Broadly Protective Antibody-Like Vaccines Against Highly Pathogenic Coronaviruses

SARS-CoV-2 and MERS-CoV are highly pathogenic and contagious coronaviruses. Despite intensive vaccination, SARS-CoV-2 continues to spread, and no FDA-approved vaccines exist for MERS-CoV; thus, more effective and safer vaccine options are needed. The receptor-binding domain (RBD) of coronaviruses is a primary target of neutralizing antibodies (nAbs); therefore, we generated three bivalent IgG1 Fc-fusion vaccines (BiVaxs) combining SARS-CoV-2 and MERS-CoV RBDs. The BiVax_Fc-Native vaccine comprises ^{omicron's-RBD}SARS-CoV-2 fused to the native Fc C-terminus and ^RBDMERS-CoV to the N-terminus. The BiVax_Fc-Reverse vaccine has a native Fc, yet ^RBDMERS-CoV was fused to the C-terminus, and the ^{omicron's-RBD}SARS-CoV-2 to the N-terminus. The third was BiVax_Fc-FcRn, which is similar to BiVax_Fc-Native, although it contains MST-HN Fc mutations (M252Y/S254T/T256E-H433K/N434F) to enhance neonatal Fc receptor (FcRn) binding on antigen-presenting cells (APCs). In mice, BiVax_Fc-FcRn showed significantly higher immunogenicity than the other two forms. It induced robust IgG and nAb responses against ^RBDMERS-CoV after two doses and moderate responses ^{omicron's-RBD}SARS-CoV-2 after the third dose. Remarkably, it also generated strong cross-reactive antibodies against SARS-CoV-1. These findings suggest that ^RBDMERS-CoV is more immunogenic than ^{omicron's-RBD}SARS-CoV-2, and that BiVax_Fc-FcRn has a high potential for further development as a broad-spectrum vaccine platform to prevent infection with the targeted coronaviruses as well as future emerging viruses.