Bivalent mRNA vaccine booster induces robust antibody immunity against Omicron subvariants BA.2, BA.2.12.1 and BA.5

Abstract As the immune protection conferred by first booster shot wanes over time and new Omicron subvariant emerges with stronger immune evasion, the need for variant-adapted COVID vaccine booster is increasingly imminent. However, the rapid replacement of dominant Omicron subvariants (from BA.1 to BA.2, then BA.2.12.1 and now BA.4/5) poses a great challenge to update COVID vaccine targeting the fast-evolving variants while maintaining potency against existing variants. It is a crucial question to ask which variant-based antigen(s) to use in the next generation COVID vaccine to elicit potent and broad response to past, present, and potential rising variants. Bivalent vaccine candidates have been under active clinical testing such as Modern mRNA-1273.214. In this study, we generate a Delta + BA.2 bivalent mRNA vaccine candidate and tested in animals. We compare the antibody response elicited by ancestral (wild type, WT), Delta, BA.2 spike based monovalent or Delta & BA.2 bivalent mRNA boosters against Omicron BA.2, BA.2.12.1 and BA.4/5 subvariants. In mice pre-immunized with two doses of WT lipid nanoparticle mRNA (LNP-mRNA), all three monovalent and one bivalent boosters elevated Omicron neutralizing antibody titers to various degree. The boosting effect of Delta and BA.2 specific monovalent or bivalent LNP-mRNAs is universally higher than that of WT LNP-mRNA, which modestly increased antibody titer in neutralization assays of Omicron BA.5, BA.2.12.1 and BA.2. The Delta & BA.2 bivalent LNP-mRNA showed better performance of titer boosting than either monovalent counterparts, which is especially evident in neutralization of Omicron BA.4 or BA.5. Interestingly compared to the neutralizing titers of BA.2 and BA.2.12.1 pseudovirus, BA.2 monovalent but not Delta & BA.2 bivalent booster suffered a significant loss of BA.4/5 neutralizing titer, indicative of broader activity of bivalent booster and strong neutralization evasion of Omicron BA.4 or BA.5 even in the BA.2 mRNA vaccinated individuals. These data provide evaluation of WT, Delta, BA.2 monovalent and bivalent boosters antibody potency against Omicron BA.2, BA.2.12.1 and BA.4/5 subvariants.