Antibodies to the SARS-CoV-2 receptor-binding domain that maximize breadth and resistance to viral escape

Abstract

An ideal anti-SARS-CoV-2 antibody would resist viral escape, have activity against diverse SARS-related coronaviruses, and be highly protective through viral neutralization and effector functions. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD), including S309, the parental antibody of the late-stage clinical antibody VIR-7831. We observe a tradeoff between SARS-CoV-2 in vitro neutralization potency and breadth of binding across SARS-related coronaviruses. Nevertheless, we identify several neutralizing antibodies with exceptional breadth and resistance to escape, including a new antibody (S2H97) that binds with high affinity to all SARS-related coronavirus clades via a unique RBD epitope centered on residue E516. S2H97 and other escape-resistant antibodies have high binding affinity and target functionally constrained RBD residues. We find that antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency, but we identify one potent RBM antibody (S2E12) with breadth across sarbecoviruses closely related to SARS-CoV-2 and with a high barrier to viral escape. These data highlight functional diversity among antibodies targeting the RBD and identify epitopes and features to prioritize for antibody and vaccine development against the current and potential future pandemics.

Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design

“…RBD-based immunogens in various oligomeric states have been investigated as genetic or protein-based vaccines for SARS-CoV-2, including monomers (27)(28)(29)(30)(31), dimers (32), trimers (33)(34)(35) and highly multivalent nanoparticles (25,(36)(37)(38)(39), several of which are now being evaluated in clinical trials. Although the RBD comprises only a minority of the total mass and antigenic surface of S and could in principle be more susceptible to escape mutations, this theoretical disadvantage may be mitigated by both functional constraints and the elicitation of antibodies targeting multiple distinct neutralizing epitopes in the RBD by infection or vaccination (25,(40)(41)(42)(43). Indeed, the vast majority of neutralizing activity elicited by SARS-CoV-2 infection and currently approved S-based vaccines targets the RBD (40,(44)(45)(46)(47)(48), as do most clinical-stage monoclonal antibodies (49).…”

Broad cross-reactivity across sarbecoviruses exhibited by a subset of COVID-19 donor-derived neutralizing antibodies

“…Indeed, S309, a class 3 anti-RBD antibody isolated from a SARS-CoV-infected donor, demonstrated cross-reactive neutralization of SARS-CoV-2 (Pinto et al, 2020). Furthermore, reports of class 4 human antibodies that exhibit cross-reactive binding and neutralization amongst sarbecoviruses Starr et al, 2021a;Tortorici et al, 2021) suggest that further investigation of antibodies from COVID-19 convalescent donors could lead to discoveries of potent and broadly cross-reactive class 4 antibodies that recognize the highly-conserved, 'cryptic' RBD epitope.…”

Keep out! SARS-CoV-2 entry inhibitors: their role and utility as COVID-19 therapeutics

“…Starr et al discovered antibodies that target conserved, functionally constrained RBD residues. One of these, S2H97, showed high affinity and neutralization breadth across SARS-CoV-2-related sarbecoviruses [80]. An accompanying study showed that S2X259, which binds to a highly conserved cryptic RBD epitope, crossneutralized all the VOCs and a wide spectrum of human and zoonotic sarbecoviruses.…”