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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, 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, View ORCID ProfileJunyu Xiao, Xiaoliang Sunney Xie
doi: https://doi.org/10.1101/2022.04.30.489997
Yunlong Cao
1Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
2Changping Laboratory, 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
1Biomedical 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
1Biomedical 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
1Biomedical 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
1Biomedical 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
1Biomedical 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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Yuanling Yu
2Changping Laboratory, Beijing, P.R. China
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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Peng Wang
2Changping 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
1Biomedical 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
2Changping Laboratory, Beijing, P.R. China
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Jing Wang
2Changping 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
2Changping Laboratory, Beijing, P.R. China
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Lijuan Zhao
2Changping 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
2Changping Laboratory, Beijing, P.R. China
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Lingling Yu
2Changping Laboratory, Beijing, P.R. China
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Can Li
2Changping Laboratory, Beijing, P.R. China
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Na Zhang
2Changping Laboratory, Beijing, P.R. China
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Rui Wang
2Changping Laboratory, Beijing, P.R. China
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Xiao Niu
1Biomedical 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
1Biomedical 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
2Changping Laboratory, Beijing, P.R. China
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Yangyang Chai
8Institute for Immunology, College of Life Sciences, Nankai University, Tianjin, P. R. China
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Ye Hu
8Institute for Immunology, College of Life Sciences, Nankai University, Tianjin, P. R. China
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Yansong Shi
8Institute for Immunology, College of Life Sciences, Nankai University, Tianjin, P. R. China
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Linlin Zheng
2Changping 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
2Changping Laboratory, Beijing, P.R. China
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Fei Shao
2Changping 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
2Changping Laboratory, Beijing, P.R. China
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
2Changping Laboratory, Beijing, P.R. China
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
2Changping Laboratory, Beijing, P.R. China
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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  • ORCID record for Junyu Xiao
  • 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
1Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, P.R. China
2Changping Laboratory, 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

SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.21. The new variants’ receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron 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-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab4 and Cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. 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.

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

  • Figure 1 updated the hACE2 binding affinity of Omicron RBDs. Figure 3 updated the epitope projection on RBD of 12 Epitope Groups. Figure 6 updated pseudovirus neutralization results to further examine the breadth of BA.1-specific NAbs.

  • 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 June 14, 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, 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
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, 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
bioRxiv 2022.04.30.489997; doi: https://doi.org/10.1101/2022.04.30.489997

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