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

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 () and Xiaoliang Sunney Xie ()
Additional contact information
Yunlong Cao: Peking University
Ayijiang Yisimayi: Peking University
Fanchong Jian: Peking University
Weiliang Song: Peking University
Tianhe Xiao: Peking University
Lei Wang: Chinese Academy of Sciences
Shuo Du: Peking University
Jing Wang: Peking University
Qianqian Li: National Institutes for Food and Drug Control (NIFDC)
Xiaosu Chen: Nankai University
Yuanling Yu: Changping Laboratory
Peng Wang: Changping Laboratory
Zhiying Zhang: Peking University
Pulan Liu: Peking University
Ran An: Peking University
Xiaohua Hao: Capital Medical University
Yao Wang: Changping Laboratory
Jing Wang: Changping Laboratory
Rui Feng: Chinese Academy of Sciences
Haiyan Sun: Changping Laboratory
Lijuan Zhao: Changping Laboratory
Wen Zhang: Capital Medical University
Dong Zhao: Capital Medical University
Jiang Zheng: Changping Laboratory
Lingling Yu: Changping Laboratory
Can Li: Changping Laboratory
Na Zhang: Changping Laboratory
Rui Wang: Changping Laboratory
Xiao Niu: Peking University
Sijie Yang: Peking University
Xuetao Song: Changping Laboratory
Yangyang Chai: Nankai University
Ye Hu: Nankai University
Yansong Shi: Nankai University
Linlin Zheng: Changping Laboratory
Zhiqiang Li: Peking University
Qingqing Gu: Changping Laboratory
Fei Shao: Changping Laboratory
Weijin Huang: National Institutes for Food and Drug Control (NIFDC)
Ronghua Jin: Capital Medical University
Zhongyang Shen: Nankai University
Youchun Wang: Changping Laboratory
Xiangxi Wang: Changping Laboratory
Junyu Xiao: Changping Laboratory
Xiaoliang Sunney Xie: Peking University

Nature, 2022, vol. 608, issue 7923, 593-602

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04980-y

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