Chimeric mRNA based COVID-19 vaccine elicits potent neutralizing antibodies and protection against Omicron and Delta

The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the efficacy and effectiveness of the two FDA-approved mRNA vaccines currently in use. Here, we explored various strategies to develop mRNA vaccines that offer potentially safer and wider coverage of VOCs. We first introduced a furin cleavage mutation into 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), and confirmed the expression and cleavage deficiency of furin mutants. We then assessed the capacity of the resultant mRNAs to induce neutralizing antibodies (nAb) in mice following intramuscular administration. The initial mouse vaccination results showed that the individual VOC mRNAs induced the generation of neutralizing antibody in a VOC-specific manner. Moreover, we discovered that the antibodies produced from mice immunized with Beta-Furin and Washington (WA)-Furin mRNAs cross-reacted with other VOCs. The broad spectrum of generated nAb was further confirmed when vaccinated mice were challenged with the respective live viruses. However, neither WA-Furin nor Beta-Furin mRNA elicited potent neutralizing activity against the omicron variant. Interestingly, in a mix-and-match booster experiment, omicron-Furin and WA-Furin mRNA elicited comparable protection against omicron. Finally, we tested the concept of bivalent vaccine by introducing the RBD of Delta strain into the intact S antigen of Omicron. The chimeric mRNA induces potent and broadly acting nAb against Omicron and Delta, which paves the way to develop vaccine candidate to target emerging variants in the future. ### Competing Interest Statement The authors have declared no competing interest.