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

Allison J Greaney,Daniel Poston,Marina Caskey,Fabian Schmidt,Alice Cho,Christopher O Barnes,Yiska Weisblum,Michel C Nussenzweig,Marianna Agudelo,Theodora Hatziioannou,Jesse D Bloom,Frauke Muecksch,Pamela J Bjorkman,Christian Gaebler,Tyler N Starr,Davide F Robbiani,Shlomo Finkin,Paul D Bieniasz,Zijun Wang

doi:10.1038/s41467-021-24435-8

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.

Highlights

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
We suggest that the skewing of the receptor-binding domain (RBD)-targeting polyclonal response toward a single antibody class is a factor in enabling a small number of viral mutations to sometimes substantially erode neutralizing antibody immunity
Antibodies targeting the RBD have been divided into four major classes based on structural analyses of their epitopes; two with epitopes overlapping with the ACE2-binding site, potent neutralizers that do not directly bind to the ACE2 contact surface, and antibodies that target a cryptic epitope outside of the receptor-binding motif and are generally less potent[25]

Summary

Introduction

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. We comprehensively map RBD mutations that reduce binding by structurally characterized representatives of three classes of neutralizing monoclonal antibodies that target the RBD’s receptor-binding motif, as well as polyclonal plasmas from convalescent individuals from whom some of the antibodies were isolated[21,25,28,29]. We make these measurements by using a deep mutational scanning approach to systematically map how all RBD amino-acid mutations affect binding to yeast-displayed RBDs30 The resulting escape maps allow us to systematically compare how RBD mutations affect binding by the monoclonal antibodies, and we find that the antibodies cluster in the space of viral escape in a way that largely recapitulates prior classifications based on structural analyses of the antibody epitopes. We suggest that the skewing of the RBD-targeting polyclonal response toward a single antibody class is a factor in enabling a small number of viral mutations to sometimes substantially erode neutralizing antibody immunity

Methods

Results

Conclusion