Stanford-led study explains why rare COVID vaccine myocarditis occurs, offers paths to prevention

A Stanford-led study published in Science Translational Medicine provides new insight into why myocarditis, an inflammation of the heart, can occur after mRNA COVID-19 vaccination. The researchers identified a subset of immune signals that appear to drive the rare condition, particularly among younger men. In vaccine recipients, myocarditis occurs in about 1 in 140,000 after the first dose and about 1 in 32,000 after the second dose; for males 30 and younger, the risk rises to about 1 in 16,750. Symptoms typically appear within one to three days and include chest pain, shortness of breath, fever and palpitations.

Using blood samples from vaccinated people—some with myocarditis, some without—the team found two proteins, CXCL10 and IFN-gamma, released by immune cells that can amplify inflammation. 'We think these two are the major drivers of myocarditis,' said study author Joseph Wu, MD, PhD. 'Your body needs these cytokines to ward off viruses. It’s essential to immune response, but can become toxic in large amounts.' In mouse and heart tissue models, high levels of these proteins produced signs of heart irritation similar to mild myocarditis.

Perhaps the most actionable finding was that blocking CXCL10 and IFN-gamma in the models reduced heart damage without shutting down the overall vaccine-induced immune response, suggesting a targeted approach to preventing or treating myocarditis in high-risk individuals. 'One of the most striking findings was how much we could reduce heart damage in our models by specifically blocking these two cytokines, without shutting down the entire (desired) immune response to the vaccine,' Wu said. 'This points to a possible future way to prevent or treat myocarditis in people who are at the highest risk, while keeping the benefits of vaccination,' he added.

Another potential avenue noted in the study is genistein, a soy-derived compound with estrogen-like activity, which reduced inflammation in lab tests though it has not been tested in humans. The researchers caution that the data come from mice and human cells in the lab, not clinical trials, and that more work is needed to determine safety and efficacy in people before any new prevention or treatment is pursued.

Despite the rare risk, vaccine safety remains a central public-health frame. Researchers emphasize that the benefits of COVID-19 vaccination continue to outweigh the small risk of myocarditis for nearly all groups, and that infection with the virus itself is a far greater risk. Wu noted that COVID-19 infection is about 10 times more likely to cause myocarditis than mRNA vaccines, underscoring the value of vaccination as a protective measure.

The study's limitations include its reliance on experimental systems—mouse models and human cells in lab settings—that cannot fully replicate myocarditis development in patients. The researchers said clinical studies will be needed to confirm whether targeted therapies are safe and effective in people, and to assess any effects on the broader immune response.

Funding for the work came from the National Institutes of Health and the Gootter-Jensen Foundation, and the research was conducted in collaboration with The Ohio State University. The findings were published in Science Translational Medicine, reflecting ongoing interest in understanding rare adverse events and how to mitigate them without diminishing vaccine benefits.

Experts urged that the results should not deter vaccination. 'mRNA vaccines remain a crucial tool against COVID‑19, and this research helps explain a rare side effect and suggests ways to make future vaccines even safer,' Wu said. 'The overall benefits of vaccination still clearly outweigh the small risk of myocarditis for nearly all groups.'