AI Tips Off Scientists to a New Drug Target for Mpox
An international team used artificial intelligence to pinpoint a viral surface protein that triggers neutralizing antibodies against monkeypox virus (MPXV). In mice, a vaccine antigen based on that protein led to antibodies that blocked the virus, suggesting a clear path for both vaccine and antibody therapy development.
The work, published in Science Translational Medicine, leans on "reverse vaccinology." Researchers started with antibodies from people previously infected or vaccinated, then worked backward to find the viral protein those antibodies hit-and engineered it into a simple, single-protein antigen.
Why this matters
- Mpox still poses risk, especially for children, pregnant women, and immunocompromised people. In 2022, more than 150,000 cases and nearly 500 deaths were reported globally.
- Current smallpox-derived vaccines are effective but complex and expensive to manufacture because they use a whole, weakened virus.
- MPXV is closely related to smallpox, so this target may support better mpox tools and potentially inform smallpox countermeasures-relevant to biodefense planning.
How the target was found
Italian researchers analyzed blood from people who had recovered from mpox or were vaccinated and identified 12 antibodies that neutralize MPXV, but their precise targets were unknown. The team at The University of Texas at Austin ran predictions with the AlphaFold 3 model to determine which of roughly 35 viral surface proteins those antibodies bind to.
The AI flagged OPG153 as a strong candidate. Lab follow-up confirmed the prediction: antibodies bound OPG153, and an engineered OPG153 antigen elicited neutralizing responses in mice.
"It would have taken years to find this target without AI," said Jason McLellan, professor of molecular biosciences at UT and co-lead author. "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."
Reverse vaccinology, applied
"We started with people who survived infection with monkeypox virus, isolated antibodies that they naturally produced and worked backward to find what part of the virus acted as the antigen for those antibodies. Then we engineered the antigen to elicit similar antibodies in mice," McLellan said. "Unlike a whole-virus vaccine that's big and complicated to produce, our innovation is just a single protein that's easy to make."
This single-protein approach could lower cost, simplify manufacturing, and streamline quality control compared with whole-virus platforms-key advantages for real-world deployment at scale.
What comes next
- Optimize the OPG153 antigen and corresponding antibodies for stronger protection and easier, cheaper production.
- Advance antibody and vaccine candidates toward human testing for mpox-and assess cross-protection potential against smallpox.
- Define epitopes and mechanisms of neutralization to support rational vaccine design and combination antibody therapies.
Details for researchers
- Target: OPG153, a previously overlooked MPXV surface protein now validated as an antigen for neutralizing responses.
- Discovery: AlphaFold 3 predictions guided antigen selection; wet-lab assays verified binding and neutralization.
- Translational angle: A protein-only antigen could replace complex whole-virus manufacturing workflows.
- IP: UT Austin filed a patent application on OPG153 (and derivatives) as a vaccine antigen; Fondazione Biotecnopolo di Siena filed on antibodies targeting OPG153.
For context on the journal and methods, see Science Translational Medicine and AlphaFold resources from DeepMind. Public health guidance on mpox remains available from the U.S. CDC.
Team and support
Key contributors include Jason McLellan and colleagues at The University of Texas at Austin (Emily Rundlet, Ling Zhou, Connor Mullins) and collaborators at the Fondazione Biotecnopolo di Siena (Rino Rappuoli, Emanuele Andreano), who identified the original neutralizing antibodies. The Welch Foundation provided partial funding.
Original news release: University of Texas at Austin, published December 10, 2025.
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