Myocarditis Risk Greater After SARS-CoV-2 Infection Than After COVID-19 Vaccination

Julia Hippisley-Cox, MD

Risk of hospital admission or death from myocarditis was reported to be greater after SARS-CoV-2 infection than COVID-19 vaccination, according to findings from a self-controlled case series study.

Although risk of myocarditis with infection remained following vaccination, the findings suggest it was substantially reduced, adding the benefit of protection from cardiovascular consequences of SARS-CoV-2 infection.

However, in contrast to these findings, the risk of myocarditis observed 1 to 28 days after a second dose of mRNA-1273 vaccine was similar to the risk after infection, particularly in younger males.

“Although the net benefit of vaccination for the individual or on a population level should not be  framed exclusively around the risks of myocarditis, quantifying this risk is important, particularly in young people who are less likely to have a severe illness with SARS-CoV-2 infection,” wrote study author Julia Hippisley-Cox, MD, Nuffield Department of Primary Health Care Sciences, University of Oxford.

Hippisley-Cox and colleagues previously reported an association between the first and second dose of COVID-19 vaccination and myocarditis, as well as an increased risk of hospital admission or death from myocarditis following both adenoviral (ChAdOx1) vaccines and mRNA vaccines.

The team noted that their findings also determined that the risk of myocarditis after vaccination was small compared with the risk after a positive SARS-CoV-2 test. However, myocarditis is found more often in those younger than 40 years and in men, making additionally analyses stratified by age and sex a priority.

They also highlighted the observation that myocarditis risk is higher after the second dose of vaccine compared to the first, making it urgent to evaluate the risk of a booster dose. Thus, the analysis was extended to patients aged ≥13 years and those receiving a booster dose between to evaluate the association between COVID-19 vaccination or infection and risk of myocarditis, stratified by age and sex.

Investigators estimated the incidence rate ratio and excess number of hospital admissions or death from myocarditis per million people for the 1 to 28 days after sequential doses of COVID-19 vaccine, or following a positive SARS-CoV-2 test.

Between December 2020 - December 2021, there were 42,842,345 individuals vaccinated with ≥1 dose of ChAdOx1 (n = 20,650,685), BNT162b2 (n = 20,979,704), or mRNA-1273 (n = 1,211,956). From this population, a total of 21,242, 629 people received a third vaccine dose.

Additionally, among those receiving ≥1 vaccine dose, data show 5,934,153 (13.9%) tested positive for SARS-CoV-2, including 2,958,026 (49.8%) before their first vaccination.

Investigators observed 2681 patients (0.007%) were hospitalized or died from myocarditis during the study period. They noted a total of 617 (0.001%) of these events occurred 1 to 28 days after any dose of vaccine.

The data suggest the risk of myocarditis was increased in the 1 to 28 days after first dose of ChAdOx1 (incidence rate ratio [IRR], 1.33; 95% CI, 1.09 - 1.62) and a first, second, and booster dose of BNT162b2 (IRR, 1.52 [95% CI, 1.24 - 1.85]; 1.57  [95%  CI,  1.28–1.92],  and  1.72  [95%  CI,  1.33–2.22],  respectively).

However, these observations were found lower than the risks after a positive SARS-CoV-2 test before or after vaccination (IRR, 11.14 [95% CI, 8.64 - 14.36] and 5.97 [95% CI, 4.54 - 7.87], respectively).

Moreover, the associations were noted to be stronger in males younger than 40 years old for all vaccines. The number of excess myocarditis events per million individuals was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91 –99] versus 16 [95% CI, 12 – 18]). Women experienced a similar increased risk of myocarditis after a second dose of mRNA-1273.

Hippisley-Cox noted that a comparison of rates of death with myocarditis between those infected with SARS-CoV-2 or vaccinated was not possible, due to the analysis only including those who were vaccinated.

“Therefore, a patient with COVID-19 who died after myocarditis before receiving a vaccination  will not be included, and rates of myocarditis death after SARS-CoV-2 will be underestimated,” Hippisley-Cox added.

The study, “Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex,” was published in Circulation.