TY - JOUR T1 - Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes JF - bioRxiv DO - 10.1101/2022.06.28.497989 SP - 2022.06.28.497989 AU - Chengcheng Fan AU - Alexander A. Cohen AU - Miso Park AU - Alfur Fu-Hsin Hung AU - Jennifer R. Keeffe AU - Priyanthi N.P. Gnanapragasam AU - Yu E. Lee AU - Leesa M. Kakutani AU - Ziyan Wu AU - Kathryn E. Malecek AU - John C. Williams AU - Pamela J. Bjorkman Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/06/28/2022.06.28.497989.abstract N2 - Protection from SARS-related coronaviruses with spillover potential and SARS-CoV-2 variants could prevent and/or end pandemics. We show that mice immunized with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicit cross-reactive anti-sarbecovirus antibodies against conserved class 1/4 and class 3 RBD epitopes. Monoclonal antibodies (mAbs) identified from initial screening of <10,000 single B-cells secreting IgGs binding two or more sarbecovirus RBDs showed cross-reactive binding and neutralization of SARS-CoV-2 variants and animal sarbecoviruses. Single-particle cryo-EM structures of antibody–spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes and revealed neutralization mechanisms, potentials for intra-spike trimer crosslinking by single IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticles to identify therapeutic pan-sarbecovirus and pan-variant mAbs and to elicit them by vaccination.Competing Interest StatementP.J.B. and A.A.C. are inventors on a US patent application filed by the California Institute of Technology that covers the mosaic nanoparticles described in this work. P.J.B. and A.A.C. are inventors on a US patent application filed by the California Institute of Technology that covers the methodology to generate cross-reactive antibodies using mosaic nanoparticles. P.J.B., A.A.C., C.F. and J.C.W. are inventors on a US patent application filed by the California Institute of Technology that covers the monoclonal antibodies elicited by vaccination with mosaic-8 RBD-mi3 nanoparticles described in this work. ER -