Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies

TLDR

Monoclonal antibodies against diverse SARS‑CoV‑2 RBD epitopes have been isolated from recovered patients, yet how these antibody classes contribute to the overall polyclonal response remains unclear. This study maps every RBD mutation that allows escape from three potent neutralizing antibody classes using a yeast‑display system. The yeast‑display escape maps are compared to analogous maps derived from convalescent plasma, including plasma from donors of the isolated antibodies. Polyclonal plasma antibody binding is disrupted by mutations across multiple RBD epitopes, but the escape pattern most closely resembles that of a single antibody class targeting the E484‑containing epitope, showing that the immune response is skewed toward this rapidly evolving site.

Abstract

Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.