PT  - JOURNAL ARTICLE
AU  - Yunlong Cao
AU  - Jing Wang
AU  - Fanchong Jian
AU  - Tianhe Xiao
AU  - Weiliang Song
AU  - Ayijiang Yisimayi
AU  - Weijin Huang
AU  - Qianqian Li
AU  - Peng Wang
AU  - Ran An
AU  - Jing Wang
AU  - Yao Wang
AU  - Xiao Niu
AU  - Sijie Yang
AU  - Hui Liang
AU  - Haiyan Sun
AU  - Tao Li
AU  - Yuanling Yu
AU  - Qianqian Cui
AU  - Shuo Liu
AU  - Xiaodong Yang
AU  - Shuo Du
AU  - Zhiying Zhang
AU  - Xiaohua Hao
AU  - Fei Shao
AU  - Ronghua Jin
AU  - Xiangxi Wang
AU  - Junyu Xiao
AU  - Youchun Wang
AU  - Xiaoliang Sunney Xie
TI  - Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies
AID  - 10.1101/2021.12.07.470392
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.07.470392
4099  - http://biorxiv.org/content/early/2021/12/22/2021.12.07.470392.short
4100  - http://biorxiv.org/content/early/2021/12/22/2021.12.07.470392.full
AB  - 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) requires immediate investigation. Here, we used high-throughput yeast display screening1,2 to determine the RBD escaping mutation profiles for 247 human anti-RBD NAbs and showed that the NAbs could be unsupervised clustered into six epitope groups (A-F), which is highly concordant with knowledge-based structural classifications3-5. Strikingly, various single mutations of Omicron could impair NAbs of different epitope groups. Specifically, NAbs in Group A-D, whose epitope overlap with ACE2-binding motif, are largely escaped by K417N, G446S, E484A, and Q493R. Group E (S309 site)6 and F (CR3022 site)7 NAbs, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but still, a subset of NAbs are escaped by G339D, N440K, and S371L. Furthermore, Omicron pseudovirus neutralization 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, the neutralization potency of LY-CoV016/LY-CoV555, REGN10933/REGN10987, AZD1061/AZD8895, and BRII-196 were greatly reduced by Omicron, while VIR-7831 and DXP-604 still function at reduced efficacy. Together, data suggest Omicron would 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.Competing Interest StatementX.S.X. and Y.C. are inventors on the patent application of DXP-604 and BD series antibodies. X.S.X. and Y.C. are founders of Singlomics Biopharmaceuticals Inc. Other authors declare no competing interests.