Inhibition of CXCL10 and IFN-? ameliorates myocarditis in preclinical models of SARS-CoV- 2 mRNA vaccination

The mRNA vaccines against COVID-19 are highly effective yet associated with rare myocarditis cases, particularly in young males post-second dose. Here we explore the mediators of this adverse effect and its potential solutions, aiming to enhance the safety of future mRNA vaccines. Analysis of post-vaccination plasma highlighted a substantial increase in CXCL10 and IFN-? levels in patients. Correspondingly, human iPSC-derived macrophages exposed to COVID-19 mRNA vaccines exhibited increased production of these two cytokines. iPSC-derived cardiomyocytes subjected to these cytokines exhibited impaired contractility, arrhythmogenicity, and myocarditis-like gene expression patterns. Genistein, an anti-inflammatory phytoestrogen, notably mitigated these effects, reducing cytokine-induced proteasomal degradation of cardiac proteins and preserving contractile function. In vivo, genistein significantly decreased cardiac injury markers and immune cell infiltration in a mouse model of cytokine-induced myocarditis. These findings underscore CXCL10 and IFN-? as key mediators of myocarditis post-mRNA vaccination and propose genistein as a potential therapeutic to mitigate associated cardiovascular risks. Overall design: (1) For human macrophage samples: human induced pluripotent stem cell-derived macrophages were treated either eitehr BNT162b2 (Pfizer), or mRNA-1273 (Moderna) COVID19 mRNA vaccine. Cells treated with PBS were included as control. were collected 24 hours after treatment and sent for bulk RNA-seq. (2) For human cardiomyocyte samples: human induced pluripotent stem cell-derived cardiomyocytes were treated with a cytokine cocktail of CXCL10 and IFN-?. Two treatment conditions were tested: a “low” concentration (1 ng/mL of CXCL10 and 0.5 ng/mL of IFN-?) and a “high” concentration (10 ng/mL CXCL10 and 5 ng/mL IFN-?). cells treated with PBS were included as control. Cells were collected 48 hours after treatment and sent for bulk RNA-seq.