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

Abstract

Monkeypox virus (MPXV) is a poxvirus endemic to Central and West Africa with high epidemic potential. Poxviruses 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.

Cite

@article{Meola2025,
   author = {Annalisa Meola and Riccardo Vernuccio and Leandro Battini and Guillermo Albericio and Pilar Delgado and Rebecca Bamford and Laura Pokorny and Manon Broutin and Alejandro Martínez León and Sébastien Gallien and María Gil and María A Noriega and Florence Guivel-Benhassine and Françoise Porrot and Jeanne Postal and Julian Buchrieser and Mathieu Hubert and Ahmed Haouz and Pierre Lafaye and Mariano Esteban and Jochen S Hub and Matthieu Mahévas and Pascal Chappert and Jason Mercer and Juan Garcia-Arriaza and Olivier Schwartz and Pablo Guardado-Calvo},
   doi = {10.1016/j.cell.2025.07.040},
   issn = {0092-8674},
   issue = {22},
   journal = {Cell},
   month = {10},
   note = {doi: 10.1016/j.cell.2025.07.040},
   pages = {6266-6282.e18},
   publisher = {Elsevier},
   title = {Structural basis of poxvirus fusion regulation and anti-A16/G9 antibody-mediated neutralization and protection},
   volume = {188},
   url = {https://doi.org/10.1016/j.cell.2025.07.040},
   year = {2025}
}