Immunogenicity and Protection of mRNA Vaccine Encoding Spike Protein of SARS-CoV-2 Omicron-XEC Subvariant

The surface spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key target for the development of Coronavirus Disease 2019 (COVID-19) vaccines. Nevertheless, the mutations in the S protein, particularly in its receptor-binding domain region, have resulted in a reduced or complete loss of immunogenicity and/or protective efficacy in early vaccines against the Omicron variant and subvariants. Accordingly, continuous efforts are required to develop effective vaccines against multiple Omicron subvariants to reduce current and future threats. In this study, we designed an mRNA vaccine targeting the S protein of a recent Omicron-XEC subvariant (XEC-S-mRNA) and assessed its immunogenicity, including its broad neutralizing activity, and its protective efficacy against multiple Omicron subvariants. Our results demonstrated that the lipid nanoparticle-formulated mRNA vaccine formed an appropriate particle size with strong stability and successful antigen expression. It elicited durable cellular immune responses and broad neutralizing antibodies against multiple early and recent Omicron subvariants, thereby cross-protecting transgenic mice from challenge with a heterologous Omicron strain (KP.3). Moreover, the vaccine-induced neutralizing antibodies alone were sufficient to prevent Omicron-KP.3 infection. Overall, this study shows promise for further development of the candidate vaccine against current and future Omicron infections.