Landscape of human antibody recognition of the SARS-CoV-2 Receptor Binding Domain

Wheatley, Adam K.; Pymm, Phillip; Esterbauer, Robyn; Dietrich, Melanie H.; Lee, Wen Shi; Drew, Damien; Kelly, Hannah G.; Chan, Li-Jin; Mordant, Francesca L.; Black, Katrina A.; Adair, Amy; Tan, Hyon-Xhi; Juno, Jennifer A.; Wragg, Kathleen M.; Amarasena, Thakshila; Lopez, Ester; Selva, Kevin J.; Haycroft, Ebene R.; Cooney, James P.; Venugopal, Hariprasad; Tan, Li Lynn; O’ Neill, Matthew T.; Allison, Cody C.; Cromer, Deborah; Davenport, Miles P.; Bowen, Richard A.; Chung, Amy W.; Pellegrini, Marc; Liddament, Mark T.; Glukhova, Alisa; Subbarao, Kanta; Kent, Stephen J.; Tham, Wai-Hong

Potent neutralising monoclonal antibodies are one of the few agents currently available to treat COVID-19. SARS-CoV-2 variants of concern (VOC) that carry multiple mutations in the viral spike protein can exhibit neutralisation resistance, potentially impacting the effectiveness of some antibody-based therapeutics. Here, generation of a diverse panel of 91 human neutralising monoclonal antibodies provides an in-depth structural and phenotypic definition of receptor binding domain (RBD) antigenic sites on the viral spike. These RBD antibodies ameliorate SARS-CoV-2 infection in mice and hamster models in a dose-dependent manner and in proportion to in vitro neutralising potency. Assessing the impact of mutations in the spike protein on antibody recognition and neutralisation highlights both potent single antibodies and stereotypic classes of antibodies that are unaffected by currently circulating VOC such as B.1.351 and P.1. These neutralizing monoclonal antibodies, and others that bind analogous epitopes, represent potentially useful future anti-SARS-CoV-2 therapeutics.