Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models
Alexander A. Cohen, Neeltje van Doremalen, Allison J. Greaney, Hanné Andersen, Ankur Sharma, Tyler N. Starr, Jennifer R. Keeffe, Chengcheng Fan, Jonathan E. Schulz, Priyanthi N.P. Gnanapragasam, Leesa M. Kakutani, Anthony P. West, Greg Saturday, Yu E. Lee, Han Gao, Claudia A. Jette, Mark G. Lewis, Tiong Kit Tan, Alain Townsend, Jesse D. Bloom, Vincent J. Munster, Pamela J. Björkman
Abstract
To combat future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles that present randomly arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded rather than variable, immunodominant, and exposed. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD nanoparticles in mice and macaques and observed stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains, including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants, including Omicrons, and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest that mosaic-8 RBD nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.