BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

• Authors: Yunlong Cao, Ayijiang Yisimayi, Fanchong Jian, Weiliang Song, Tianhe Xiao, Lei Wang, Shuo Du, Jing Wang, Qianqian Li, Xiaosu Chen, Yuanling Yu, Peng Wang, Zhiying Zhang, Pulan Liu, Ran An, Xiaohua Hao, Yao Wang, Jing Wang, Rui Feng, Haiyan Sun, Lijuan Zhao, Wen Zhang, Dong Zhao, Jiang Zheng, Lingling Yu, Can Li, Na Zhang, Rui Wang, Xiao Niu, Sijie Yang, Xuetao Song, Yangyang Chai, Ye Hu, Yansong Shi, Linlin Zheng, Zhiqiang Li, Qingqing Gu, Fei Shao, Weijin Huang, Ronghua Jin, Zhongyang Shen, Youchun Wang, Xiangxi Wang, Junyu Xiao, Xiaoliang Sunney Xie
• Journal: Nature (Nature) Vol. 608 Issue 7923 Pg. 593-602 (08 2022) ISSN: 1476-4687 [Electronic] England
• PMID: 35714668 (Publication Type: Comparative Study, Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Antibodies, Viral
• COVID-19 Vaccines
• Epitopes, B-Lymphocyte
• Spike Glycoprotein, Coronavirus
• spike protein, SARS-CoV-2
• cilgavimab
• bebtelovimab
• Angiotensin-Converting Enzyme 2

Topics

• Angiotensin-Converting Enzyme 2 (metabolism)
• Antibodies, Monoclonal (immunology)
• Antibodies, Neutralizing (immunology)
• Antibodies, Viral (immunology)
• Antigenic Drift and Shift (genetics, immunology)
• COVID-19 (immunology, transmission, virology)
• COVID-19 Vaccines (immunology)
• Epitopes, B-Lymphocyte (chemistry, genetics, immunology)
• Humans
• Immune Tolerance
• Immunity, Humoral
• Immunization, Secondary
• Mutation
• Neutralization Tests
• SARS-CoV-2 (classification, genetics, immunology, metabolism)
• Spike Glycoprotein, Coronavirus (genetics, immunology, metabolism)