Broad protection and respiratory immunity of dual mRNA vaccination against SARS-CoV-2 variants

A broadly protective vaccine for COVID-19 is needed to end the pandemic and to prevent its future recurrence. While the first-generation, spike-based vaccines are effective against early SARS-CoV-2 strains, the convergent evolution of the new Omicron variants with rapid spike mutations have substantively reduced vaccine efficacy. Another important question is whether intramuscular immunization, especially with mRNA vaccines, elicits effective respiratory immunity. Our group has developed a nucleoside-modified mRNA vaccine expressing nucleocapsid (N) protein of ancestral SARS-CoV-2 virus and tested its use in combination with spike mRNA vaccine (mRNA-S). In this study, we examined efficacy of mRNA-N alone or in combination with mRNA-S (mRNA-S+N) against newer Omicron variants in hamsters. Our study shows that mRNA-N alone induces a modest, but significant protection against both Omicron BA.5 and BQ.1, and that dual mRNA-S+N vaccination confers complete protection against both variants, preventing detection of virus in the hamster lungs. Further analysis of respiratory immune response in mice shows that intramuscular immunization with the dual mRNA-S+N vaccine induces strong respiratory antigen-specific T cell responses in the lungs and in bronchoalveolar lavage (BAL), as well as antigen-specific binding IgG in BAL. Together, our data support mRNA-S+N as a potential pan-COVID-19 vaccine for broad protection against current and emerging SARS-CoV-2 variants. A broadly protective vaccine for COVID-19 is needed to end the pandemic and to prevent its future recurrence. While the first-generation, spike-based vaccines are effective against early SARS-CoV-2 strains, the convergent evolution of the new Omicron variants with rapid spike mutations have substantively reduced vaccine efficacy. Another important question is whether intramuscular immunization, especially with mRNA vaccines, elicits effective respiratory immunity. Our group has developed a nucleoside-modified mRNA vaccine expressing nucleocapsid (N) protein of ancestral SARS-CoV-2 virus and tested its use in combination with spike mRNA vaccine (mRNA-S). In this study, we examined efficacy of mRNA-N alone or in combination with mRNA-S (mRNA-S+N) against newer Omicron variants in hamsters. Our study shows that mRNA-N alone induces a modest, but significant protection against both Omicron BA.5 and BQ.1, and that dual mRNA-S+N vaccination confers complete protection against both variants, preventing detection of virus in the hamster lungs. Further analysis of respiratory immune response in mice shows that intramuscular immunization with the dual mRNA-S+N vaccine induces strong respiratory antigen-specific T cell responses in the lungs and in bronchoalveolar lavage (BAL), as well as antigen-specific binding IgG in BAL. Together, our data support mRNA-S+N as a potential pan-COVID-19 vaccine for broad protection against current and emerging SARS-CoV-2 variants.