Emerging SARS-CoV-2 variants with frequent mutations largely evaded humoral immunity induced by Spike-based COVID-19 vaccines. This study develops an mRNA-based T-cell-inducing antigen targeting conserved SARS-CoV-2 proteome regions enriched in human HLA-I epitopes. Immunization induces potent cellular responses, preventing infection in humanized HLA transgenic mice and showing enhanced efficacy against Beta and Omicron BA.1 variants when combined with RBD-based mRNA in mice and rhesus macaques. The study highlights the importance of stimulating both humoral and cellular responses for effective COVID-19 vaccine design.
