Booster vaccination with SARS-CoV-2 mRNA vaccines and myocarditis in adolescents and young adults: a Nordic cohort study

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Abstract

Background and Aims

The SARS-CoV-2 mRNA vaccines are associated with an increased risk of myocarditis. This association appears to be strongest in male adolescents and younger males and after the second dose. The aim was to evaluate the risk of myocarditis following SARS-CoV-2 mRNA booster vaccination in 12-to-39-year-olds.

Methods

A multinational cohort study was conducted using nationwide register data in Denmark, Finland, Norway, and Sweden and comprising all 8.9 million individuals residing in each of the four countries. Participants were followed for an inpatient diagnosis of myocarditis. In each of the four countries, Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) of myocarditis comparing vaccination schedules, with associated 95% confidence intervals (CIs). Country-specific results were combined in meta-analyses.

Results

A total of 8.9 million residents were followed for 12 271 861 person-years and 1533 cases of myocarditis were identified. In 12-to-39-year-old males, the 28-day acute risk period following the third dose of BNT162b2 or mRNA-1273 was associated with an increased incidence rate of myocarditis compared to the post-acute risk period 28 days or more after the second dose [IRR 2.08 (95% CI 1.31–3.33) and 8.89 (2.26–35.03), respectively]. For females, the corresponding IRR was only estimable for BNT162b2, 3.99 (0.41–38.64). The corresponding absolute risks following the third dose of BNT162b2 and mRNA-1273 in males were 0.86 (95% CI 0.53–1.32) and 1.95 (0.53–4.99) myocarditis events within 28 days per 100 000 individuals vaccinated, respectively. In females, the corresponding absolute risks following the third dose of BNT162b2 were 0.15 (0.04–0.39) events per 100 000 individuals vaccinated. No deaths occurred within 30 days of vaccine-related cases.

Conclusions

The results suggest that a booster dose is associated with increased myocarditis risk in adolescents and young adults. However, the absolute risk of myocarditis following booster vaccination is low.

Related collections

Most cited references 15

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Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study

Jens Sundbøll, Kasper Adelborg, Troels Munch … (2016)

Objective The majority of cardiovascular diagnoses in the Danish National Patient Registry (DNPR) remain to be validated despite extensive use in epidemiological research. We therefore examined the positive predictive value (PPV) of cardiovascular diagnoses in the DNPR. Design Population-based validation study. Setting 1 university hospital and 2 regional hospitals in the Central Denmark Region, 2010–2012. Participants For each cardiovascular diagnosis, up to 100 patients from participating hospitals were randomly sampled during the study period using the DNPR. Main outcome measure Using medical record review as the reference standard, we examined the PPV for cardiovascular diagnoses in the DNPR, coded according to the International Classification of Diseases, 10th Revision. Results A total of 2153 medical records (97% of the total sample) were available for review. The PPVs ranged from 64% to 100%, with a mean PPV of 88%. The PPVs were ≥90% for first-time myocardial infarction, stent thrombosis, stable angina pectoris, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, takotsubo cardiomyopathy, arterial hypertension, atrial fibrillation or flutter, cardiac arrest, mitral valve regurgitation or stenosis, aortic valve regurgitation or stenosis, pericarditis, hypercholesterolaemia, aortic dissection, aortic aneurysm/dilation and arterial claudication. The PPVs were between 80% and 90% for recurrent myocardial infarction, first-time unstable angina pectoris, pulmonary hypertension, bradycardia, ventricular tachycardia/fibrillation, endocarditis, cardiac tumours, first-time venous thromboembolism and between 70% and 80% for first-time and recurrent admission due to heart failure, first-time dilated cardiomyopathy, restrictive cardiomyopathy and recurrent venous thromboembolism. The PPV for first-time myocarditis was 64%. The PPVs were consistent within age, sex, calendar year and hospital categories. Conclusions The validity of cardiovascular diagnoses in the DNPR is overall high and sufficient for use in research since 2010.

