Bispecific Targeting of Conserved Epitopes Enables Pan-Hantavirus Neutralization

Hantaviruses cause renal and cardiopulmonary syndromes with case-fatality rates up to 40%, yet no approved antiviral therapy exists. Antigenic divergence between Old World and New World hantaviruses has impeded the development of broadly protective antibody therapeutics. Here, we isolated neutralizing antibodies from convalescent donors and identified two lead antibodies targeting distinct conserved epitopes. XA-3H12 potently neutralizes Old World hantaviruses, whereas XA-044 broadly neutralizes HTNV, SNV and ANDV. Cryo-EM structures revealed that XA-044 recognizes the apical Gn-Gc interface, whereas XA-3H12 binds the basal region of Gc domain II, defining two non-overlapping conserved neutralization sites. Guided by these structures, we engineered a bispecific IgG-scFv that integrates the breadth and potency of both parental antibodies and achieves broad hantavirus neutralization. In mouse models, the IgG-scFv blocked entry of diverse hantavirus pseudoviruses in vivo and conferred post-exposure protection against lethal HTNV challenge, establishing a dual-epitope bispecific antibody candidate for broad hantavirus intervention.