In 2022, monkeypox virus (mpox) caused more than 150,000 cases—causing flu-like symptoms and painful rashes and lesions. The outbreak resulted in almost 500 deaths. At the time, vaccines developed to fight smallpox were repurposed to help the most vulnerable patients. But that vaccine—manufactured from a whole, weakened virus—is complicated and costly to make.
Now, a major inroad towards a new and more effective way to fight monkeypox virus has been published. A team used the AlphaFold 3 model to identify a viral surface protein—OPG153—as a good target for developing new antibody therapies to treat mpox or for use in a vaccine. When mice were injected with the viral surface protein, the animals produced antibodies that neutralized the monkeypox virus, suggesting the breakthrough could be used in a new mpox vaccine or antibody therapy.
This work is published in Science Translational Medicine in the paper, “Antigen-agnostic identification of poxvirus broadly neutralizing antibodies targeting OPG153.”
“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, PhD, professor of molecular biosciences at The University of Texas at Austin.
Using the blood of patients who had been previously infected with the virus or vaccinated against it, the researchers identified 12 antibodies that effectively neutralize MPXV. However, they did not know what parts of the virus they targeted.
The Alphafold 3 AI model predicted which of the roughly 35 proteins on the surface of the virus the antibodies strongly bind to. In addition, they found antibodies that bound to the viral surface protein OPG153, suggesting that the protein would make a good target for developing new antibody therapies to treat mpox or for use in a vaccine.
“It would have taken years to find this target without AI,” said McLellan. “It was really exciting because no one had ever considered it before for vaccine or antibody development. It had never been shown to be a target of neutralizing antibodies.”
The team is now working to develop versions of the vaccine antigen and antibodies that are more effective at fighting disease while cheaper and easier to produce than existing versions that use a weakened version of a closely related poxvirus. Ultimately, the researchers hope to test vaccine antigens and antibody therapies to protect against mpox and smallpox in people. McLellan calls the approach used in this study “reverse vaccinology.”
“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,” he said.
