A designed overlapping variant immunogen pool elicits broad sarbecovirus neutralization

A central problem in achieving vaccine-based protection against viral infections is eliciting antibodies that are resilient to viral variation. Successive waves of SARS-CoV-2 infection during the COVID19 pandemic were driven by variants that acquired resistance to neutralizing antibodies elicited by prior SARS-CoV-2 variants. To the extent that serum neutralization breadth occurs in individuals with multiple exposures to SARS-CoV-2 antigens, we and others find that it is largely comprised of antibodies that target the variable receptor binding domain (RBD), rather than more conserved spike protein domains. By designing synthetic dimeric RBD immunogens we show that limiting divergence in heterodimeric components favors the generation of cross-reactive B cells and antibodies. We thus devised a vaccine approach based on a two-dose immunization with a pool of five overlapping heterodimeric synthetic RBD variants. Collectively, the RBD heterodimer pool was designed to cover 10% sequence variation and elicited greater antibody cross-reactivity and neutralization breadth than homodimers or heterodimers with highly divergent components. Using an unconventional prospective challenge model in mice, we demonstrate the effectiveness of the RBD heterodimer pool in inducing antibody responses that attenuate infection by future SARS-CoV-2 variants, as well as protection in a challenge model based on a chimeric vesicular stomatitis virus bearing a spike protein from SARS-CoV-1. Significance statementViral antigenic escape undermines both vaccination efforts and the development of herd immunity, resulting in an enormous viral disease burden. A central problem in eliciting vaccine-based protection against some viral infections is achieving antibody neutralization breadth. To elicit collections of antibodies that overcome the problem of limited antibody tolerance of viral variation, we designed a novel strategy based on an overlapping series of immunogens. This immunogen pool conferred at least partial protection against subsequently prevalent SARS-CoV-2 variants as well as a chimeric SARS-CoV-1 based model virus.