Respiratory syncytial virus (RSV) is a leading cause of severe respiratory illness, imposing a significant burden on global health and society. Here, we report a novel mRNA vaccine that can offer potent and endure protection for RSV. We designed various vaccines based on mRNA that encoded the RSV prefusion F and established an AI screening model for the prediction of expression and immunogenicity of the RSV F protein variants. An optimized candidate sequence was obtained, from empirical structural design pool, through AI-assisted screening and a comprehensive trial screening process in terms of in vitro conformational stability and in vivo neutralizing antibody levels. The resulting mRNA was delivered via YK-009 lipid nanoparticles, which demonstrated robust delivery efficiency. This candidate vaccine (RSV-mF03) produced a more stable prefusion F protein and elicited durable neutralizing antibody titers over 10 times higher than those induced by mRNA-1345 (mRESVIA®). Notably, our vaccine provided complete protection against RSV challenge, with no evidence of vaccine-associated enhanced respiratory disease. Collectively, these findings demonstrate the production of a potent RSV vaccine candidate and the feasibility of integrating AI into RSV vaccine development.
