Landscape of human antibody recognition of the SARS-CoV-2 receptor binding domain

Abstract

Potent neutralising monoclonal antibodies are one of the few agents currently available to treat COVID-19. SARS-CoV-2 variants of concern (VOC) that carry multiple mutations in the viral spike protein can exhibit neutralisation resistance, potentially impacting the effectiveness of some antibody-based therapeutics. Here, generation of a diverse panel of 91 human neutralising monoclonal antibodies provides an in-depth structural and phenotypic definition of receptor binding domain (RBD) antigenic sites on the viral spike. These RBD antibodies ameliorate SARS-CoV-2 infection in mice and hamster models in a dose-dependent manner and in proportion to in vitro neutralising potency. Assessing the impact of mutations in the spike protein on antibody recognition and neutralisation highlights both potent single antibodies and stereotypic classes of antibodies that are unaffected by currently circulating VOC such as B.1.351 and P.1. These neutralizing monoclonal antibodies, and others that bind analogous epitopes, represent potentially useful future anti-SARS-CoV-2 therapeutics.

The Persistence of Neutralising Antibodies up to 11 months after SARS-CoV-2 Infection in the Southern Region of New Zealand

“…Neutralising antibodies were measured using a surrogate Viral Neutralisation test (sVNT), based on the receptor binding domain of the spike protein (cPass™ SARS-CoV-2 Neutralization Antibody Detection Kit, GenScript). This domain contains >90% of neutralising antibody epitopes -that is regions that block the entry of the virus into host cells via the hACE-2 receptor (6). Specificity was previously determined to be 100% using the 300 pre-pandemic ANS, as well as an additional 113 pre-pandemic samples (7).…”

“…Recent analyses suggest that the level of neutralising antibodies is an important component of a correlate of protection (8). There is now intense effort on understanding how sequence changes within the receptor binding domain in VoC might impact on neutralising antibody activity, and protection from re-infection (6). In this study neutralising antibodies were assessed to alpha (B.1.1.7, United Kingdom), beta (B.1.351, South Africa) and delta (B.1.617.2, India) VoC using an adapted sVNT assay that incorporates receptor binding domains corresponding to the sequence for each of these variants (9).…”

A large-scale systematic survey of SARS-CoV-2 antibodies reveals recurring molecular features

“…These antibodies are also able to potently neutralize multiple variants of concern (VOC) [9, 48, 50]. We compared two previously determined structures of IGHV1-58/IGKV3-20 antibodies in complex with RBD [40, 51], where one has the germline-encoded V L S29 ( Figure 5B ) and the other carries a somatically mutated V L R29 ( Figure 5C ). While neither V L S29 nor V L R29 directly interact with RBD, V L R29 is able to form a cation-π interaction with V L Y32, which in turn forms a T-shaped π-π stacking with RBD-F486 and H-bonds with RBD-C480 ( Figure 5C ).…”

“… (A) An overall view of SARS-CoV-2 RBD in complex with the IGHV1-58/IGKV3-20 antibody PDI 222 (PDB 7RR0) [51]. The RBD is shown in white, while the heavy and light chains of the antibody are in dark and light green, respectively.…”

“…The ridge region (residues 471-491) is shown in pink, with F486 highlighted as sticks. (B-C) Structural comparison between two IGHV1-58/IGKV3-20 antibodies that either (B) carry germline residues V L S29/G92 (COVOX-253, PDB 7BEN) [40] and (C) somatically hypermutated residues V L R29/D92 (PDI 222, PDB 7RR0) [51]. SARS-CoV-2 RBD is in white, while antibodies are in yellow (COVOX-253) and green (PDI 222).…”