mRNA vaccines, the origin of inflammation identified

The myocarditis associated with mRN vaccinesA against the COVID-19while representing a rare event, has raised fundamental scientific questions about immune mechanisms that can occasionally damage heart tissue. A group of researchers at Stanford Medicine has now identified the biological cascade responsible for this adverse reactionwhile identifying a preventive strategy based on a natural compound derived from soy. The study, published in the journal Science Translational Medicine on December 10, sheds light on a phenomenon that predominantly affects young males and represents an important step towards the personalization of vaccination strategies.

The team led by Joseph Wu, director of the Stanford Cardiovascular Institute, and Masataka Nishiga, now at the Ohio State University, analyzed blood samples from vaccinated individuals, comparing those who had developed myocarditis with those who had not shown any cardiac reaction. The investigation revealed a two-stage immune process: i macrophagescells of the first line of defense, react to the vaccine by releasing high quantities of CXCL10a cytokine that acts as an alarm signal. This molecule in turn stimulates the T lymphocyteswhich respond by producing massive quantities of interferon gamma (IFN-gamma)another cytokine with potent inflammatory effects.

Experimentation conducted on human cell cultures demonstrated that this biological sequence does not occur when T cells are directly exposed to the vaccine, confirming the crucial role of macrophages as intermediaries. The epidemiological data highlights that post-vaccination myocarditis occurs in approximately one case every 140,000 people after the first dosewith an incidence rising to one in 32,000 after the second administration. In males under thirty, the frequency reaches one case for every 16,750 vaccinated, making this demographic particularly vulnerable.

To understand the direct effects of these cytokines on the heart, researchers used mouse models and sophisticated three-dimensional systems of human cardiac tissue developed in the laboratory. These “cardiac spheroids“, obtained by converting skin or blood cells into pluripotent stem cells which are then differentiated into cardiomyocytes, endothelial cells and immune cells, form pulsating aggregates that mimic cardiac function. Exposure to CXCL10 and IFN-gamma resulted in a significant increase in cardiac troponina specific biomarker of myocardial damage, while the infiltration of neutrophils and macrophages into cardiac tissue replicated what was observed in patients with myocarditis.

The most promising aspect of the research concerns the genisteinan isoflavone abundant in soy that Wu’s group had previously studied for its anti-inflammatory properties in the context of cannabis-induced vascular damage. When cells, cardiac spheroids, and mice were pretreated with genistein before vaccination, myocardial damage was significantly reduced. In human cardiac tissue models, contractile function and beating rhythm, impaired by exposure to cytokines, were restored by the action of the compound. Genistein, characterized by limited intestinal absorption and therefore a high safety profile, has demonstrated effectiveness even when administered orally to mice in high quantities.

Wu strongly emphasized that these results should not obscure the extremely favorable risk-benefit balance of mRNA vaccines. “COVID-19 infection causes myocarditis with a frequency of approximately ten times higher compared to vaccination, in addition to all the other risks associated with the disease“, specified the researcher. Most cases of post-vaccination myocarditis resolve spontaneously without leaving permanent damage, and cardiac function is preserved or completely recovered. Unlike classic myocardial infarction, no occlusion of the coronary vessels occurs, and when the symptoms are mild the therapeutic approach is essentially observational.

The research opens up broader questions about the inflammatory response induced by mRNA vaccines, which could extend beyond heart tissue. The researchers observed preliminary evidence of similar effects on the lungs, liver and kidneys, suggesting that genistein may have a systemic protective action. Interferon gamma, while essential for defense against foreign genetic material including viruses, becomes toxic when present in high concentrations, causing degradation of cardiac muscle proteins and myocarditis-like symptoms. The phenomenon is not exclusive to COVID vaccines: other vaccine formulations can cause myocarditis, but intense public and media surveillance of mRNA vaccines has led to more frequent and timely diagnosis.