The mRNA-based COVID-19 vaccines have proven remarkably safe and effective against the deadly pandemic. But, like all medical procedures, they have some risks. One is that a very small number of vaccinated people develop inflammation of and around their heart – conditions called myocarditis, pericarditis, or the combination of the two, myopericarditis. These side effects usually affect men in their teens and early 20s, usually after a second dose of vaccine. Fortunately, the conditions are usually mild and resolve on their own.
With the rarity and mildness of these conditions, studies have concluded and experts agree that the benefits of vaccination outweigh the risks – male teens and young adults should get vaccinated. In fact, they are significantly more likely to develop myocarditis or pericarditis from a COVID-19 infection than from a COVID-19 vaccination. According to a large 2022 study led by researchers at Harvard University and the Centers for Disease Control and Prevention, the group at the highest risk of post-vaccination myocarditis and pericarditis — men ages 12 to 17 — saw 35.9 cases per 100,000 (0.0359 percent) after a second vaccine dose, while the rate almost doubled after a COVID-19 infection in the same age group, with 64.9 cases per 100,000 (0.0649 percent)
Still, the conditions are a bit of a puzzle. Why do a small number get this complication after vaccination? Why does it only seem to affect the heart? How does the damage occur? And what does all this mean for the many other mRNA-based vaccines now being developed?
A new study in Science Immunology offers new insight. The study, led by researchers at Yale University, took a deep look at the immune responses of 23 people — mostly male and ranging in age from 13 to 21 — who developed myocarditis and/or pericarditis after vaccination.
Explore possibilities
Since the rare phenomenon was first noticed, immunologists and other experts have hypothesized that the vaccine could trigger various aberrant immune responses that could explain the inflamed hearts, such as an autoimmune response or an allergic reaction. And the new study rules out some of them.
The researchers used blood samples from a subset of the patients to watch immune responses and compare them to those of matched vaccinated controls. They first compared antibodies to SARS-CoV-2 and found no evidence of “exaggerated” or enhanced antibody responses to the virus that could explain the myocarditis and pericarditis. The anti-SARS-CoV-2 antibody responses in the two groups were similar, with the patients with the heart disease having similar, if not slightly blunted, antibody responses.
The researchers then screened for autoantibodies, that is, antibodies spurred by the vaccine that are misdirected against a person’s body rather than the virus. They used an established screening tool to scan for autoantibodies against more than 6,000 human proteins and molecules. The researchers focused on more than 500 of the probes related to heart tissue. They found no relative increase in the number of autoantibodies compared to controls, suggesting that an autoimmune response was unlikely.
The researchers then took a broad, unbiased approach to compare the profiles of immune responses between the patients and controls. They found different immune signatures between the two groups, with patients showing elevated levels of immune signaling chemicals (cytokines) associated with acute, systemic inflammation. And those cytokines were accompanied by corresponding increases in inflammatory cellular responses, particularly cytotoxic T cells. Furthermore, the gene expression profiles of those T cells showed the potential to cause cardiac tissue damage.
Persistent questions
Taken together, the researchers concluded that the most likely explanation is that in these rare cases of myocarditis and pericarditis, the vaccine causes a generalized, potent inflammatory response leading to inflammation and damage to the heart tissue.
“These individuals’ immune systems get a little overexcited and produce too many cytokine and cellular responses,” senior study author Carrie Lucas, a professor of immunobiology at Yale, said in a statement.
While the study offers a possible answer to the “how,” it doesn’t answer all the questions, including some why questions, such as why young men? And why the heart? The researchers note that young men, especially in their late teens, are the most common group to develop myocarditis overall, regardless of the cause. Medical experts don’t know why this is the case, but have hypothesized that it is due to a mix of environmental, genetic, and hormones, particularly testosterone. As for why the heart appears to be uniquely damaged, co-author Akiko Iwasaki, also a professor of immunobiology at Yale, speculated that it could be because the heart is constantly working and has limited potential for tissue regeneration, because of which it more sensitive to inflammation.
Finally, it remains unclear what exactly causes the enhanced inflammatory response in the vaccine: the lipid nanoparticles in the vaccines carrying SARS-CoV-2 mRNA or the SARS-CoV-2 mRNA itself. Preliminary evidence suggests that both components may trigger inflammatory responses on their own. The authors hypothesize that the two components may be working together to produce the exaggerated response, but researchers will need more data and research to understand this and further optimize the safety profile of the vaccines.
For now, the finding that there is an inflammatory response behind the cases may aid in treatment and prevention. A Canadian study last year suggested that extending the interval between mRNA vaccine doses may reduce the risk of myocarditis and pericarditis in young men. But the new study may bring some relief if it does occur — self-resolving inflammation is less of a concern than a hard-to-treat autoimmune reaction.
