Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy
Abstract
The efficacy of VIR-7831, a class 3 anti-SARS-CoV-2 monoclonal antibody (mAb), was demonstrated repeatedly in clinical trials; yet, reduced neutralization against Omicron variants in cell-line-based neutralization assays led to its withdrawal from clinical use. We developed organoid-based neutralization assays to measure mAb potency. We found that most class 3 mAbs, especially those not blocking receptor-binding domain-ACE2 binding, including VIR-7831, were substantially underestimated in cell-line-based assays. Nasal organoids adequately recapitulated the real-world effectiveness of VIR-7831 because of biologically relevant low ACE2 expression, and exclusively reproduced the in vivo protection of S2 mAbs due to the high TMPRSS2 expression, reminiscent of native human respiratory epithelial cells. Collectively, the robust organoid culture system and biologically relevant expression profiles of ACE2 and TMPRSS2 make nasal organoids present a correlate of in vivo protection of neutralizing mAbs exclusively. The organoid-based neutralization assays, superior to conventional cell-line-based assays, can recapitulate and predict the real-world efficacy of mAbs.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (26)
Zhixin Wan
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Cun Li
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Ying Zhou
Yifei Yu
Man Chun Chiu
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jingjing Huang
College of Life Sciences, South China Agricultural University
Shuxin Zhang
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Xiaoxin Zhu
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Qiaoshuai Lan
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Yanlin Deng
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Wei Xue
Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Engineering Technology Research Center of Drug Carrier of Guangdong, Department of Biomedical Engineering
Chengfan Jiang
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jiali Wu
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Zijun Zhao
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jian-Piao Cai
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Lin Huang
Yong Zhang
Xiaojuan Liu
Spin-X Institute, School of Chemistry and Chemical Engineering, State Key Laboratory of Luminescent Materials and Devices
Zheng Zhang
Hin Chu
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Linqi Zhang
Pandemic Research Alliance Unit at the University of Hong Kong
Zhiwei Chen
Kelvin Kai-Wang To
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Kwok-Yung Yuen
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Hans Clevers
Jie Zhou