Structural basis of poxvirus fusion regulation and anti-A16/G9 antibody-mediated neutralization and protection
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.
Authors
- Pierre Lafaye (ORCID: https://orcid.org/0000-0002-5761-1342)
- Pablo Guardado‐Calvo (ORCID: https://orcid.org/0000-0001-7292-5270)
- Pilar Delgado (ORCID: https://orcid.org/0000-0002-8431-8002)
- Alejandro Martínez León (ORCID: https://orcid.org/0009-0005-6162-7303)
- Sébastien Gallien (ORCID: https://orcid.org/0000-0002-8033-0936)
- Rebecca Bamford (ORCID: https://orcid.org/0000-0002-7382-3548)
- Julian Buchrieser (ORCID: https://orcid.org/0000-0003-4790-7577)
- Mariano Estéban (ORCID: https://orcid.org/0000-0003-0846-2827)
- Matthieu Mahévas (ORCID: https://orcid.org/0000-0001-9913-7741)
- Françoise Porrot (ORCID: https://orcid.org/0000-0001-8995-3614)
- Guillermo Albericio (ORCID: https://orcid.org/0000-0003-0190-4848)
- Florence Guivel‐Benhassine (ORCID: https://orcid.org/0000-0003-3410-5671)
- Jason Mercer (ORCID: https://orcid.org/0000-0003-1466-9541)
- Leandro Battini
- Olivier Schwartz (ORCID: https://orcid.org/0000-0002-0729-1475)
- Manon Broutin (ORCID: https://orcid.org/0000-0002-7641-036X)
- Jochen S. Hub (ORCID: https://orcid.org/0000-0001-7716-1767)
- Pascal Chappert (ORCID: https://orcid.org/0000-0002-9799-4608)
- Annalisa Meola (ORCID: https://orcid.org/0000-0003-2582-4463)
- Laura Pokorny (ORCID: https://orcid.org/0009-0001-0976-255X)
- Juan García‐Arriaza (ORCID: https://orcid.org/0000-0002-5167-5724)
- Mathieu Hubert (ORCID: https://orcid.org/0000-0002-2190-0177)
- María A. Noriega
- Riccardo Vernuccio (ORCID: https://orcid.org/0009-0009-8319-0922)
- María Concepción Robles Gil (ORCID: https://orcid.org/0000-0003-0641-7539)
- Ahmed Haouz (ORCID: https://orcid.org/0000-0002-0843-1580)
- Jeanne Postal
Institutions
- Centre National de la Recherche Scientifique (FR)
- Consejo Superior de Investigaciones Científicas (ES)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Paris-Est Créteil (FR)
- Université Paris Cité (FR)
- Centre Hospitalier Universitaire Henri-Mondor (FR)
- Institut Necker Enfants Malades (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centro Nacional de Biotecnología (ES)
- Centro de Investigación Biomédica en Red (ES)
- Institut de Recherche Vaccinale (FR)
- Institut Mondor de Recherche Biomédicale (FR)
- University College London (GB)
- University of Birmingham (GB)
- Saarland University (DE)
Publication Details
- Journal
- Cell
- Published
- 2025-08-26
- DOI
- https://doi.org/10.1016/j.cell.2025.07.040
- Citations
- 12
- Primary Topic
- Poxvirus research and outbreaks
- Type
- article
- Field-Weighted Citation Impact
- 12.44
Funders
- Ministerio de Ciencia, Innovación y Universidades
- European Commission
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Consejo Superior de Investigaciones Científicas