Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition

Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and are a major contributor to neutralizing antibody responses 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 surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies. They further enable the design of escape-resistant antibody cocktails-including cocktails of antibodies that compete for binding to the same RBD surface 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.

Automated summary

Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are key in neutralizing antibody responses, and a deep mutational scanning method was used to assess the impact of all amino-acid mutations in the RBD on antibody binding with 10 human monoclonal antibodies. The study identified the clustered escape mutations in different surfaces of the RBD that correspond to structurally defined antibody epitopes, showing that even antibodies targeting the same surface can have distinct escape mutations.