PT  - JOURNAL ARTICLE
AU  - Allison J. Greaney
AU  - Tyler N. Starr
AU  - Pavlo Gilchuk
AU  - Seth J. Zost
AU  - Elad Binshtein
AU  - Andrea N. Loes
AU  - Sarah K. Hilton
AU  - John Huddleston
AU  - Rachel Eguia
AU  - Katharine H.D. Crawford
AU  - Adam S. Dingens
AU  - Rachel S. Nargi
AU  - Rachel E. Sutton
AU  - Naveenchandra Suryadevara
AU  - Paul W. Rothlauf
AU  - Zhuoming Liu
AU  - Sean P.J. Whelan
AU  - Robert H. Carnahan
AU  - James E. Crowe, Jr.
AU  - Jesse D. Bloom
TI  - Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition
AID  - 10.1101/2020.09.10.292078
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.10.292078
4099  - http://biorxiv.org/content/early/2020/09/28/2020.09.10.292078.short
4100  - http://biorxiv.org/content/early/2020/09/28/2020.09.10.292078.full
AB  - Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and make a major contribution to the neutralizing antibody response elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding, and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same RBD surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies, and enable us to design escape-resistant antibody cocktails–including cocktails of antibodies that compete for binding to the same surface of the RBD but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution.Competing Interest StatementJ.E.C. has served as a consultant for Sanofi; is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines; is a recipient of previous unrelated research grants from Moderna and Sanofi; and is a founder of IDBiologics. Vanderbilt University has applied for patents concerning SARS-CoV-2 antibodies analyzed in this work. S.P.J.W. and P.W.R. have filed a disclosure with Washington University for the recombinant VSV. The other authors declare no competing interests.