Human monoclonal antibodies that target the SFTSV glycoprotein Gn head from four neutralizing epitope groups

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a lethal bunyavirus lacking approved countermeasures. From SFTS survivors, we isolate 84 human monoclonal antibodies (mAbs) against the viral glycoproteins Gn and Gc. Gn-specific mAbs demonstrate superior neutralization breadth and potency compared to the restricted neutralizing activity observed with Gc. Using a high-throughput yeast display deep mutational scanning (DMS) platform, we classify Gn-head mAbs into eight epitope groups, among which four groups (IA, ID, IIIA, IIIB) conferring neutralization. Notably, mAbs BD70-4003 (group IA) and BD70-4017 (group IIIA) exhibit broad neutralization and provide 100% protection in a lethal mouse model. Cryo-EM structural analysis of these mAbs in complex with the Gn-head reveal their binding interfaces, directly validating the epitope residues identified by DMS. Our study delineates the antigenic landscape of SFTSV Gn, identifies potent therapeutic candidates, and establishes DMS coupled with structural validation as a powerful framework for antibody discovery against bunyavirus.