The Rare Mutation That Makes People Immune to Viruses

Some people carry a rare mutation that makes them resistant to viruses.

Now scientists have copied that effect with an experimental mRNA therapy that stopped both flu and COVID in animal trials — raising hopes for a universal antiviral.

Rare Mutation Unlocks Viral Immunity

For only a few dozen people worldwide, living with a rare immune disorder comes with an unexpected advantage: the ability to resist every virus that comes their way.

About 15 years ago, Columbia immunologist Dusan Bogunovic first uncovered this remarkable protection shortly after identifying the genetic mutation behind the condition.

Initially, the disorder appeared to simply make people more susceptible to certain bacterial infections. But as more cases were studied, a surprising benefit became clear. Bogunovic, now a professor of pediatric immunology at Columbia University’s Vagelos College of Physicians and Surgeons, found that everyone with the mutation, which leads to a shortage of an immune regulator known as ISG15, experiences mild but persistent whole-body inflammation.

Hidden Antiviral Clues

“The type of inflammation they had was antiviral, and that’s when it dawned on me that these individuals could be hiding something,” Bogunovic recalls. When he and his colleagues looked at the individuals’ immune cells, they could see encounters with all sorts of viruses—flu, measles, mumps, chickenpox. But the patients had never reported any overt signs of infection or illness.

“In the back of my mind, I kept thinking that if we could produce this type of light immune activation in other people, we could protect them from just about any virus,” Bogunovic says.

Now, after years of research, he is developing a potential therapy that could replicate this unusual form of protection and serve as a powerful safeguard in the next pandemic.

Breakthrough Experiment Shows Promise

In his latest study, published on August 13 in Science Translational Medicine, Bogunovic and his team report that an experimental therapy they’ve developed temporarily gives recipients (hamsters and mice, so far) the same antiviral superpower as people with ISG15 deficiency. When administered prophylactically into the animals’ lungs via a nasal drip, the therapy prevented viral replication of influenza and SARS-CoV-2 viruses and lessened disease severity.

In cell culture, “we have yet to find a virus that can break through the therapy’s defenses,” Bogunovic says.

How the Therapy Works

Bogunovic’s therapy is designed to mimic what happens in people with ISG15 deficiency, but only for a short time.

Instead of turning off ISG15 directly—which leads to the production of more than 60 proteins—Bogunovic’s therapeutic turns on the production of 10 proteins that are primarily responsible for the broad antiviral protection.

The current design resembles COVID mRNA vaccines but with a twist: Ten mRNAs encoding the 10 proteins are packaged inside a lipid nanoparticle. Once the nanoparticles are absorbed by the recipient’s cells, the cells generate the ten host proteins to produce the antiviral protection.

“We only generate a small amount of these ten proteins, for a very short time, and that leads to much less inflammation than what we see in ISG15-deficient individuals,” Bogunovic says. “But that inflammation is enough to prevent antiviral diseases.”

Next-Gen Pandemic Preparedness

Bogunovic’s team views their technology as a weapon against the next pandemic, providing protection for first responders, individuals in nursing homes, and family members of infected individuals, regardless of the responsible virus.

“We believe the technology will work even if we don’t know the identity of the virus,” Bogunovic says. Importantly, the antiviral protection provided by the technology will not prevent people from developing their own immunological memory to the virus for longer-term protection.

But the technology’s drug delivery and absorption properties still need optimization. When delivered to animals via nanoparticles, the 10 proteins were produced in the lungs, “but probably not at high enough levels that makes us comfortable going into people immediately,” Bogunovic says.

Fine-Tuning for Human Use

“Once the therapy reaches our cells, it works, but the delivery of any nucleic acid, DNA or RNA, into the part of the body you want to protect is currently the biggest challenge in the field.” The researchers also need to determine how long the therapy’s antiviral protection will last, currently estimated at three to four days.

“Our findings reinforce the power of research driven by curiosity without preconceived notions,” Bogunovic says. “We were not looking for an antiviral when we began studying our rare patients, but the studies have inspired the potential development of a universal antiviral for everyone.”

Reference: “An mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo” by Yemsratch T. Akalu, Roosheel S. Patel, Justin Taft, Rodrigo Canas-Arranz, Rachel Geltman, Ashley Richardson, Sofija Buta, Marta Martin-Fernandez, Christos Sazeides, Rebecca L. Pearl, Gayatri Mainkar, Andrew P. Kurland, Haylen Rosberger, Diana D. Kang, Ann Anu Kurian, Keerat Kaur, Jennie Altman, Yizhou Dong, Jeffrey R. Johnson, Lior Zangi, Jean K. Lim, Randy A. Albrecht, Adolfo García-Sastre, Brad R. Rosenberg and Dusan Bogunovic, 13 August 2025, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adx5758

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