Science ( IF 41.845 ) Pub Date : 2020-11-20 , DOI: 10.1126/science.abe3354 M Alejandra Tortorici,Martina Beltramello,Florian A Lempp,Dora Pinto,Ha V Dang,Laura E Rosen,Matthew McCallum,John Bowen,Andrea Minola,Stefano Jaconi,Fabrizia Zatta,Anna De Marco,Barbara Guarino,Siro Bianchi,Elvin J Lauron,Heather Tucker,Jiayi Zhou,Alessia Peter,Colin Havenar-Daughton,Jason A Wojcechowskyj,James Brett Case,Rita E Chen,Hannah Kaiser,Martin Montiel-Ruiz,Marcel Meury,Nadine Czudnochowski,Roberto Spreafico,Josh Dillen,Cindy Ng,Nicole Sprugasci,Katja Culap,Fabio Benigni,Rana Abdelnabi,Shi-Yan Caroline Foo,Michael A Schmid,Elisabetta Cameroni,Agostino Riva,Arianna Gabrieli,Massimo Galli,Matteo S Pizzuto,Johan Neyts,Michael S Diamond,Herbert W Virgin,Gyorgy Snell,Davide Corti,Katja Fink,David Veesler
Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo–electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.