Rational Design of a Modular mRNA Vaccine Platform for Rapid Adaptation to SARS-CoV-2 Variants

The ongoing emergence of novel SARS-CoV-2 variants due to viral mutations poses a persistent challenge to the efficacy of existing vaccines. To address this challenge, we engineered and comprehensively tested three optimized mRNA vaccine candidates, evaluating the kinetics, quality, and magnitude of antibody responses as well as antigen-specific T cell immunity during a prime-boost vaccination regimen in mice. Among the tested candidates, TP2A encoding secreted receptor-binding domains (RBDs) derived from SARS-CoV-2 wild type, Delta and Omicron variants demonstrated superior immunogenicity, inducing an early and robust IgG2a-dominated antibody response against distinct SARS-CoV-2 spike protein variants. In addition, TP2A elicited IFN-γ-producing T cells in both spleen and draining lymph nodes and antigen-specific cytotoxic T lymphocytes. Notably, beyond the broad immunity induced by the vaccine, TP2A functions as a modular platform, thus enabling flexible antigen assembly and rapid vaccine adaptation to newly emerging variants or even other viral pathogens. These findings position TP2A as a promising next-generation mRNA vaccine candidate.