mRNA vaccine induces cytotoxic CD8+ T-cell cross-reactivity against SARS-CoV-2 Omicron variant and regulates COVID-19 severity

Understanding the T-cell responses involved in inhibiting COVID-19 severity is crucial for developing new therapeutic and vaccine strategies. Here, we characterized SARS-CoV-2 spike-specific CD8+ T cells interacting with overlapping peptides on peripheral blood mononuclear cells from acute-phase COVID-19 patients. Relative to severe COVID-19, patients with mild COVID-19 had more frequent antigen-specific CD8+ T cells, and significantly increased SARS-CoV-2 spike-specific CD8+ T cells simultaneously expressing granzyme A, granzyme B, and perforin, suggesting that inducing highly cytotoxic CD8+ T cells during early infection suppresses COVID-19 severity. The BNT162b2 mRNA vaccine induced these antigen-specific CD8+ T cells in healthy donors, although lesser than in infected patients, and the induced subpopulation was not maintained long-term after second vaccination. Importantly, these CD8+ T cells showed cross-reactivity with the Delta and Omicron strains of SARS-CoV-2. Incorporating factors that efficiently induce CD8+ T cells with polyfunctional cytotoxic activity may improve future vaccine efficacy against such variants.