Abstract
The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening1,2 to determine the profiles of RBD escaping mutations for 247 human anti-RBD neutralizing antibodies and show that the neutralizing antibodies can be classified by unsupervised clustering into six epitope groups (A–F)—a grouping that is highly concordant with knowledge-based structural classifications3,4,5. Various single mutations of Omicron can impair neutralizing antibodies of different epitope groups. Specifically, neutralizing antibodies in groups A–D, the epitopes of which overlap with the ACE2-binding motif, are largely escaped by K417N, G446S, E484A and Q493R. Antibodies in group E (for example, S309)6 and group F (for example, CR3022)7, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but a subset of neutralizing antibodies are still escaped by G339D, N440K and S371L. Furthermore, Omicron pseudovirus neutralization showed that neutralizing antibodies that sustained single mutations could also be escaped, owing to multiple synergetic mutations on their epitopes. In total, over 85% of the tested neutralizing antibodies were escaped by Omicron. With regard to neutralizing-antibody-based drugs, the neutralization potency of LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 and BRII-196 was greatly undermined by Omicron, whereas VIR-7831 and DXP-604 still functioned at a reduced efficacy. Together, our data suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the sarbecovirus conserved region will remain most effective. Our results inform the development of antibody-based drugs and vaccines against Omicron and future variants.
Highlights
This is a PDF file of a peer-reviewed paper that has been accepted for publication
E human anti-receptor-binding domain (RBD) NAbs and showed that the NAbs could be unsupervised clustered into six epitope groups (A-F), which is highly concordant with knowledge-based
The NAbs that survived Beta strain, such as BRII196 and DXP-604, are insensitive to the K417N single site change but could be heavily affected by the combination of K417N and other RBD mutations located on their epitopes, like S477N, Q493R, G496S, Q498R, N501Y, and Y505H of Omicron, causing lost or reduction of neutralization (Fig 2d; Extended Data Fig. 7a)
Summary
Yunlong Cao1,2,11 ✉, Jing Wang[1,3,11], Fanchong Jian[1,4,11], Tianhe Xiao[1,5,11], Weiliang Song[1,3,11], Ayijiang Yisimayi[1,3,11], Weijin Huang[6,11], Qianqian Li6, Peng Wang[1], Ran An1, Jing Wang[1], Yao Wang[1], Xiao Niu[1,4], Sijie Yang[1,7], Hui Liang[1], Haiyan Sun[1], Tao Li6, Yuanling Yu6, Qianqian Cui[6], Shuo Liu[6], Xiaodong Yang[8], Shuo Du3, Zhiying Zhang[3], Xiaohua Hao[9], Fei Shao[1], Ronghua Jin[9], Xiangxi Wang10 ✉, Junyu Xiao2,3 ✉, Youchun Wang6 ✉ & Xiaoliang Sunney Xie1,2 ✉. The NAbs that survived Beta strain, such as BRII196 and DXP-604, are insensitive to the K417N single site change but could be heavily affected by the combination of K417N and other RBD mutations located on their epitopes, like S477N, Q493R, G496S, Q498R, N501Y, and Y505H of Omicron, causing lost or reduction of neutralization (Fig 2d; Extended Data Fig. 7a). NAbs mainly contains the VH3-53/VH3-66 germline gene-encoded Inferred from the escaping mutation profiles (Fig. 3b), Group E NAbs antibodies, which are abundantly present in our current collection are often sensitive to changes of G339, T345, and R346 (Extended Data of SARS-CoV-2 neutralizing antibodies[17,21,22,26,41,42,43], including several Fig. 6e, 7e). Monoclonal antibody HG1K (IgG1 antibody against Influenza A virus subtype H7N9) was used as the negative control
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