Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy

TY - JOUR

T1 - Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy

AU - Wan, Zhixin

AU - Li, Cun

AU - Zhou, Ying

AU - Yu, Yifei

AU - Chiu, Man Chun

AU - Huang, Jingjing

AU - Zhang, Shuxin

AU - Zhu, Xiaoxin

AU - Lan, Qiaoshuai

AU - Deng, Yanlin

AU - Xue, Wei

AU - Jiang, Chengfan

AU - Wu, Jiali

AU - Zhao, Zijun

AU - Cai, Jian-Piao

AU - Huang, Lin

AU - Zhang, Yong

AU - Liu, Xiaojuan

AU - Zhang, Zheng

AU - Chu, Hin

AU - Zhang, Linqi

AU - Chen, Zhiwei

AU - To, Kelvin Kai-Wang

AU - Yuen, Kwok-Yung

AU - Clevers, Hans

AU - Zhou, Jie

PY - 2025/9/2

Y1 - 2025/9/2

N2 - 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.

AB - 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.

KW - SARS-CoV-2/immunology

KW - Humans

KW - Organoids/immunology

KW - Antibodies, Neutralizing/immunology

KW - Angiotensin-Converting Enzyme 2/metabolism

KW - Antibodies, Monoclonal/immunology

KW - Serine Endopeptidases/metabolism

KW - COVID-19/immunology

KW - Neutralization Tests/methods

KW - Antibodies, Viral/immunology

KW - Animals

KW - Spike Glycoprotein, Coronavirus/immunology

KW - Mice

U2 - 10.1073/pnas.2509616122

DO - 10.1073/pnas.2509616122

M3 - Article

C2 - 40875807

SN - 0027-8424

VL - 122

SP - e2509616122

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 35

ER -