Potent pan huACE2-dependent sarbecovirus neutralizing monoclonal antibodies isolated from a BNT162b2-vaccinated SARS survivor
Wan Ni Chia, Chee Wah Tan, Aaron Tan, Barnaby Edward Young, Tyler N. Starr, Ester López, G. Fibriansah, Jennifer Barr, Samuel M. S. Cheng, Aileen Ying-Yan Yeoh, Wee Chee Yap, Beng Lee Lim, Thiam‐Seng Ng, Wan Rong Sia, Feng Zhu, Shiwei Chen, Jinyan Zhang, Madeline Sheng Si Kwek, Allison J. Greaney, Mark Chen, Gough G. Au, Prasad N. Paradkar, Malik Peiris, Amy W. Chung, Jesse D. Bloom, David Chien Lye, Shee‐Mei Lok, Lin‐Fa Wang
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron hampered efforts in controlling the ongoing coronavirus disease 2019 pandemic due to their ability to escape neutralizing antibodies induced by vaccination or prior infection, highlighting the need to develop broad-spectrum vaccines and therapeutics. Most human monoclonal antibodies (mAbs) reported to date have not demonstrated true pan-sarbecovirus neutralizing breadth especially against animal sarbecoviruses. Here, we report the isolation and characterization of highly potent mAbs targeting the receptor binding domain (RBD) of huACE2-dependent sarbecovirus from a SARS-CoV survivor vaccinated with BNT162b2. Among the six mAbs identified, one (E7) showed better huACE2-dependent sarbecovirus neutralizing potency and breadth than any other mAbs reported to date. Mutagenesis and cryo-electron microscopy studies indicate that these mAbs have a unique RBD contact footprint and that E7 binds to a quaternary structure-dependent epitope.