Abstract
The continued emergence of SARS-CoV-2 variants of concern (VOCs), particularly the highly transmissible Omicron strains, poses a persistent public health threat. The mutations in the SARS-CoV-2 spike (S) proteins reduced efficacy of the first-generation, S-targeting COVID-19 vaccines. We hypothesize that an immunization approach targeting more conserved viral proteins, in addition to the S protein, will elicit cross-reactive immunity and provide broad protection against SARS-CoV-2 VOCs without requiring vaccine adaptation to emerging strains. We have developed a nucleoside-modified mRNA vaccine encapsulated in LNP expressing the nucleocapsid (N) protein of the prototypical SARS-CoV-2 (mRNA-N). We show that combining mRNA-N with the clinically proven mRNA-S vaccine (mRNA-S+N) induces strong respiratory T and B cell responses in the lungs and bronchoalveolar lavage (BAL) as well as antigen-specific binding IgG in BAL and nasal wash (NW) in a mouse model. Induction of respiratory immunity correlates with broad protection of dual mRNA-S+N vaccination against a range of SARS-CoV-2 variants, including Delta, BA.1, BA.5, and BQ.1 in preclinical hamster models. In vivo CD8 T cell depletion suggests a critical role for CD8 T cells in mRNA-S+N vaccine protection. Our findings support that mRNA-S+N is a promising pan-COVID-19 vaccine approach and warrants further clinical development.
