On Dec. 23rd, 2021, the Xie Group and collaborators published a paper entitled “Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies” in Nature, revealing that VIR-7831 and DXP-604 were still effective to Omicron variant. This work offers instructions for developing NAb drugs and vaccines against Omicron and future variants.

　　A high-throughput yeast display system was developed by Xiaoliang Xie's group by virtue of MACS (Fig. 1), compared to the FACS-based similar techniques published last year in the U.S. that improved the experiment throughput by 1-2 orders of magnitude. Based on the high-throughput yeast display system, they profiled RBD escaping mutation map for 247 human anti-RBD NAbs and clustered NAbs into six epitope groups (A-F). Furthermore, they found that the Omicron variant escapes more than 85% of known neutralizing antibodies, and only VIR-7831 and DXP-604 were still effective among existing neutralizing antibodies but with significantly lower efficacy compared to the original and Delta strains (Fig. 2). The VIR-7831 neutralizing antibody was jointly developed by two companies in the U.K. and the U.S.; the DXP-604 neutralizing antibody was developed by Xiaoliang Xie's team in collaboration with Dan Sequence Biology and others.

　　Fig. 1: Omicron greatly reduces the neutralization potency of NAbs of diverse epitopes.  a, Schematic of MACS-based high-throughput yeast display mutation scanning. b, Representative NAb structures of each epitope group. c, t-SNE embedding and unsupervised clustering of SARS-CoV-2 human NAbs based on each antibody escaping mutation profile. A total of 6 epitope groups (Group A-F) could be defined.

　　Fig. 2: Omicron escapes most NAb drugs a, Neutralization of SARS-CoV-2 variants of concern (pseudotyped VSV) by 9 NAb drugs. The pseudovirus neutralization assays for every VOC were performed in biological triplicates. IC50 labeled is the average of three replicates. b, The sarbecovirus neutralization and binding capability of selected potent Omicron-neutralizing antibodies. Monoclonal antibody HG1K (IgG1 antibody against Influenza A virus subtype H7N9) was used as the negative control.

　　Additionally, the collaborative team identified several NAbs (Groups E and F NAbs) that have shown high potency against Omicron and broad pan-sarbecovirus neutralization ability from the blood of SARS-CoV-1 convalescents who received a vaccine against SARS-CoV-2, which is promising for NAb drug development.

　　To date, a large number of SARS-CoV-2 NAbs have been identified from convalescents and vaccines. The most potent NAbs are frequently found in Groups A-D, but Omicron would escape from the majority of SARS-CoV-2 NAbs in this collection. While Groups E and F NAbs are less affected by Omicron, likely because they are not abundant in the population. Together, their results offer instructions for developing NAb drugs and vaccines against Omicron and future variants.

　　Dr. Yunlong Cao, Ph.D. Candidates Jing Wang, Fanchong Jian, Tianhe Xiao, Weiliang Song, Ayijiang Yisimayi, and Weijin Huang are the co-first authors of the paper. Dr. Yunlong Cao, Prof. Xiangxi Wang, Prof. Junyu Xiao, Prof. Youchun Wang, and Prof. Xiaoliang Sunney Xie are the co-corresponding authors of the paper.