Stanford study links immune proteins to COVID-19 vaccine–related myocarditis, suggesting targeted prevention options

A Stanford-led study, conducted with The Ohio State University, identified two immune proteins, CXCL10 and IFN-gamma, as major drivers of the rare myocarditis observed after mRNA COVID-19 vaccination. The researchers analyzed blood samples from vaccinated people, some with myocarditis and some without, and found that these proteins are released by immune cells and can amplify inflammation. In mouse and human heart tissue models, high levels of these proteins produced signs of heart irritation consistent with mild myocarditis. The team said that blocking these two cytokines could substantially reduce heart damage in the models without shutting down the overall immune response.

Myocarditis after vaccination is rare: about 1 in 140,000 after the first dose and about 1 in 32,000 after the second dose. Among males 30 and younger, the risk rises to roughly 1 in 16,750. Symptoms include chest pain, shortness of breath, fever and palpitations, typically appearing one to three days after vaccination. Elevated levels of cardiac troponin, a marker of heart muscle damage, are also observed.

The study's senior author, Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute, said the findings help explain why myocarditis occurs in rare cases following vaccination. The inflammation is not a heart attack caused by blocked vessels; when symptoms are mild and there is no structural damage, doctors typically monitor patients as they recover. In rare cases, however, severe myocarditis can lead to hospitalization, critical illness or death.

A key implication is that myocarditis from vaccination may be prevented or mitigated by a targeted immune approach. The researchers found that while CXCL10 and IFN-gamma are essential for fighting viruses, excessive activity can push the heart across a damage threshold. Blocking these cytokines in models reduced heart damage without compromising the overall immune response, suggesting a potential path for safer vaccines or adjunct therapies for at-risk individuals.

In additional lab work, the team reported that genistein, a compound found in soybeans with estrogen-like activity, reduced inflammation in the cell and tissue models. This potential approach has not yet been tested in humans and remains experimental.

The findings were published in Science Translational Medicine. The researchers cautioned that the study relied largely on experimental systems, including mice and human cells in the lab, which cannot fully replicate how myocarditis develops in real patients. Clinical studies will be needed to confirm whether targeted treatments are safe and effective.

The study also noted that COVID-19 vaccines have been heavily scrutinized for safety but have an excellent safety record overall. The authors emphasized that COVID-19 infection remains far more likely to cause myocarditis and other complications than vaccination. They concluded that mRNA vaccines remain a crucial tool against COVID-19, and the research should be viewed as a step toward making future vaccines even safer.

Limitations include the preclinical nature of much of the work and the need to test targeted cytokine-blocking approaches in humans. The researchers added that myocarditis risk could vary with other vaccines beyond the COVID-19 vaccines studied. They stressed that the current work does not change public health guidance; people who experience chest pains after vaccination should seek medical evaluation, as troponin elevation would indicate myocarditis.

Funding came from the National Institutes of Health and the Gootter-Jensen Foundation. The study was conducted by Stanford clinicians and The Ohio State University investigators.