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

View ORCID ProfileYunlong Cao, Ayijiang Yisimayi, Fanchong Jian, Weiliang Song, Tianhe Xiao, Lei Wang, Shuo Du, Jing Wang, Qianqian Li, Xiaosu Chen, 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, Linlin Zheng, Zhiqiang Li, Qingqing Gu, Fei Shao, Weijin Huang, Ronghua Jin, Zhongyang Shen, Youchun Wang, Xiangxi Wang, Junyu Xiao, Xiaoliang Sunney Xie
doi: https://doi.org/10.1101/2022.04.30.489997
Yunlong Cao
1Changping Laboratory, Beijing, P.R. China
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
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  • ORCID record for Yunlong Cao
  • For correspondence: yunlongcao@pku.edu.cn zhongyangshen@nankai.edu.cn wangyc@nifdc.org.cn xiangxi@ibp.ac.cn junyuxiao@pku.edu.cn sunneyxie@biopic.pku.edu.cn
Ayijiang Yisimayi
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
3School of Life Sciences, Peking University, Beijing, P.R. China
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Fanchong Jian
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
4College of Chemistry and Molecular Engineering, Peking University, Beijing, P.R. China
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Weiliang Song
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
3School of Life Sciences, Peking University, Beijing, P.R. China
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Tianhe Xiao
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
5Joint Graduate Program of Peking-Tsinghua-NIBS, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
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Lei Wang
6CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China
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Shuo Du
3School of Life Sciences, Peking University, Beijing, P.R. China
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Jing Wang
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
3School of Life Sciences, Peking University, Beijing, P.R. China
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Qianqian Li
7Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, P.R. China
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Xiaosu Chen
8Institute for Immunology, College of Life Sciences, Nankai University, Tianjin, P. R. China
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Peng Wang
1Changping Laboratory, Beijing, P.R. China
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Zhiying Zhang
3School of Life Sciences, Peking University, Beijing, P.R. China
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Pulan Liu
3School of Life Sciences, Peking University, Beijing, P.R. China
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Ran An
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
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Xiaohua Hao
9Beijing Ditan Hospital, Capital Medical University, Beijing, P.R. China
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Yao Wang
1Changping Laboratory, Beijing, P.R. China
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Jing Wang
1Changping Laboratory, Beijing, P.R. China
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Rui Feng
6CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China
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Haiyan Sun
1Changping Laboratory, Beijing, P.R. China
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Lijuan Zhao
1Changping Laboratory, Beijing, P.R. China
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Wen Zhang
9Beijing Ditan Hospital, Capital Medical University, Beijing, P.R. China
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Dong Zhao
9Beijing Ditan Hospital, Capital Medical University, Beijing, P.R. China
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Jiang Zheng
1Changping Laboratory, Beijing, P.R. China
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Lingling Yu
1Changping Laboratory, Beijing, P.R. China
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Can Li
1Changping Laboratory, Beijing, P.R. China
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Na Zhang
1Changping Laboratory, Beijing, P.R. China
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Rui Wang
1Changping Laboratory, Beijing, P.R. China
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Xiao Niu
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
4College of Chemistry and Molecular Engineering, Peking University, Beijing, P.R. China
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Sijie Yang
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
10Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, P.R. China
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Xuetao Song
1Changping Laboratory, Beijing, P.R. China
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Linlin Zheng
1Changping Laboratory, Beijing, P.R. China
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Zhiqiang Li
10Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, P.R. China
11Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, P.R. China
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Qingqing Gu
1Changping Laboratory, Beijing, P.R. China
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Fei Shao
1Changping Laboratory, Beijing, P.R. China
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Weijin Huang
7Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, P.R. China
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Ronghua Jin
9Beijing Ditan Hospital, Capital Medical University, Beijing, P.R. China
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Zhongyang Shen
12Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, P. R. China.
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  • For correspondence: yunlongcao@pku.edu.cn zhongyangshen@nankai.edu.cn wangyc@nifdc.org.cn xiangxi@ibp.ac.cn junyuxiao@pku.edu.cn sunneyxie@biopic.pku.edu.cn
Youchun Wang
7Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, P.R. China
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  • For correspondence: yunlongcao@pku.edu.cn zhongyangshen@nankai.edu.cn wangyc@nifdc.org.cn xiangxi@ibp.ac.cn junyuxiao@pku.edu.cn sunneyxie@biopic.pku.edu.cn
Xiangxi Wang
6CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China
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  • For correspondence: yunlongcao@pku.edu.cn zhongyangshen@nankai.edu.cn wangyc@nifdc.org.cn xiangxi@ibp.ac.cn junyuxiao@pku.edu.cn sunneyxie@biopic.pku.edu.cn
Junyu Xiao
3School of Life Sciences, Peking University, Beijing, P.R. China
10Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, P.R. China
11Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, P.R. China
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  • For correspondence: yunlongcao@pku.edu.cn zhongyangshen@nankai.edu.cn wangyc@nifdc.org.cn xiangxi@ibp.ac.cn junyuxiao@pku.edu.cn sunneyxie@biopic.pku.edu.cn
Xiaoliang Sunney Xie
1Changping Laboratory, Beijing, P.R. China
2Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
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  • For correspondence: yunlongcao@pku.edu.cn zhongyangshen@nankai.edu.cn wangyc@nifdc.org.cn xiangxi@ibp.ac.cn junyuxiao@pku.edu.cn sunneyxie@biopic.pku.edu.cn
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Abstract

The recently emerged SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.21. The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we show that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 displays the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization evasion against the plasma of 3-dose vaccinees and, most strikingly, of vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure induced by Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2 due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab4) and COV2-2130 (Cilgavimab5) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

Competing Interest Statement

X.S.X. and Y.C. are inventors on the provisional patent applications of BD series antibodies, which includes BD30-604 (DXP-604), BD55-5840 (SA58) and BD55-5514 (SA55). X.S.X. and Y.C. are founders of Singlomics Biopharmaceuticals. Other authors declare no competing interests.

Footnotes

  • ↵# These authors contributed equally.

  • https://github.com/jianfcpku/SARS-CoV-2-RBD-DMS-broad

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 02, 2022.
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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, 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, Linlin Zheng, Zhiqiang Li, Qingqing Gu, Fei Shao, Weijin Huang, Ronghua Jin, Zhongyang Shen, Youchun Wang, Xiangxi Wang, Junyu Xiao, Xiaoliang Sunney Xie
bioRxiv 2022.04.30.489997; doi: https://doi.org/10.1101/2022.04.30.489997
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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, 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, Linlin Zheng, Zhiqiang Li, Qingqing Gu, Fei Shao, Weijin Huang, Ronghua Jin, Zhongyang Shen, Youchun Wang, Xiangxi Wang, Junyu Xiao, Xiaoliang Sunney Xie
bioRxiv 2022.04.30.489997; doi: https://doi.org/10.1101/2022.04.30.489997

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