MERS-CoV RBD-mRNA Presents Better Immunogenicity and Protection than the Spike-mRNA

Pathogenic Middle East respiratory syndrome CoV (MERS-CoV), first identified in Saudi Arabia in 2012, continues to pose a threat to public health. The trimeric spike (S) protein of MERS-CoV binds to the cellular receptor through the receptor-binding domain (RBD) in the S1 subunit to initiate virus entry and infection. Therefore, both the S protein and its RBD are targets for the development of MERS-CoV vaccines. Nevertheless, a direct comparison of the immune efficiency of S- and RBD-based MERS-CoV vaccines has not been made. Here, we compared two mRNA vaccines, respectively, targeting the S (S-mRNA) and RBD (RBD-mRNA) of MERS-CoV for their durable immunogenicity, neutralizing activity, and protective efficacy in a mouse model. Both mRNAs encapsulated with lipid nanoparticles (LNPs) maintained strong stability at various temperatures during the detection period. LNP-encapsulated RBD-mRNA elicited significantly higher and more durable antibodies than LNP-encapsulated S-mRNA, maintaining stronger and broadly neutralizing activity against the MERS-CoV original strain, as well as multiple variants containing key mutations within the RBD region. Importantly, RBD-mRNA provided durable protective efficacy against MERS-CoV infection in middle-aged mice, and this protection was associated positively with serum neutralizing antibody titers. Overall, this study identifies RBD-mRNA as an effective vaccine against MERS-CoV, with great potential for further development.