LAUSR

Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2. Critically, combining mRNA-N with the clinically proven S-expressing mRNA vaccine (mRNA-S+N) induced robust protection against both Delta and Omicron variants. In the hamster models of SARS-CoV-2 VOC challenge, we demonstrated that, compared to mRNA-S alone, combination mRNA-S+N vaccination not only induced more robust control of the Delta and Omicron variants in the lungs but also provided enhanced protection in the upper respiratory tract. In vivo CD8+ T cell depletion suggested a potential role for CD8+ T cells in protection conferred by mRNA-S+N vaccination. Antigen-specific immune analyses indicated that N-specific immunity, as well as augmented S-specific immunity, was associated with enhanced protection elicited by the combination mRNA vaccination. Our findings suggest that combined mRNA-S+N vaccination is an effective approach for promoting broad protection against SARS-CoV-2 variants. Description An mRNA vaccine encoding the nucleocapsid and spike proteins induces protection against SARS-CoV-2 Omicron and Delta variants in preclinical models. Doubling up on antigens As additional SARS-CoV-2 variants evolve, vaccines that maintain efficacy across these variants become increasingly important. Here, Hajnik et al. tested whether an mRNA vaccine encoding the more conserved nucleocapsid (N) protein of SARS-CoV-2 can elicit responses that protect against SARS-CoV-2 challenge in vivo. mRNA-N vaccination alone elicited immune responses that could control SARS-CoV-2. Furthermore, combining mRNA-N vaccination with an mRNA vaccine encoding the spike protein (mRNA-S+N) induced better viral control than mRNA-S vaccination alone, including against the Omicron variant. Thus, incorporating the N protein into SARS-CoV-2 vaccines may promote protection against existing and future variants.