Researchers using artificial intelligence have identified a surface protein on the monkeypox virus that provokes strong neutralizing antibodies in mice. The protein, called OPG153, could form the basis of simpler vaccines and antibody therapies against mpox and may also inform future smallpox countermeasures, according to a study in Science Translational Medicine.
An international team of scientists has reported a potential new weak spot in the monkeypox virus (MPXV), using artificial intelligence to highlight a little‑studied surface protein, OPG153, as a promising vaccine and drug target.
In work published in Science Translational Medicine, the researchers show that OPG153 is targeted by potent neutralizing antibodies isolated from people who had recovered from mpox or had been vaccinated against related poxviruses. The study found that using this protein as a vaccine component in mice triggered a strong neutralizing antibody response, suggesting a more focused way to design future vaccines and antibody therapies.
The research builds on the 2022 global mpox outbreak, which spread to multiple countries and infected more than 150,000 people, causing nearly 500 deaths and symptoms including flulike illness, rashes and lesions. Children, pregnant women and people with compromised immune systems have been identified as at higher risk for severe disease. During that outbreak, health authorities leaned heavily on smallpox vaccines, which rely on weakened whole viruses and can be costly and complex to manufacture.
"Unlike a whole-virus vaccine that's big and complicated to produce, our innovation is just a single protein that's easy to make," said Jason McLellan, a professor of molecular biosciences at The University of Texas at Austin and co-lead author of the study, in a statement released by the university.
Co-lead authors Rino Rappuoli and Emanuele Andreano of the Fondazione Biotecnopolo di Siena in Italy identified 12 monoclonal antibodies that neutralize MPXV by analyzing blood from people who had been infected or vaccinated. To determine which viral components those antibodies recognized among roughly 35 known surface proteins, McLellan’s team at UT Austin used the AlphaFold 3 AI model to predict likely binding partners.
The model pointed with high confidence to OPG153, a surface protein encoded by orthopoxviral gene 153. Laboratory experiments confirmed that several of the patient-derived antibodies bound tightly to OPG153 and neutralized multiple MPXV clades and vaccinia virus in vitro. In mouse studies, immunization with MPXV OPG153 generated a potent neutralizing antibody response against MPXV and vaccinia, supporting its potential as a vaccine antigen.
"It would have taken years to find this target without AI," McLellan said. "It was really exciting because no one had ever considered this protein before for vaccine or antibody development. It had never been shown to be a target of neutralizing antibodies."
Because MPXV is closely related to the virus that causes smallpox, the team notes that OPG153-focused approaches may also aid efforts to develop improved smallpox vaccines or antibody treatments.
The researchers describe their strategy as a form of "reverse vaccinology": starting with antibodies naturally produced by people who survived infection or had been vaccinated, then working backward to identify the viral antigen and engineering versions that can elicit similar antibodies in animal models.
The University of Texas at Austin has filed a patent application covering the use of OPG153 and related constructs as vaccine antigens, while the Fondazione Biotecnopolo di Siena has applied for patents on antibodies that target OPG153. According to UT Austin, the work was funded in part by the Welch Foundation.
