Structurally conserved human anti-A35 antibodies protect mice and macaques from mpox virus infection.

The A35 protein, expressed on the enveloped virion of monkeypox (mpox) virus (MPXV), is essential for viral infection and spread within the host, making it an effective antiviral target. In this study, we demonstrated two human anti-A35 monoclonal antibodies (mAbs) displayed potential protection against MPXV in CAST/EiJ mice and rhesus macaques. Using cryo-electron microscopy, we determined two high-resolution structures of the A35 dimer in complex with the fragment of antigen binding of mAb 975 or mAb 981, revealing detailed interactions at the antigen-antibody interfaces. Structural analysis showed that these structurally conserved mAbs bind to a groove region at the interface of A35 dimer. Overall, we provided a proof of concept for a single administration of anti-A35 mAbs mitigating the pathogenic effects of MPXV infection in rhesus macaques. These human-derived mAbs could be served as antibody drug candidates, and their binding models to the A35 dimer will provide valuable insights for future vaccine design.