Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

Abstract

The SARS-CoV-2 B.1.1.529 variant (Omicron) contains 15 mutations on the receptor-binding domain (RBD). How Omicron would evade RBD neutralizing antibodies (NAbs) and humoral immunity requires immediate investigation. Here, we used high-throughput yeast display screening to determine the RBD escaping mutation profiles for 247 human anti-RBD NAbs identified from SARS-CoV/SARS-CoV-2 convalescents and vaccinees. Based on the results, NAbs could be unsupervised clustered into six epitope groups (A-F), which is highly concordant with knowledge-based structural classifications. Strikingly, various single mutations of Omicron could impair NAbs of different epitope groups. Specifically, NAbs in Group A-D, whose epitope overlaps with ACE2-binding motif, are largely escaped by K417N, N440K, G446S, E484A, Q493K, and G496S. Group E (S309 site) and F (CR3022 site) NAbs, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but still, a subset of NAbs are escaped by G339D, S371L, and S375F. Furthermore, B.1.1.529 pseudovirus neutralization and RBD binding assay showed that single mutation tolerating NAbs could also be escaped due to multiple synergetic mutations on their epitopes. In total, over 85% of the tested NAbs are escaped by Omicron. Regarding NAb drugs, LY-CoV016/LY-CoV555 cocktail, REGN-CoV2 cocktail, AZD1061/AZD8895 cocktail, and BRII-196 were escaped by Omicron, while VIR7831 and DXP-604 still function at reduced efficacy. Together, data suggest Omicron could cause significant humoral immune evasion, while NAbs targeting the sarbecovirus conserved region remain most effective. Our results offer instructions for developing NAb drugs and vaccines against Omicron and future variants.

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

“…3b-c). These findings are consistent with two recent reports 18,20 and, together with serological data, support the notion of Omicron antigenic shift.…”

“…The potential for booster doses to ameliorate this decline in neutralization is still being explored. In addition, the neutralizing activity of several therapeutic mAbs was shown to be decreased or abolished against SARS-CoV-2 Omicron 18,20 .…”

Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa

“…These RBD mutations coupled with four amino acid substitutions (A67V, T95I, G142D, and L212I), three deletions (69-70, 143-145 and 211) and an insertion (EPE between 214 and 215) in the N-terminal domain (NTD) 25 , are predicted to underlie the substantially reduced sensitivity of Omicron to neutralization by anti-SARS-CoV-2 antibodies induced by either infection or vaccination 26,27 . These mutations also involve key structural epitopes targeted by some of the currently authorized monoclonal antibodies, particularly bamlanivimab + etesevimab and casirivimab + imdevimab [28][29][30] . Preliminary analysis suggests that although the spike mutations involve a number of T cell and B cell epitopes, the majority of epitopes (>70%) remain unaffected 31 .…”

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

“…In addition to the impact on ACE2 binding, the mutations in the RBD enable the Omicron variant to escape from antibody recognition and neutralization. Several recent studies have evaluated the neutralizing activities of antibodies against the Omicron variant [1,2,17,18] . Their results showed that most of the studied antibodies, especially Class I and Class II antibodies, lost their neutralizing activities due to mutations in the epitopes such as K417N and E484A, which is consistent with previous studies [19–21] .…”