Structure and function of a pair of non-competing monoclonal antibodies against Langya henipavirus attachment glycoprotein

Langya henipavirus (LayV) is a zoonotic Parahenipavirus (Para-HNV) identified in recent years, discovered via surveillance of febrile patients with recent animal exposure in eastern China. The attachment glycoprotein (G) of HNV is critical for host cell entry and a key immune target. However, LayV-G exhibits notable antigenic differences from G of highly pathogenic bat-borne Hendra virus (HEV) and Nipah virus (NiV), implying vaccines or antibody therapies developed against HeV/NiV-G might be ineffective against LayV. Here, we immunize mice with LayV-G ectodomain and isolate a panel of LayV-G-targeting monoclonal antibodies (mAbs). We characterize two potent mAbs with pronounced crystallizable fragment (Fc)-mediated antiviral function and determine their cryo-electron microscopy (cryo-EM) structure binding to distinct epitopes of LayV-G head domain at a resolution of 2.92 Å, revealing antibody recognition mechanisms and potential conformational dynamics of LayV-G. Overall, our study defines two function-related epitopes of LayV-G, laying the foundation for therapeutic antibody development and vaccine design.