Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models

• Published in: Science (American Association for the Advancement of Science) Vol. 377; no. 6606; p. eabq0839
• Main Authors: Cohen, Alexander A., van Doremalen, Neeltje, Greaney, Allison J., Andersen, Hanne, Sharma, Ankur, Starr, Tyler N., Keeffe, Jennifer R., Fan, Chengcheng, Schulz, Jonathan E., Gnanapragasam, Priyanthi N. P., Kakutani, Leesa M., West, Anthony P., Saturday, Greg, Lee, Yu E., Gao, Han, Jette, Claudia A., Lewis, Mark G., Tan, Tiong K., Townsend, Alain R., Bloom, Jesse D., Munster, Vincent J., Bjorkman, Pamela J.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 05.08.2022; American Association for the Advancement of Science
• Subjects: Animal models; Animals; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antisera; Avidity; Betacoronavirus - immunology; Binding; Coronavirus Infections - prevention & control; Coronaviruses; COVID-19; COVID-19 vaccines; Disease Models, Animal; Domains; Epitope mapping; Epitopes - chemistry; Epitopes - immunology; Epitopes - therapeutic use; Global health; Immunization; Immunodominance; Immunology; Lymphocytes B; Macaca; Mice; Microbio; Monoclonal antibodies; Mosaics; Nanoparticles; Nanoparticles - therapeutic use; Neutralization; Pandemics; Protein Domains - immunology; Public health; Receptors; Respiratory diseases; Sarbecovirus; SARS-CoV-2 - immunology; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - immunology; Trimers; Vaccines; Viral diseases; Zoonoses - prevention & control; Zoonoses - virology
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abq0839

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. The COVID-19 pandemic has been ongoing for more than 2 years now, and new variants such as Omicron are less susceptible to the vaccines developed against earlier lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, there is continued risk of spillovers of other animal sarbecoviruses into humans. There is thus a need for vaccines that will give broader protection. Cohen et al . developed mosaic nanoparticles that display the receptor-binding domains (RBDs) from SARS-CoV-2 and seven other animal sarbecoviruses. Mosaic nanoparticles protected against both SARS-CoV-2 and SARS-CoV challenges in animal models even though the SARS-CoV RBD was not present on the mosaic-8 RBD nanoparticles. By contrast, a homotypic SARS-CoV-2 RBD nanoparticle (presenting only SARS-CoV-2 RBDs) only protected against a SARS-CoV-2 challenge. —VV A mosaic sarbecovirus nanoparticle protects against SARS-2 and SARS-1, whereas a SARS-2 nanoparticle only protects against SARS-2.