Myocarditis Risk Low Overall After COVID-19 Vax, but Higher in Some Groups

(UPDATED) One of the largest studies to date confirms once again that the risk of myocarditis is low after COVID-19 vaccination, and in most cases, the hazard is even lower than what accompanies SARS-CoV-2 infection itself. That’s according to a study of nearly 43 million people who received at least one vaccine dose in England.

The risk varies on the basis age, sex, and shot type, however, with vaccine-associated myocarditis risks being highest in men younger than 40, especially after a second dose of Moderna’s vaccine, lead author Martina Patone, PhD (University of Oxford, England), and colleagues reported in a study published Monday online in Circulation.

Overall, the findings, derived from an extremely large data set, confirm prior research on myocarditis associated with the COVID-19 vaccines, study author Keith Channon, MBChB, MD (University of Oxford), told TCTMD. Previous studies have shown that myocarditis is rare after vaccination and carries benign consequences in the vast majority of patients.

“By far the biggest risk of inflammation of the heart is related to COVID infection. That is very clear. The risk is still not very high, but statistically it’s by far the most clear risk: if you get COVID, you are much more likely to then get myocarditis, or other cardiac problems, afterwards,” Channon said. He noted, too, that myocarditis is just one of the many adverse health consequences of COVID-19.

“The overwhelming recommendation is strongly in favor of COVID vaccination, even when myocarditis is the endpoint,” Channon said.

Commenting for TCTMD, Yuk Law, MD (Seattle Children’s Hospital and the University of Washington School of Medicine, Seattle), said via email that these findings “will aid health officials in further stratifying who should receive which vaccines, including boosters.”

They also “allow for a frank and transparent discussion on the pros and cons of vaccination,” said Law, who is chair of the American Heart Association’s scientific statement on myocarditis in children. “Does a completely healthy teenage male, without high-risk family members or close contacts, require a full set of vaccines at the interval prescribed? Or should he be selective of the vaccine available/accessible to him? For healthcare officials, further assessment of the risk-to-benefit balance regarding age and sex with comorbidities should be done using data from this and other nationwide-based studies.”

The overwhelming recommendation is strongly in favor of COVID vaccination, even when myocarditis is the endpoint. Keith Channon

A previous study from the Oxford group, published in Nature Medicine in December 2021, demonstrated a greater risk of myocarditis-related hospitalization or death following one dose of the adenoviral vaccine from Oxford/AstraZeneca and two doses of the mRNA vaccines from Pfizer/BioNTech and Moderna, although the risk was even higher after a positive SARS-CoV-2 test.

This new study expands on those findings by including a much larger sample size with a wider range of ages, as well as data on booster doses of vaccine. The analysis, a self-controlled case series, included data on more than 42.8 million individuals ages 13 and older who received at least one dose of COVID-19 vaccine in England between December 1, 2020, and December 15, 2021. The investigators drew on information from UK national databases of COVID-19 vaccination, mortality, hospital admissions, and SARS-CoV-2 infection.

Of the individuals included in the study, about 21.2 million received three doses of vaccine (which means they received a booster) and 5.9 million had a recorded SARS-CoV-2 infection either before or after vaccination.

Overall, myocarditis-related hospitalization or death occurred in 2,861 individuals (0.007% of the total vaccinated cohort), with 617 events (0.001% of the total cohort) recorded 1 to 28 days after any dose of vaccine.

In comparison, the rate of myocarditis 1 to 28 days after a positive SARS-CoV-2 test was 0.003%, with most of these events (58.5%) occurring before any vaccine doses had been administered.

The investigators then estimated incidence rate ratios (IRRs) for myocarditis, finding increased risks of the complication 1 to 28 days after vaccination associated with one dose of the Oxford/AstraZeneca vaccine (IRR 1.33) and any of three doses of the Pfizer/BioNTech vaccine (IRRs 1.52-1.72). Though risk was not significantly increased after the first Moderna dose, it was substantially higher after the second dose (IRR 11.76) and remained elevated after a booster dose (IRR 2.64).

All of those figures, with the exception of the IRR following the second Moderna dose, were lower than the risks associated with getting a positive SARS-CoV-2 test result either before or after vaccination (IRR 11.14 and 5.97, respectively). “Although the risk of myocarditis with SARS-CoV-2 infection remains after vaccination, it was substantially reduced, suggesting vaccination provides some protection from the cardiovascular consequences of SARS-CoV-2,” Patone et al write.

The relationships between vaccination and myocarditis were stronger in men younger than 40 than in other age/sex groups for all vaccines. In this group, the number of excess myocarditis events was higher after a second Moderna dose than after a positive SARS-CoV-2 test (97 vs 16 per million people vaccinated); excess events were fewer with other vaccine types and doses than with SARS-CoV-2 infection.

Higher Risk With Moderna Vaccine

The increased likelihood of myocarditis after receipt of the Moderna vaccine, particularly after the second dose, is consistent with prior analyses of data from Denmark, the United States, and four Nordic countries, with public health agencies in some countries recommending against use of the shot in certain age/sex groups.

Channon advised caution in interpreting that finding, however, pointing out that the number of people who received the Moderna vaccine was lower than the number who received the others—with a lower absolute number of myocarditis cases, too—and that the shot was rolled out later in the pandemic after many people had already had COVID-19 or been vaccinated with either the Oxford/AstraZeneca or Pfizer/BioNTech vaccines. Thus, the pandemic landscape was different when Moderna shots were going into people’s arms.

The results showing a higher risk after a second Moderna dose are “interesting and they’re provocative and they should make us be cautious about the way we think about recommending different types of vaccines for different age groups potentially. That’s something for the vaccine policy makers to take on board,” Channon said. But, he added, “there are some reservations about the interpretation of a single study, even though this study is very large.”

Nonetheless, this type of study should be a part of discussions around vaccination guidance, Channon said. “Policy makers will need to take into consideration a wide range of different factors. At the very least, this paper should be very much part of the evidence base that vaccine policy makers draw on to make their recommendations in the future.”

Ultimately, he said, “it’s important for us to take these findings into consideration, but it doesn’t alter the strong recommendation that vaccination is by far the lower-risk strategy than not having a vaccination based on possible complications and then exposing oneself to the risk of COVID infection.”

For Law, the results of the study should be extended to children cautiously because they made up a small proportion of the cohort, but they “shed light on our understanding of myocarditis in children in that the central hypothesis to the pathogenesis of myocarditis in children is that it starts with a viral infection, but that the additional and progressive injury to the heart is likely related to the robust immune response,” he said. “Although the study by Patone et al did not study children per se, the observation of a younger age predisposition to vaccine-related myocarditis may be like the heightened immune response in viral myocarditis in children.”

Aside from the public health implications, Channon also highlighted what the study demonstrates when it comes to conducting this type of research. He pointed to the massive scale and comprehensive nature of the data set, which allows for the detection of very small effect sizes that would otherwise remain hidden. “By marrying the academic expertise of the University of Oxford with access to a very, very large national data set, via the UK’s National Health Service, this is an exemplar of how you can come up with some really important, powerful findings, and this ought to be the way that this type of research is done in the future,” Channon said.