A potent Gc neutralizing antibody reveals architecture-dependent bispecific protection against SFTSV

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), with a mortality rate of up to 30%. Currently, there are no approved vaccines or therapeutics for clinical use. Although neutralizing antibodies against the viral glycoprotein Gn have been reported, their efficacy can be limited by epitope inaccessibility and viral escape. Here, we isolated human monoclonal antibodies from convalescent donors and identified multiple neutralizing antibodies targeting the Gc glycoprotein, including CAV-Gc-2H1, which binds a previously undefined epitope in Gc domain II and exhibits strong neutralizing activity. To enhance breadth and potency, we engineered bispecific antibodies (bsAbs) that co-engage Gn and Gc. Across several architectural formats, scFv-Ig bsAbs exhibited synergistic neutralization <i>in vitro</i> and complete protection <i>in vivo</i>, outperforming parental monospecific antibodies. Mechanistic studies revealed that these bsAbs block both viral attachment and membrane fusion. Our findings establish bsAbs as a promising therapeutic platform against SFTSV and provide a design framework for next-generation antivirals targeting bunyaviruses.