Selmer, Pihlström, Hansen, Gunnes, Sundström, Grünewald, Ljung.

Obtained funding: Gulseth, Hviid.

Administrative, technical, or material support: Karlstad, Nohynek, Gulseth.

Supervision: Hovi, Husby, Nohynek, Wohlfahrt, Hviid, Ljung.

Conflict of Interest Disclosures: Dr Karlstad reported participating in research projects funded by Novo Nordisk and LEO Pharma, all regulator-mandated phase 4 studies with funds paid to his institution and outside the submitted work. Dr Hovi reported being affiliated with the Finnish Institute for Health and Welfare and was thus obligated by legislation to investigate the potential postmarketing harmful effects of vaccines during the conduct of the study. Dr Husby reported receiving funding from the Lundbeck Foundation. Dr Nohynek reported receiving nonfinancial support from WHO SAGE (Strategic Advisory Group of Experts) and the Global Advisory Committee on Vaccine Safety during the conduct of the study; and being employed by the Finnish Institute for Health and Welfare (THL), which receives research funding from Sanofi Pasteur, GlaxoSmithKline, and Pfizer for research studies not related to the current study nor to COVID-19. Dr Sundström reported participating in research funded by governmental agencies, universities, Astellas Pharma, Janssen Biotech, AstraZeneca, Pfizer, Roche, (then) Abbott Laboratories, (then) Schering-Plough, UCB Nordic, and Sobi, with all funds paid to Karolinska Institutet, outside the submitted work. Dr Nieminen reported receiving grants from Sanofi Pasteur outside the submitted work; and being employed by THL. Dr Grünewald reported being involved in the European Medicines Agency regulatory assessment of Comirnaty; being previously employed at a drug development consultancy firm with cross-product responsibilities; and being involved on a project for pertussis vaccines funded by Sanofi Pasteur, Merck Sharp & Dohme Corp, and GlaxoSmithKline at the Swedish Agency of Infectious Disease Control. Dr Gulseth reported participating in research projects and clinical trials funded by Novo Nordisk, GlaxoSmithKline, AstraZeneca, and Boehringer-Ingelheim paid to Oslo University Hospital; and receiving personal fees from Sanofi-Aventis. Dr Hviid reported receiving grants from The Lundbeck Foundation during the conduct of the study. Dr Ljung reported receiving grants from Sanofi Aventis paid to his institution outside the submitted work; and receiving personal fees from Pfizer outside the submitted work. No other disclosures were reported.

Additional Information: Among us, Dr Hviid had full access to all the Danish data, Dr Hovi had full access to all the Finnish data, Dr Karlstad had full access to all the Norwegian data, Dr Ljung had full access to all the Swedish data, and Dr Härkänen had full access to all the meta-analyses data in the study, and each investigator takes responsibility for the integrity of the data and the accuracy of the respective analyses. In addition, Drs Husby, Hansen, and Wohlfahrt, of the Statens Serum Institut, analyzed the Danish data and are responsible for those analyses; Drs Karlstad, Selmer, and Gunnes, of the Norwegian Institute of Public Health, conducted and are responsible for the analyses of the Norwegian data; Drs Hovi and Härkänen, of the Finnish Institute for Health and Welfare, conducted and are responsible for the analyses of the Finnish data; and Drs Pihlström, Sundström, Grünewald, and Ljung, of the Swedish Medical Products Agency, conducted and are responsible for the analyses of the Swedish data.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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