Antigen-agnostic identification of poxvirus broadly neutralizing antibodies targeting OPG153

Ida Paciello; Ling Zhou; Emily J. Rundlet; Giulia Realini; Federica Perrone; Giulio Pierleoni; Marco Troisi; Jeanne Postal; Florence Guivel‐Benhassine; Françoise Porrot; Connor M. Mullins; Davide Moschese; Maria Vittoria Cossu; Federico Sabaini; Silvia Accordini; Natasha Gianesini; Rebeca Passarelli Mantovani; Francesca Panza; Massimiliano Fabbiani; Mario Tumbarello; Spinello Antinori; Concetta Castilletti; Francesca Montagnani; Olivier Schwartz; Rino Rappuoli; Jason S. McLellan; Emanuele Andreano

doi:10.1126/scitranslmed.aeb3840

MicrobiologyScience Translational MedicineDec 10, 2025

Peer-reviewed journal article

Antigen-agnostic identification of poxvirus broadly neutralizing antibodies targeting OPG153

Ida Paciello iD, Ling Zhou iD, Emily J. Rundlet iD, Giulia Realini iD, Federica Perrone iD, Giulio Pierleoni iD, Marco Troisi iD, Jeanne Postal iD, Florence Guivel‐Benhassine iD, Françoise Porrot iD, Connor M. Mullins, Davide Moschese iD, Maria Vittoria Cossu iD, Federico Sabaini iD, Silvia Accordini iD, Natasha Gianesini iD, Rebeca Passarelli Mantovani iD, Francesca Panza iD, Massimiliano Fabbiani iD, Mario Tumbarello iD, Spinello Antinori iD, Concetta Castilletti iD, Francesca Montagnani iD, Olivier Schwartz iD, Rino Rappuoli iD, , Emanuele Andreano iD

Abstract

Recurrent mpox outbreaks caused by the monkeypox virus (MPXV) have prompted the World Health Organization to declare a Public Health Emergency of International Concern and have stimulated the development of medical interventions. Here, antigen-agnostic isolation of neutralizing monoclonal antibodies from convalescent or vaccinated people, AlphaFold 3-based predictive modeling, and cryo-electron microscopy were synergistically combined to identify the protein encoded by orthopoxviral gene (OPG) 153 (MPXV A28) as a target of broadly neutralizing antibodies. OPG153-targeting antibodies neutralized MPXV clade Ib, IIb, and vaccinia virus (VACV), and cross-reacted with OPG153 orthologs from cowpox and variola viruses. Immunization with MPXV OPG153 elicited a potent neutralizing antibody response against MPXV and VACV, substantiating OPG153 as a promising vaccine antigen and a potent target for preventive and therapeutic antibodies.

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