Structural basis of poxvirus fusion regulation and A16/G9 antibody mediated neutralization and protection

Abstract

Monkeypox virus (MPXV) is a poxvirus endemic to Central and West Africa with high epidemic potential. Pox-viruses enter host cells via a conserved entry-fusion complex (EFC), which mediates viral fusion to the cell membrane. The EFC is a promising therapeutic target, but the absence of structural data has limited the development of fusion-inhibiting treatments. Here, we investigated A16/G9, a subcomplex of the EFC that controls fusion timing. Using cryo-electron microscopy, we showed how A16/G9 interacts with A56/K2, a viral fusion suppressor that prevents superinfection. Immunization with A16/G9 elicited a protective immune response in mice. Using X-ray crystallography, we characterized two neutralizing antibodies and engineered a chimeric antibody that cross-neutralizes several poxviruses more efficiently than 7D11, the most potent antibody targeting the EFC described to date. These findings highlight the potential of A16/G9 as a candidate for subunit vaccines and identify regions of the EFC as targets for antiviral development.

Accepted for publication, to appear October 30, 2025.

Publication
Cell (Accepted)
Jochen Hub
Jochen Hub
Professor of Computational Biophysics