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Q&A: What Causes Rare Instances of Myocarditis After mRNA COVID-19 Vaccines?

May 16, 2023
by Isabella Backman

Myocarditis is a rare side effect of mRNA COVID-19 vaccines, which have been used with great success as protection against the SARS CoV-2 virus and its variants. Generally, the condition is highly treatable, but it has caused concern in some quarters about the vaccines’ safety. We spoke with Carrie Lucas, PhD, associate professor of immunobiology at Yale School of Medicine, and Akiko Iwasaki, PhD, Sterling Professor of Immunobiology, about their recent study which uncovers clues to why this complication can occur.

What is myocarditis?

Lucas: Myocarditis is inflammation of the heart muscle. It occurs most commonly after an infection but can also be triggered by other things. There are several forms of myocarditis, but generally, what they all have in common is the inflamed heart muscle.

What is the likelihood of developing myocarditis post-vaccination, and who is most at risk?

Iwasaki: Myocarditis risk depends on the age and sex of the vaccine recipient. It is most common in younger males—adolescents or young adults. The highest risk group is males between 12 and 17 years of age. And in that highest risk group, the myocarditis risk after the second dose, which is the highest, is 35.9 per 100,000 people. In comparison, the risk post-infection in that same group is 64.9 per 100,000.

What were your hypotheses for why this happens, and how did you test them?

Iwasaki: We considered three hypotheses. One is autoimmune myocarditis, which is when the immune cells start to attack our own host cells. This can be serious, because once you generate autoimmune responses, it’s difficult to revert back to baseline. Our second hypothesis was myocarditis caused by hypersensitivity. This is an allergic response that some people experience after drug toxicity that is demarcated by these cell types known as eosinophils. Eosinophils are normally immune effectors that are activated during an allergic response but can also be activated in response to other stimuli, including drugs or potentially components of the vaccine.

And then the third hypothesis is the one that we found to be most likely, which is inflammation-related myocarditis. This is immune cell mediated. We found that activated immune cells like cytotoxic killer cells and myeloid cells are elevated in these patients, which appears to suggest that mRNA vaccine-associated myocarditis is the most consistent with being inflammatory cell-mediated.

Professor Iwasaki, you have said you are “a little relieved” to have found myocarditis cases to be inflammation-induced. Why is that?

Iwasaki: Autoimmune-related myocarditis is more difficult to treat. It would be more chronic, because once you trigger an autoimmune response, it’s very difficult to shut it down. For example, if you develop auto antibodies against components of the cardiac muscle, it’s difficult to get rid of those B cells that are secreting those antibodies, creating chronic disease. Whereas inflammation-induced myocarditis is more transient—we actually found that inflammation as well as the immune cell types go back to normal after patients recover. So we know that it’s a resolving kind of myocarditis. We don’t want to diminish patients’ suffering, but this kind of myocarditis is better than other types.

Lucas: The other thing that’s good is how treatable it is. Something empirically that our clinical colleagues have found is that treatments like NSAIDs or steroids—temporary measures that can calm the inflammation back down—can help these young patients bounce back quickly. Another point is that if you space the dosing of the mRNA vaccines far enough apart, you might allow time for the waning of the inflammatory response and reduce the risk of myocarditis. That’s still yet to be widely tested, but because of the nature of the inflammation, it’s a very plausible possibility.

For those at risk of developing myocarditis, is vaccination or becoming infected with SARS-CoV-2 safer?

Iwasaki: It’s hard to compare head-to-head, but it’s important to remember that with infection, you not only get myocarditis, but you also get all these other symptoms and damage to your lungs and other organs. You could also develop long COVID. There are many other sequelae (residual effects) after infection than after vaccination, which causes a more transient type of myocarditis.

Lucas: Studies have also shown that the severity of disease and length of recovery are greater in myocarditis post-COVID, in contrast to this transient experience of inflammation after vaccination.

Why are men more at risk than women?

Iwasaki: There could be many reasons—genetics, hormones, potentially environment. In the cases of myocarditis that occur after viral infections, animal models have studied the impact of testosterone. In these studies, testosterone was involved in some of the features that we see in vaccine-associated myocarditis. So it’s possible testosterone may be involved in vaccine-related myocarditis, but we don’t have any proof of it.

Why can the mRNA vaccine affect the heart?

Lucas: This is a question we have thought a lot about but one we can’t yet answer. We can propose some hypotheses, but why the heart tissue is affected and not other tissues in the body is not known. One speculation is based on our thinking about the different organ systems. In our analyses, some of the cells associated with inflammation have signatures consistent with immune molecules that can recognize what we call ‘stress ligands’ on tissue cells. And you can imagine, the heart pumping and the mechanical stress that it experiences could make it express some of these ligands more than other tissues. But again, this is pure speculation and more studies would be needed to be able to figure out why the heart and not other tissues—we don’t have data on that directly.

Why are studies on the adverse effects of vaccines important?

Iwasaki: We both think vaccines are just a miracle. They saved millions of lives during this pandemic. But no medicine is without any side effects. So vaccines, unfortunately, in a subset of people, are causing some inflammation and other adverse events. So it’s very important that we understand better what those adverse events are and how they’re mediated so that we can improve on the already amazing vaccines that we have, and also to mitigate any risks further in the future. For instance, a study from Canada that showed that spacing apart the first and second dose does seem to reduce the risk for developing myocarditis. Every insight can be used to help future vaccines become safer.

What would you like to say to those concerned about getting vaccinated due to myocarditis risk?

Iwasaki: First of all, myocarditis after vaccination for the most part appears to be transient, and these patients recover. In comparison, getting COVID could lead to more severe, more prolonged myocarditis. Secondly, there are ways to reduce the risk for myocarditis, like spacing apart the first and second dose. And now that we have seen enough of these cases, doctors are learning how to treat these events when they do occur. And it’s also important to emphasize that instances of myocarditis have not been seen after the booster doses. So it’s mostly confined to the second dose of the primary series, and we shouldn’t be expecting these things to occur for future booster doses. And if the COVID boosters become like an annual flu vaccine, we wouldn’t expect myocarditis to occur because they are spaced so far apart.

Lucas: Awareness about these things is important. For males in this age group, if they experience some of the signs—chest pain, shortness of breath, etc.—to take it seriously and go get treatment, because again, it can be treated with anti-inflammatory medicines. And the sooner it is treated, the sooner it will resolve. But with the wider spacing now, we hope this won’t be an issue. I think it’s also important to remember that the community has seen this signal for myocarditis during the pandemic because everyone was synchronized in the timing of getting the vaccines. But this isn’t the only vaccine that induced myocarditis. There are others, such as the smallpox vaccine, that can also on rare occasion cause a similar thing. So we hope that our studies are informing these rare cases and will help us strategize how to reduce risk further.

Do you have any further research planned?

Lucas: One thing that I think that would be very exciting is to study what’s happening in the tissue. This is not something we’re yet capable of doing because in our cohorts, we don't have access to these samples. Our study was restricted to clinical analyses and imaging of the heart with investigation of immune cells and molecules from blood samples, but we didn’t do any cellular analysis of the affected tissue since this would require biopsies. So future studies with colleagues who may have collected such biopsies during care of these patients can hopefully corroborate our findings from the blood using tissue samples.

Anything else you would like to add?

Iwasaki: I want to emphasize that it’s important to study these events in a rigorous manner. We’re hearing a lot on Twitter that people are very appreciative that we are actually studying this and not dismissing the cases. And the more we understand, the less fear that people will have about these things. So I think it’s important that we continue to study these events as they emerge.

Submitted by Robert Forman on May 16, 2023