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

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          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.

          Abstract

          This cohort study conducted using nationwide registers assesses the risks of myocarditis and pericarditis after SARS-CoV-2 messenger RNA vaccinations in a combined population of 23.1 million individuals across Denmark, Finland, Norway, and Sweden.

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          Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant

          Nick Andrews, Julia Stowe, Freja Kirsebom … (2022)
          Background A rapid increase in coronavirus disease 2019 (Covid-19) cases due to the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 in highly vaccinated populations has aroused concerns about the effectiveness of current vaccines. Methods We used a test-negative case–control design to estimate vaccine effectiveness against symptomatic disease caused by the omicron and delta (B.1.617.2) variants in England. Vaccine effectiveness was calculated after primary immunization with two doses of BNT162b2 (Pfizer–BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), or mRNA-1273 (Moderna) vaccine and after a booster dose of BNT162b2, ChAdOx1 nCoV-19, or mRNA-1273. Results Between November 27, 2021, and January 12, 2022, a total of 886,774 eligible persons infected with the omicron variant, 204,154 eligible persons infected with the delta variant, and 1,572,621 eligible test-negative controls were identified. At all time points investigated and for all combinations of primary course and booster vaccines, vaccine effectiveness against symptomatic disease was higher for the delta variant than for the omicron variant. No effect against the omicron variant was noted from 20 weeks after two ChAdOx1 nCoV-19 doses, whereas vaccine effectiveness after two BNT162b2 doses was 65.5% (95% confidence interval [CI], 63.9 to 67.0) at 2 to 4 weeks, dropping to 8.8% (95% CI, 7.0 to 10.5) at 25 or more weeks. Among ChAdOx1 nCoV-19 primary course recipients, vaccine effectiveness increased to 62.4% (95% CI, 61.8 to 63.0) at 2 to 4 weeks after a BNT162b2 booster before decreasing to 39.6% (95% CI, 38.0 to 41.1) at 10 or more weeks. Among BNT162b2 primary course recipients, vaccine effectiveness increased to 67.2% (95% CI, 66.5 to 67.8) at 2 to 4 weeks after a BNT162b2 booster before declining to 45.7% (95% CI, 44.7 to 46.7) at 10 or more weeks. Vaccine effectiveness after a ChAdOx1 nCoV-19 primary course increased to 70.1% (95% CI, 69.5 to 70.7) at 2 to 4 weeks after an mRNA-1273 booster and decreased to 60.9% (95% CI, 59.7 to 62.1) at 5 to 9 weeks. After a BNT162b2 primary course, the mRNA-1273 booster increased vaccine effectiveness to 73.9% (95% CI, 73.1 to 74.6) at 2 to 4 weeks; vaccine effectiveness fell to 64.4% (95% CI, 62.6 to 66.1) at 5 to 9 weeks. Conclusions Primary immunization with two doses of ChAdOx1 nCoV-19 or BNT162b2 vaccine provided limited protection against symptomatic disease caused by the omicron variant. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course substantially increased protection, but that protection waned over time. (Funded by the U.K. Health Security Agency.)
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            Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination

            Nina Schultz, Ingvild Sørvoll, Annika Michelsen … (2021)
            We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4–polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.
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              Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting

              Noam Barda, Noa Dagan, Yatir Ben-Shlomo … (2021)
              Background Preapproval trials showed that messenger RNA (mRNA)–based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations. An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed. Methods We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine. For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables. Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan–Meier estimator. To place these results in context, we performed a similar analysis involving SARS-CoV-2–infected persons matched to uninfected persons. The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses. Results In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons. Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2). SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia. Conclusions In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined. The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons). The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.)
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                Author and article information

                Journal
                Journal ID (nlm-ta): JAMA Cardiol
                Journal ID (iso-abbrev): JAMA Cardiol
                Title: JAMA Cardiology
                Publisher: American Medical Association
                ISSN (Print): 2380-6583
                ISSN (Electronic): 2380-6591
                Publication date (Electronic): 20 April 2022
                Publication date (Print): June 2022
                Publication date PMC-release: 20 April 2022
                Volume: 7
                Issue: 6
                Pages: 600-612
                Affiliations
                [1 ]Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
                [2 ]Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
                [3 ]Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
                [4 ]Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
                [5 ]Division of Licensing, Swedish Medical Products Agency, Uppsala, Sweden
                [6 ]Health Security, Finnish Institute for Health and Welfare, Helsinki, Finland
                [7 ]Norwegian Research Centre for Women’s Health, Oslo University Hospital, Oslo, Norway
                [8 ]Division of Use and Information, Swedish Medical Products Agency, Uppsala, Sweden
                [9 ]Information Services, Finnish Institute for Health and Welfare, Helsinki, Finland
                [10 ]Department of Drug Design and Pharmacology, Pharmacovigilance Research Center, University of Copenhagen, Copenhagen, Denmark
                [11 ]Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                Author notes
                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@ 123456lakemedelsverket.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.
                Article
                Publisher ID: hoi220012
                DOI: 10.1001/jamacardio.2022.0583
                PMC ID: 9021987
                PubMed ID: 35442390
                SO-VID: 560c908b-7e3b-45f3-ac7f-b05eac9da873
                Copyright © Copyright 2022 Karlstad Ø et al. JAMA Cardiology.
                License:

                This is an open access article distributed under the terms of the CC-BY License.

                History
                Date received : 30 November 2021
                Date accepted : 23 February 2022
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                Subject: Original Investigation
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