The emergence of numerous SARS-CoV-2 variants has challenged global COVID-19 control efforts. This study identified two cross-neutralizing antibodies (7D6 and 6D6) targeting the Sarbecovirus receptor-binding domain (RBD) with high affinity and potent neutralization of authentic SARS-CoV-2. Crystal structures revealed that these antibodies bind a cryptic, highly conserved site across Sarbecoviruses, disrupting the viral spike. The antibodies demonstrated resistance to mutations in circulating variants, suggesting potential for therapeutic and prophylactic applications, and informing pan-sarbecovirus vaccine design.

Tingting Li, Wenhui Xue, Qingbing Zheng, Shuo Song, Chuanlai Yang, Hualong Xiong, Sibo Zhang, Minqing Hong, Yali Zhang, Hai Yu, Yuyun Zhang, Hui Sun, Yang Huang, Tingting Deng, Xin Chi, Jinjin Li, Shaojuan Wang, Lizhi Zhou, Tingting Chen, Yingbin Wang, Tong Cheng, Tianying Zhang, Quan Yuan, Qinjian Zhao, Jun Zhang, Jason S. McLellan, Z. Hong Zhou, Zheng Zhang, Shaowei Li, Ying Gu, Ningshao Xia