Potent and protective IGHV3-53/3-66 public antibodies and their shared escape mutant on the spike of SARS-CoV-2

Abstract

Neutralizing antibodies (nAbs) to SARS-CoV-2 hold powerful potentials for clinical interventions against COVID-19 disease. However, their common genetic and biologic features remain elusive. Here we interrogate a total of 165 antibodies from eight COVID-19 patients, and find that potent nAbs from different patients have disproportionally high representation of IGHV3-53/3-66 usage, and therefore termed as public antibodies. Crystal structural comparison of these antibodies reveals they share similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor angiotensin-converting enzyme-2 (ACE2) in binding to RBD. Site-directed mutagenesis confirms these common binding features although some minor differences are found. One representative antibody, P5A-3C8, demonstrates extraordinarily protective efficacy in a golden Syrian hamster model against SARS-CoV-2 infection. However, virus escape analysis identifies a single natural mutation in RBD, namely K417N found in B.1.351 variant from South Africa, abolished the neutralizing activity of these public antibodies. The discovery of public antibodies and shared escape mutation highlight the intricate relationship between antibody response and SARS-CoV-2, and provide critical reference for the development of antibody and vaccine strategies to overcome the antigenic variation of SARS-CoV-2.

Hybrid immunity improves B cells and antibodies against SARS-CoV-2 variants

“…To better characterize these predominant gene families, we evaluated their neutralization potency and breadth against SARS-CoV-2 and VoCs. In this analysis, we could not evaluate IGHV3-33;IGHJ4-1 nAbs, as only three of these antibodies were expressed, but we included the IGHV3-53 closely related family IGHV3-66;IGHJ4-1, as this family was previously described to be mainly involved in the neutralization of the SARS-CoV-2 virus 11 , 19 . A large part of nAbs deriving from these predominant germlines had a very broad range of neutralization potency against the original SARS-CoV-2 virus detected in Wuhan, with the IC 100 spanning from less than 10 to over 10,000 ng ml −1 (Fig.…”

Delta variant (B.1.617.2) sublineages do not show increased neutralization resistance

“…These viruses harbor the K417N mutation (Fig. 1A, B ), which is also found in the Beta (B.1.351) variant and is associated with neutralization resistance [ 7 ]. Furthermore, another sublineage of the Delta variant was observed in Vietnam and might contribute to a recent surge in cases.…”

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

“…To identify the sequence features in RBD, NTD, and S2 antibodies, we first performed an analysis on V gene usage. Our analysis identified several commonly used IGHV/IGK(L)V pairs among RBD antibodies ( Figure 1A ), such as IGHV3-53/IGKV1-9 and IGHV3-53/IGKV3-20, which represent two known public clonotypes [25-30]. We also observed substantial enrichment of IGHV1-24 among NTD antibodies over the naïve baseline ( Figure 1B ), which was established by published datasets of antibody repertoire sequencing from 26 healthy donors [31-33].…”

“…The largest cluster (cluster 1) consisted of 139 antibodies from 57 donors ( Figure 2B ). Most of the antibodies in cluster 1 belonged to a well-characterized public clonotype to RBD that is encoded by IGHV3-53/3-66 and IGKV1-9 [25-27, 29, 30]. IGHV3-53/3-66, which is frequently used in RBD antibodies [28], was also enriched among antibodies in several other major CDR H3 clusters (e.g.…”