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A subset of Memory B-derived antibody repertoire from 3-dose vaccinees is ultrapotent against diverse and highly transmissible SARS-CoV-2 variants, including Omicron

Kang Wang, Zijing Jia, Linlin Bao, Lei Wang, Lei Cao, Hang Chi, Yaling Hu, Qianqian Li, Yinan Jiang, Qianhui Zhu, Yongqiang Deng, Pan Liu, Nan Wang, Lin Wang, Min Liu, Yurong Li, Boling Zhu, Kaiyue Fan, Wangjun Fu, Peng Yang, Xinran Pei, Zhen Cui, Lili Qin, Pingju Ge, Jiajing Wu, Shuo Liu, Yiding Chen, Weijin Huang, Cheng-Feng Qin, Youchun Wang, Chuan Qin, Xiangxi Wang
doi: https://doi.org/10.1101/2021.12.24.474084
Kang Wang
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Zijing Jia
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
8University of Chinese Academy of Sciences, Beijing 100049, China
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Linlin Bao
2Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
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Lei Wang
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
8University of Chinese Academy of Sciences, Beijing 100049, China
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Lei Cao
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Hang Chi
3State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
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Yaling Hu
4Sinovac Biotech Ltd, Beijing, China
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Qianqian Li
5Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
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Yinan Jiang
6Acrobiosystems Inc, Beijing, China
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Qianhui Zhu
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
8University of Chinese Academy of Sciences, Beijing 100049, China
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Yongqiang Deng
3State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
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Pan Liu
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Nan Wang
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Lin Wang
4Sinovac Biotech Ltd, Beijing, China
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Min Liu
4Sinovac Biotech Ltd, Beijing, China
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Yurong Li
4Sinovac Biotech Ltd, Beijing, China
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Boling Zhu
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Kaiyue Fan
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
8University of Chinese Academy of Sciences, Beijing 100049, China
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Wangjun Fu
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
8University of Chinese Academy of Sciences, Beijing 100049, China
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Peng Yang
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
8University of Chinese Academy of Sciences, Beijing 100049, China
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Xinran Pei
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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Zhen Cui
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
8University of Chinese Academy of Sciences, Beijing 100049, China
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Lili Qin
6Acrobiosystems Inc, Beijing, China
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Pingju Ge
6Acrobiosystems Inc, Beijing, China
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Jiajing Wu
5Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
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Shuo Liu
5Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
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Yiding Chen
6Acrobiosystems Inc, Beijing, China
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Weijin Huang
5Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
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Cheng-Feng Qin
2Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
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  • For correspondence: xiangxi@ibp.ac.cn qincf@bmi.ac.cn wangyc@nifdc.org.cn qinchuan@pumc.edu.cn
Youchun Wang
5Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
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  • For correspondence: xiangxi@ibp.ac.cn qincf@bmi.ac.cn wangyc@nifdc.org.cn qinchuan@pumc.edu.cn
Chuan Qin
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
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  • For correspondence: xiangxi@ibp.ac.cn qincf@bmi.ac.cn wangyc@nifdc.org.cn qinchuan@pumc.edu.cn
Xiangxi Wang
1CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
7Guangzhou Laboratory, Guangzhou, Guangdong, China, 510320
8University of Chinese Academy of Sciences, Beijing 100049, China
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  • For correspondence: xiangxi@ibp.ac.cn qincf@bmi.ac.cn wangyc@nifdc.org.cn qinchuan@pumc.edu.cn
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Abstract

Omicron, the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. We examined whether sera from individuals who received two or three doses of inactivated vaccine, could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2/60) and 95% (57/60) for 2- and 3-dose vaccinees, respectively. For three-dose recipients, the geometric mean neutralization antibody titer (GMT) of Omicron was 15, 16.5-fold lower than that of the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in 3-dose vaccinees, half of which recognize the receptor binding domain (RBD) and show that a subset of them (24/163) neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron, potently. Therapeutic treatments with representative broadly neutralizing mAbs individually or antibody cocktails were highly protective against SARS-CoV-2 Beta infection in mice. Atomic structures of the Omicron S in complex with three types of all five VOC-reactive antibodies defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to one major class of antibodies bound at the right shoulder of RBD through altering local conformation at the binding interface. Our results rationalize the use of 3-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are a rational target for a universal sarbecovirus vaccine.

One sentence summary A sub-set of antibodies derived from memory B cells of volunteers vaccinated with 3 doses of an inactivated SARS-CoV-2 vaccine work individually as well as synergistically to keep variants, including Omicron, at bay.

Competing Interest Statement

The authors have declared no competing interest.

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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 December 26, 2021.
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A subset of Memory B-derived antibody repertoire from 3-dose vaccinees is ultrapotent against diverse and highly transmissible SARS-CoV-2 variants, including Omicron
Kang Wang, Zijing Jia, Linlin Bao, Lei Wang, Lei Cao, Hang Chi, Yaling Hu, Qianqian Li, Yinan Jiang, Qianhui Zhu, Yongqiang Deng, Pan Liu, Nan Wang, Lin Wang, Min Liu, Yurong Li, Boling Zhu, Kaiyue Fan, Wangjun Fu, Peng Yang, Xinran Pei, Zhen Cui, Lili Qin, Pingju Ge, Jiajing Wu, Shuo Liu, Yiding Chen, Weijin Huang, Cheng-Feng Qin, Youchun Wang, Chuan Qin, Xiangxi Wang
bioRxiv 2021.12.24.474084; doi: https://doi.org/10.1101/2021.12.24.474084
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A subset of Memory B-derived antibody repertoire from 3-dose vaccinees is ultrapotent against diverse and highly transmissible SARS-CoV-2 variants, including Omicron
Kang Wang, Zijing Jia, Linlin Bao, Lei Wang, Lei Cao, Hang Chi, Yaling Hu, Qianqian Li, Yinan Jiang, Qianhui Zhu, Yongqiang Deng, Pan Liu, Nan Wang, Lin Wang, Min Liu, Yurong Li, Boling Zhu, Kaiyue Fan, Wangjun Fu, Peng Yang, Xinran Pei, Zhen Cui, Lili Qin, Pingju Ge, Jiajing Wu, Shuo Liu, Yiding Chen, Weijin Huang, Cheng-Feng Qin, Youchun Wang, Chuan Qin, Xiangxi Wang
bioRxiv 2021.12.24.474084; doi: https://doi.org/10.1101/2021.12.24.474084

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