A bispecific nanobody dimer broadly neutralizes SARS-CoV-1 & 2 variants of concern and offers substantial protection against Omicron via low-dose intranasal administration

Current SARS-CoV-2 Omicron subvariants evade immunity from most neutralizing antibodies and vaccines. This study identified a nanobody (aS3A) cross-reactive with SARS-CoV-1 and SARS-CoV-2 RBD. A bispecific nanobody dimer (2-3-Fc), engineered by fusing aS3A-Fc to aRBD-2, exhibited potent neutralization against all major variants of concern, including BA.5. In hamsters, a single systemic dose (10 mg/kg) or a lower intranasal dose (5 mg/kg) of 2-3-Fc provided complete or drastic protection against Omicron infection, respectively. A variant, Y296-3-Fc, showed enhanced neutralization of BA.2.75. This research provides potential therapeutic and prophylactic candidates against SARS-CoV-2 variants.

Huan Ma, Xinghai Zhang, Weihong Zeng, Junhui Zhou, Xiangyang Chi, Shaohong Chen, Peiyi Zheng, Meihua Wang, Yan Wu, Dan Zhao, Fanwu Gong, Haofeng Lin, Hancong Sun, Changming Yu, Zhengli Shi, Xiaowen Hu, Huajun Zhang, Tengchuan Jin, Sandra Chiu