A SARS-CoV and SARS-CoV-2 RBD Heterodimer Vaccine Candidate.

The continuous evolution of SARS-CoV-2 through accumulating mutations, combined with the persistent risk of zoonotic sarbecovirus transmission events, highlights the critical demand for broadly protective vaccines. Building on our previous findings that a heterodimeric receptor-binding domain (RBD) design substantially improves cross-reactive immunogenicity in vaccine candidates, we propose this strategy as a foundation for developing pan-sarbecovirus vaccines with cross-neutralizing capacity against diverse and emerging variants. In this study, we developed a sarbecovirus immunogen, utilizing a heterodimeric strategy incorporating the RBDs from both SARS-CoV and SARS-CoV-2. Pseudovirus neutralization assays revealed that mice immunized with the SARS-CoV-2 prototype (PT)-SARS-CoV heterodimer (PT-SARS) developed 39.9- to 305.6-fold higher neutralizing antibody (NAb) titers against SARS-CoV-2 sub-variants compared to the SARS-CoV RBD homodimer (SARS-SARS). Furthermore, PT-SARS elicited 17.6- and 31.2-fold enhanced neutralization against WIV1 and SARS-CoV, respectively, relative to the SARS-CoV-2 PT homodimer (PT-PT). To address evolving Omicron sub-variants, we further updated BA.1-SARS and BA.2-SARS immunogens. Notably, BA.2-SARS exhibited a 6.2-fold increase in neutralizing potency against BA.2.86 compared to PT-SARS. Crucially, the heterodimeric immunogen induced balanced and broadly reactive NAbs against multiple sarbecoviruses, including RaTG13, Pangolin GD, SARS-CoV, and SARS-CoV-2 variants/sub-variants, demonstrating its potential as a sarbecovirus immunogen candidate.