Abstract
Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus that causes severe human disease, with a case fatality rate of up to 30%. However, no licensed therapeutics are currently available for clinical use. Here, we identified two SFTSV neutralizing nanobodies (Nbs), N2C1 and N2D2, which inhibited both viral attachment and membrane fusion. Structural analysis revealed that N2C1 spanned Gn domain I and domain III, while N2D2 targeted domain I, located at the inner and outer sides of the Gn–Gc hexamer crown, respectively. They also exhibited synergistic neutralization, and their bispecific antibody (bsAb) displayed dramatically enhanced neutralizing potency. In a lethal mouse model, the bsAb demonstrated superior protective efficacy over the parental Nbs in both preexposure and postexposure administration regimens. More importantly, in preclinical ferret models, the bsAb N2D2-Fc-N2C1 conferred complete protection against SFTSV not only at a low dose of 5 mg/kg but also when administered as late as 2 d postinfection. These results demonstrate the potent protective efficacy of N2D2-Fc-N2C1, supporting its development as a promising clinical candidate against SFTSV infection.