Broad sarbecovirus neutralizing antibodies define a key site of vulnerability on the SARS-CoV-2 spike protein

Wec, Anna Z.; Wrapp, Daniel; Herbert, Andrew S.; Maurer, Daniel; Haslwanter, Denise; Sakharkar, Mrunal; Jangra, Rohit K.; Dieterle, M. Eugenia; Lilov, Asparouh; Huang, Deli; Tse, Longping V.; Johnson, Nicole V.; Hsieh, Ching-Lin; Wang, Nianshuang; Nett, Juergen H.; Champney, Elizabeth; Burnina, Irina; Brown, Michael; Lin, Shu; Sinclair, Melanie; Johnson, Carl; Pudi, Sarat; Bortz, Robert; Wirchnianski, Ariel S.; Laudermilch, Ethan; Florez, Catalina; Fels, J. Maximilian; O’Brien, Cecilia M.; Graham, Barney S.; Nemazee, David; Burton, Dennis R.; Baric, Ralph S.; Voss, James E.; Chandran, Kartik; Dye, John M.; McLellan, Jason S.; Walker, Laura M.

Broadly protective vaccines against known and pre-emergent coronaviruses are urgently needed. Critical to their development is a deeper understanding of cross-neutralizing antibody responses induced by natural human coronavirus (HCoV) infections. Here, we mined the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a new target for the rational design of pan-sarbecovirus vaccines.