Chimeric mRNA-based COVID-19 vaccine induces protective immunity Omicron and Delta variants

The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the effec-tiveness of currently approved mRNA vaccines. To achieve wider coverage of VOCs, we first constructed a cohort of mRNAs harboring a furin cleavage mutation in the spike (S) protein of predominant VOCs, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). The muta-tion abolished the cleavage between the S1 and S2 subunits. Systematic evaluation in vaccinated mice discovered that indi-vidual VOC mRNAs elicited strong neutralizing activity in a VOC-specific manner. In particular, the neutralizing anti-bodies (nAb) produced by immunization with Beta-Furin and Washington (WA)-Furin mRNAs showed potent cross -reactivity with other VOCs. However, neither mRNA elicited strong neutralizing activity against the Omicron variant. Hence, we further developed an Omicron-specific mRNA vac-cine that restored protection against the original Omicron variant and some sublineages. Finally, to broaden the protec-tion spectrum of the new Omicron mRNA vaccine, we engi-neered an mRNA-based chimeric immunogen by introducing the receptor-binding domain of Delta variant into the entire S antigen of Omicron. The resultant chimeric mRNA induced potent and broadly nAbs against Omicron and Delta, which paves the way to developing new vaccine candidates to target emerging variants in the future.