A bivalent COVID-19 mRNA vaccine, PTX-COVID19-M1.2, elicited broad immune responses and protected animals from SARS-CoV-2 Omicron subvariants infection

The continuous emergence of SARS-CoV-2 Omicron subvariants poses a serious threat thwarting the effectiveness of currently approved COVID-19 vaccines, demanding a vaccine that can provide broad protection against these subvariants. Although bivalent vaccines containing Omicron subvariant spikes have been shown to elicit high neutralizing antibodies (nAbs) and afford protection against homologous or antigenically close Omicron subvariants, the breadth and degree of the protection provided by the bivalent vaccines against antigenically distant Omicron subvariants is unclear. Here, we report the immunogenicity and efficacy of a bivalent mRNA vaccine, PTX-COVID19-M1.2 (M1.2), which encodes native spike proteins from Wuhan-Hu-1 (D614G) and Omicron BA.2.12.1, in mouse and hamster models. Both primary series and booster vaccination using M1.2 elicited potent and broad nAbs against Wuhan-Hu-1 (D614G) and Omicron subvariants, including BA.1, BA.2, BA.2.12.1, and BA.4/BA.5. Strong spike-specific T cell responses against Wuhan-Hu-1 and Omicron subvariants were also induced. In contrast, monovalent BA.2.12.1 spike-based mRNA vaccine elicited potent but narrower immune responses. Vaccination with M1.2 protected animals from Wuhan-Hu-1 and BA.1, BA.2, BA.5, and XBB.1.5 challenges. Interestingly, protection against XBB.1.5 lung infection did not correlate with nAb levels. These results indicate that M1.2 can generate a broadly protective immune response against multiple Omicron subvariants, including antigenically distant subvariants, and spike-specific T cells probably contribute to the breadth of the protection. Our findings have potential implications for designing COVID-19 booster vaccination strategies.