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Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection

Martina Patone, Xue Mei, Lahiru Handunnetthi … (2021)

Although myocarditis and pericarditis were not observed as adverse events in coronavirus disease 2019 (COVID-19) vaccine trials, there have been numerous reports of suspected cases following vaccination in the general population. We undertook a self-controlled case series study of people aged 16 or older vaccinated for COVID-19 in England between 1 December 2020 and 24 August 2021 to investigate hospital admission or death from myocarditis, pericarditis and cardiac arrhythmias in the 1–28 days following adenovirus (ChAdOx1, n = 20,615,911) or messenger RNA-based (BNT162b2, n = 16,993,389; mRNA-1273, n = 1,006,191) vaccines or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (n = 3,028,867). We found increased risks of myocarditis associated with the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine over the 1–28 days postvaccination period, and after a SARS-CoV-2 positive test. We estimated an extra two (95% confidence interval (CI) 0, 3), one (95% CI 0, 2) and six (95% CI 2, 8) myocarditis events per 1 million people vaccinated with ChAdOx1, BNT162b2 and mRNA-1273, respectively, in the 28 days following a first dose and an extra ten (95% CI 7, 11) myocarditis events per 1 million vaccinated in the 28 days after a second dose of mRNA-1273. This compares with an extra 40 (95% CI 38, 41) myocarditis events per 1 million patients in the 28 days following a SARS-CoV-2 positive test. We also observed increased risks of pericarditis and cardiac arrhythmias following a positive SARS-CoV-2 test. Similar associations were not observed with any of the COVID-19 vaccines, apart from an increased risk of arrhythmia following a second dose of mRNA-1273. Subgroup analyses by age showed the increased risk of myocarditis associated with the two mRNA vaccines was present only in those younger than 40.

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SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study

Anders Husby, Jørgen Hansen, Emil Loldrup Fosbøl … (2021)

Abstract Objective To investigate the association between SARS-CoV-2 vaccination and myocarditis or myopericarditis. Design Population based cohort study. Setting Denmark. Participants 4 931 775 individuals aged 12 years or older, followed from 1 October 2020 to 5 October 2021. Main outcome measures The primary outcome, myocarditis or myopericarditis, was defined as a combination of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours. Follow-up time before vaccination was compared with follow-up time 0-28 days from the day of vaccination for both first and second doses, using Cox proportional hazards regression with age as an underlying timescale to estimate hazard ratios adjusted for sex, comorbidities, and other potential confounders. Results During follow-up, 269 participants developed myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male. Of 3 482 295 individuals vaccinated with BNT162b2 (Pfizer-BioNTech), 48 developed myocarditis or myopericarditis within 28 days from the vaccination date compared with unvaccinated individuals (adjusted hazard ratio 1.34 (95% confidence interval 0.90 to 2.00); absolute rate 1.4 per 100 000 vaccinated individuals within 28 days of vaccination (95% confidence interval 1.0 to 1.8)). Adjusted hazard ratios among female participants only and male participants only were 3.73 (1.82 to 7.65) and 0.82 (0.50 to 1.34), respectively, with corresponding absolute rates of 1.3 (0.8 to 1.9) and 1.5 (1.0 to 2.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 1.48 (0.74 to 2.98) and the absolute rate was 1.6 (1.0 to 2.6) per 100 000 vaccinated individuals within 28 days of vaccination. Among 498 814 individuals vaccinated with mRNA-1273 (Moderna), 21 developed myocarditis or myopericarditis within 28 days from vaccination date (adjusted hazard ratio 3.92 (2.30 to 6.68); absolute rate 4.2 per 100 000 vaccinated individuals within 28 days of vaccination (2.6 to 6.4)). Adjusted hazard ratios among women only and men only were 6.33 (2.11 to 18.96) and 3.22 (1.75 to 5.93), respectively, with corresponding absolute rates of 2.0 (0.7 to 4.8) and 6.3 (3.6 to 10.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 5.24 (2.47 to 11.12) and the absolute rate was 5.7 (3.3 to 9.3) per 100 000 vaccinated individuals within 28 days of vaccination. Conclusions Vaccination with mRNA-1273 was associated with a significantly increased risk of myocarditis or myopericarditis in the Danish population, primarily driven by an increased risk among individuals aged 12-39 years, while BNT162b2 vaccination was only associated with a significantly increased risk among women. However, the absolute rate of myocarditis or myopericarditis after SARS-CoV-2 mRNA vaccination was low, even in younger age groups. The benefits of SARS-CoV-2 mRNA vaccination should be taken into account when interpreting these findings. Larger multinational studies are needed to further investigate the risks of myocarditis or myopericarditis after vaccination within smaller subgroups.