Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals
Alexander A. Cohen, Jennifer R. Keeffe, Ariën Schiepers, Sandra Dross, Allison J. Greaney, Annie V. Rorick, Han Gao, Priyanthi N.P. Gnanapragasam, Chengcheng Fan, Anthony P. West, Arlene I. Ramsingh, Jesse H. Erasmus, Janice D. Pata, Hiromi Muramatsu, Norbert Pardi, Paulo J.C. Lin, Scott Baxter, Rita Cruz, Martina Quintanar‐Audelo, Ellis Robb, Cristina Serrano-Amatriain, Leonardo Magneschi, Ian Fotheringham, Deborah H. Fuller, Gabriel D. Victora, Pamela J. Björkman
Abstract
Immunization with mosaic-8b (nanoparticles presenting 8 SARS-like betacoronavirus [sarbecovirus] receptor-binding domains [RBDs]) elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated the effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding the greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate mapping, in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19-vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.