Abstract Body (Do not enter title and authors here): Introduction: Although highly effective, mRNA COVID-19 vaccines are associated with rare cases of myocarditis, particularly in young males. The underlying mechanism remains unclear, presenting a critical knowledge gap for improving the safety of current and future mRNA-based technologies such as cancer vaccines and gene therapies.
Hypothesis: Here we hypothesized that an innate hyperinflammatory response, driven by elevated circulating cytokines, is a key mediator of mRNA vaccine-associated myocardial injury.
Approach: We employed a multifaceted approach combining analysis of published human plasma data, in vitro experiments using induced pluripotent stem cell (iPSC)-derived cardiomyocytes and macrophages, human primary T-cells, and 3D cardiac spheroids, and in vivo mouse models of both vaccine- and cytokine-induced cardiac injury.
Results: Analysis of human plasma data identified CXCL10 and IFN-γ as key candidate cytokines. Subsequent in vitro experiments using macrophages and T-cells confirmed that mRNA vaccination significantly increases the release of these two cytokines. We developed a mouse model in which mRNA vaccination induced cardiac injury, marked by elevated serum cardiac Troponin I (cTnI) and increased circulating CXCL10 and IFN-γ. Neutralizing these two cytokines in mice significantly reduced the vaccine-induced cTnI elevation and cardiac immune cell infiltration while largely preserving anti-Spike IgG titers. Direct exposure of human iPSC-derived cardiomyocytes to CXCL10 and IFN-γ in vitro impaired contractility, induced arrhythmogenicity, and activated immunoproteasome pathways. Genistein, an anti-inflammatory phytoestrogen, mitigated these cytokine-induced effects in vitro by blocking immunoproteasome activity. Furthermore, in our in vivo mouse model, oral genistein treatment significantly reduced vaccine-induced cardiac injury markers and attenuated immune cell infiltration into the heart without compromising humoral immunity.
Conclusion: The CXCL10-IFN-γ axis is a critical driver of myocardial injury following mRNA vaccination, acting partly through the direct induction of cardiomyocyte damage via immunoproteasome activation. Genistein represents a promising therapeutic strategy to mitigate this adverse effect without impairing the desired immune response, offering a potential solution to enhance the safety of mRNA vaccines.