A promising mRNA vaccine derived from the JN.1 spike protein confers protective immunity against multiple emerged Omicron variants.

Despite the declared end of the COVID-19 pandemic, SARS-CoV-2 continues to evolve, with emerging JN.1-derived subvariants (e.g., KP.2, KP.3) compromising the efficacy of current XBB.1.5-based vaccines. To address this, we developed an mRNA vaccine encoding the full-length spike protein of JN.1, incorporating GSAS and 2P mutations and encapsulated in lipid nanoparticles (LNPs). The JN.1-mRNA vaccine elicited robust humoral and cellular immune responses in mice, including high JN.1-specific IgG titers, cross-neutralizing antibodies, and increased T follicular helper (Tfh) cells, germinal center (GC) B cells, and T cell cytokines. Importantly, immunity persisted for up to six months and induced RBD-specific long-lived plasma cells. We also compared the immune responses induced by homologous and heterologous vaccination regimens, and our results demonstrated that the heterologous regimen-combining JN.1-mRNA with a recombinant protein vaccine (RBDJN.1-HR)-induced stronger responses. These findings highlight the JN.1-mRNA vaccine constitutes an effective prophylactic approach against JN.1-related variants, as it induces potent neutralizing antibody responses across all tested lineages. This enhanced immunogenicity is expected to significantly reduce hospitalization rates and mitigate post-COVID complications associated with JN.1 and KP.3 infections. This study emphasizes the need for timely vaccine updates and the adaptability of mRNA vaccines in addressing emerging pathogens, providing a framework for combating future infectious diseases. Collectively, these results offer critical insights for vaccine design and public health strategies in response to emerging SARS-CoV-2 variants.