Myocarditis Risk Varies Among mRNA-Based COVID-19 Vaccines

In one of the largest studies to explore the occurrence of myocarditis after mRNA-based COVID-19 vaccination to date, risk of the complication—though low overall—was higher among people who received the Moderna shot than it was with the one from Pfizer/BioNTech, researchers report.

Males ages 16 to 24 were most likely to develop vaccine-associated myocarditis within 28 days of vaccination, and in this group, the estimated number of excess events per 100,000 vaccine recipients was between four and seven after a second dose of the Pfizer/BioNTech shot and between nine and 28 after a second dose of the Moderna shot.

The difference between mRNA vaccines, consistent with prior research, has now been confirmed in one of the best data sources available—pooled national registry data on more than 23.1 million people living in Denmark, Finland, Norway, and Sweden, according to senior author Rickard Ljung, MD, PhD (Swedish Medical Products Agency, Uppsala, Sweden).

“The risk is clearly higher for Moderna,” Ljung told TCTMD, saying that the higher amount of mRNA in that shot versus the one from Pfizer/BioNTech might explain the disparity. He noted that “not only in Sweden, but also in Finland and in Norway, the public health agencies have altered the recommendations [to advise] not using Moderna, for younger men at least.”

Some other countries have followed suit. Advisors to the US Centers for Disease Control and Prevention (CDC) discussed the issue at a February meeting, as reported by CNBC, although the CDC has not issued a recommendation to limit use of the Moderna vaccine to certain age groups.

The higher rate of myocarditis with the Moderna shot should be considered in the context of other research suggesting the vaccine may provide greater protection against SARS-CoV-2 than the Pfizer/BioNTech vaccine, the study authors indicate: “This risk should be balanced against the benefits of protecting against severe COVID-19 disease.”

Myocarditis and Pericarditis Rare Overall

After countries started rolling out the mRNA vaccines, which have been shown to safely reduce the risk of severe COVID-19 outcomes, reports of myocarditis associated with vaccination began to crop up. Subsequent research has established a clear link between the Moderna and Pfizer/BioNTech vaccines and an increased risk of myocarditis, with cases clustered after the second dose and among younger males. The clinical course of affected patients has generally been mild. Other analyses have established that the myocarditis/pericarditis risks posed by COVID-19 infection itself exceeds the risk following vaccination, even in younger males.

The current study—published online Wednesday ahead of print in JAMA Cardiology, with lead author Øystein Karlstad, MScPharm, PhD (Norwegian Institute of Public Health, Oslo, Norway)—delves into the issue by pooling data on residents ages 12 and older from four Nordic countries. The study period ran from December 27, 2020, when national vaccination campaigns were launched, through October 5, 2021, the day before Swedish health authorities recommended against use of the Moderna vaccine in men and women younger than 30. Cases of myocarditis and pericarditis were identified using diagnostic codes.

During the study period, 81% of people received at least one vaccine dose—65% with the Pfizer/BioNTech vaccine, 10% with the Moderna vaccine, and 6% with the Oxford/AstraZeneca shot.

In the 28 days after vaccination or during unvaccinated periods, there were 1,077 incident cases of myocarditis and 1,149 cases of pericarditis identified. Both first and second doses of the mRNA vaccines were associated with greater risks of those complications compared with unvaccinated periods, particularly in the first 7 days after the second doses and among males.

Among those with a homologous schedule (the same vaccine for both doses), the second dose was associated with a higher risk of myocarditis compared with unvaccinated periods, both for the Pfizer/BioNTech shot (adjusted incidence rate ratio [IRR] 1.75; 95% CI 1.43-2.14) and the Moderna vaccine (adjusted IRR 6.57; 95% CI 4.64-9.28). Both figures were higher for males versus females.

Males ages 16 to 24 were most at risk, with adjusted IRRs of 5.31 and 13.83 after second doses of the Pfizer/BioNTech and Moderna vaccines, respectively. The numbers of excess events per 100,000 vaccinees in this group were 5.55 and 18.39 with the two vaccines. Excess events reached a high of 27.49 per 100,000 vaccine recipients among young males who received a mixed series involving a Pfizer/BioNTech first dose followed by a Moderna second dose.

Generally, there were similar estimates for pericarditis, the authors report.

Deaths in patients with myocarditis were rare, they say, citing a 28-day mortality rate of 0.8% among unvaccinated cases, 0.2% after a second Pfizer/BioNTech dose, and 4.5% after a second Moderna dose. There were no deaths associated with myocarditis in people younger than 40.

“Although studies on the long-term prognosis of vaccine-associated cases of myocarditis are lacking and are urgently needed, some evidence suggests that the 28-day risk of death, hospital readmission rates, and development of heart failure appear low, especially in the younger age groups,” the researchers write.

Ljung added, “It’s not apparent that this myocarditis after vaccination should be more severe than a normal myocarditis. I think that’s important. And it’s also important to know that in general, most of the myocarditis that you can get is fairly mild. Even though it’s a severe event, it’s not usually a life-threatening event.”

Balancing Risks and Benefits

In an accompanying note, Ann Marie Navar, MD, PhD (UT Southwestern Medical Center, Dallas, TX), deputy editor for diversity, equity, and inclusion of JAMA Cardiology, and Robert Bonow, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), editor of the journal, look to the clinical implications of the findings.

First, “older adults, who are at the highest risk of COVID-19 complications, appear to be at extremely low risk of vaccine-associated myocarditis,” they point out, adding that “the benefits of immunization in those older than 40 years clearly outweigh the risks.”

Navar and Bonow suggest that considerations might be different in younger people, particularly males, in whom the risk of myocarditis is much higher. Young men, they say, may opt for the shot from Pfizer/BioNTech over the one from Moderna to mitigate the risk of myocarditis, and healthcare professionals may consider recommending that approach for certain groups, “including young men and other individuals for whom concerns about myocarditis present a barrier to immunization.”

Like the study authors, however, Navar and Bonow advise weighing the lower risk of myocarditis with the Pfizer/BioNTech vaccine against the possibly enhanced protection against severe COVID-19 outcomes with the Moderna vaccine.

And taking a broader view, they say that “the risk of myocarditis following COVID-19 immunization is real, but this low risk must be considered in context of the overall benefit of vaccine,” both at the individual level and at the population level.

Vaccination prevents serious outcomes up to and including death for recipients and “helps to decrease community spread, decrease the chances of new variants emerging, protect people who are immunocompromised, and ensure our healthcare system can continue to provide for our communities,” Navar and Bonow write.