UBC Faculty Research and Publications

Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains Chen, Chuan; Saville, James; Marti, Michelle M.; Schäfer, Alexandra; Cheng, Mary Hongying; Mannar, Dhiraj; Zhu, Xing; Berezuk, Alison; Banerjee, Anupam; Sobolewski, Michele D.; Kim, Andrew; Treat, Benjamin R.; Castanha, Priscila Mayrelle Da Silva; Enick, Nathan; McCormick, Kevin D.; Liu, Xianglei; Adams, Cynthia; Hines, Margaret Grace; Sun, Zehua; Chen, Weizao; Jacobs, Jana L.; Barratt-Boyes, Simon M.; Mellors, John W.; Baric, Ralph S.; Bahar, Ivet; Dimitrov, Dimiter S.; Subramaniam, Sriram; Martinez, David R.; Li, Wei

Abstract

The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human VH domain, F6, which we generated by sequentially panning large phage-displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized VH domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants.