Antigen-agnostic identification of poxvirus broadly neutralizing antibodies targeting OPG153

Paciello, I.; Zhou, L.; Rundlet, E. J.; Realini, G.; Perrone, F.; Pierleoni, G.; Troisi, M.; Postal, J.; Guivel-Benhassine, F.; Porrot, F.; Mullins, C. M.; Moschese, D.; Cossu, M. V.; Sabaini, F.; Accordini, S.; Gianesini, N.; Passarelli Mantovani, R.; Panza, F.; Fabbiani, M.; Tumbarello, M.; Antinori, S.; Castilletti, C.; Montagnani, F.; Schwartz, O.; Rappuoli, R.; McLellan, J. S.; Andreano, E.

doi:10.1101/2025.08.15.670377

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bioRxiv · 10.1101/2025.08.15.670377

Antigen-agnostic identification of poxvirus broadly neutralizing antibodies targeting OPG153

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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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Paciello, I., Zhou, L., Rundlet, E. J., Realini, G., Perrone, F., Pierleoni, G., Troisi, M., Postal, J., Guivel-Benhassine, F., Porrot, F., Mullins, C. M., Moschese, D., Cossu, M. V., Sabaini, F., Accordini, S., Gianesini, N., Passarelli Mantovani, R., Panza, F., Fabbiani, M., Tumbarello, M., Antinori, S., Castilletti, C., Montagnani, F., Schwartz, O., Rappuoli, R., McLellan, J. S., Andreano, E.. 2025-08-18. Antigen-agnostic identification of poxvirus broadly neutralizing antibodies targeting OPG153. https://doi.org/10.1101/2025.08.15.670377

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