Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition

TLDR

Antibodies against the SARS‑CoV‑2 spike receptor‑binding domain are key therapeutics and major contributors to neutralization after infection. The study aims to map the effect of every RBD amino‑acid mutation on antibody binding using deep mutational scanning applied to ten human monoclonal antibodies. The authors use deep mutational scanning to assess how each RBD mutation alters binding of these ten antibodies. Escape mutations cluster on distinct RBD surfaces that correspond to antibody epitopes, yet antibodies targeting the same surface often have different escape profiles; the complete escape maps predict mutations selected under antibody pressure and guide the design of escape‑resistant antibody cocktails, enabling rational therapeutic design and evaluation of viral evolution.

Abstract

Abstract 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.