Cases of myocarditis and pericarditis have been reported following the receipt of Covid-19 mRNA vaccines. As vaccination campaigns are still to be extended, we aimed to provide a comprehensive assessment of the association, by vaccine and across sex and age groups. Using nationwide hospital discharge and vaccine data, we analysed all 1612 cases of myocarditis and 1613 cases of pericarditis that occurred in France in the period from May 12, 2021 to October 31, 2021. We perform matched case-control studies and find increased risks of myocarditis and pericarditis during the first week following vaccination, and particularly after the second dose, with adjusted odds ratios of myocarditis of 8.1 (95% confidence interval [CI], 6.7 to 9.9) for the BNT162b2 and 30 (95% CI, 21 to 43) for the mRNA-1273 vaccine. The largest associations are observed for myocarditis following mRNA-1273 vaccination in persons aged 18 to 24 years. Estimates of excess cases attributable to vaccination also reveal a substantial burden of both myocarditis and pericarditis across other age groups and in both males and females.
On July 19, 2021 the European Medicines Agency advised that myocarditis and pericarditis be added to the list of adverse effects of both messenger RNA (mRNA) based vaccines (BNT162b2 [Pfizer–BioNTech] and mRNA-1273 [Moderna]) against coronavirus disease 2019 (Covid-19)1. This statement followed pharmacovigilance reports of an increased risk of myocarditis among recipients of mRNA vaccines that showed certain common patterns2,3. Several reports indicate that adverse events typically occur within a week after injection, mostly after the second dose of vaccine, cluster in young males, and result in a mild clinical course and short duration of hospitalization4,5,6. However, the predominance of a vaccine-associated risk in males7 and its extent regarding pericarditis, as a specific condition, remains uncertain8,9,10,11. Population-based risks estimates for each condition and across sex and age groups and by vaccine type remains crucial as vaccination campaigns are still to be extended especially towards the youngest and with subsequent doses. The Covid-19 vaccination campaign began in France in late 2020 with the gradual roll-out of the two mRNA vaccines, BNT162b2 and mRNA-1273 alongside viral vector-based vaccines. Initially reserved for the oldest and most vulnerable groups, as well as healthcare professionals, vaccination was opened up to the entire population over the age of 18 years as of May 12, 2021, and to all over 12 years old as of June 15, 2021. As of October 31, 2021 approximately 50 million people (88% of the eligible population, i.e. over 12 years old) in France had received a full vaccination schedule12. Here, we aimed to estimate the age and sex-specific associations between each mRNA Covid-19 vaccine and the risk of myocarditis and pericarditis, using nationwide hospital discharge and vaccine data for France.
Characteristics of the study population
Between May 12, 2021 and October 31, 2021, within a population of 32 million persons aged 12 to 50 years, 21.2 million first (19.3 million second) doses of the BNT162b2 vaccine and 2.86 million first (2.58 million second) doses of the mRNA-1273 vaccine were received (Table S1). In the same period, 1612 cases of myocarditis (of which 87 [5.4%] had also a pericarditis as associated diagnosis) and 1613 cases of pericarditis (37 [2.3%] with myocarditis as associated diagnosis) were recorded in France. We matched those cases to 16,120 and 16,130 control subjects, respectively. The characteristics of the cases and their matched controls are shown in Table 1. For both myocarditis and pericarditis, key differences between cases and controls included a higher proportion among cases of a history of myocarditis or pericarditis, of history of SARS-CoV-2 infection, and receipt of an mRNA Covid-19 vaccine. The mean age and proportion of women were lower among patients with myocarditis than those with pericarditis.
Risk of myocarditis and pericarditis associated with vaccination
For both vaccines, the risk of myocarditis was increased in the seven days post vaccination (Table 2; in the rest of the text, we will refer to multivariable odds ratios). For the BNT162b2 vaccine, odds ratios were 1.8 (95% confidence interval [CI]: 1.3–2.5) for the first dose and 8.1 (95% CI, 6.7–9.9) for the second. The association was stronger for the mRNA-1273 vaccine with odds-ratios of 3.0 (95% CI, 1.4–6.2) for the first dose and 30 (95% CI, 21–43) for the second. The risk of pericarditis was increased in the seven days following the second dose of both vaccines, with odds ratios of 2.9 (95% CI, 2.3–3.8) for the BNT162b2 vaccine and 5.5 (95% CI, 3.3–9.0) for the mRNA-1273 vaccine. Vaccination in the previous 8 to 21 days, with either the BNT162b2 or mRNA-1273 vaccine was not associated with a risk of myocarditis or pericarditis. Independently of vaccination status, a history of myocarditis was strongly associated with a risk of contracting myocarditis during the study period, with an odds-ratios of 160 (95% CI, 83–330). The same was true for pericarditis, with an odds ratio of 250 (95% CI, 120–540). No interaction was found between history of myocarditis or pericarditis and vaccine exposure. Infection with SARS-CoV-2 in the preceding month was also associated with a risk of myocarditis (odds ratio, 9.0 [95% CI, 6.4–13]) or pericarditis (odds ratio, 4.0 [95% CI, 2.7–5.9]).
Subgroup estimates by sex and age classes
The risk of myocarditis was substantially increased within the first week post vaccination in both males and females (Fig. 1 and Table S2). Odds-ratios associated with the second dose of the mRNA-1273 vaccine were consistently the highest, with values up to 44 (95% CI, 22–88) and 41 (95% CI, 12–140), respectively in males and females aged 18 to 24 years but remaining high in older age groups. Odds-ratios for the second dose of the BNT162b2 vaccine tended to decrease with age, from 18 (95% CI, 9–35) and 7.1 (95% CI, 1.5–33), respectively in males and females aged 12 to 17 years, down to 3.0 (95% CI, 1.5–5.9) and 1.9 (95% CI, 0.39–9.3), respectively in males and females aged 40 to 51 years.