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VUMC, Oxford team develops ‘blueprint’ to block lethal virus

Jun. 22, 2023, 8:39 AM


by Bill Snyder

Researchers at Vanderbilt University Medical Center and the University of Oxford have determined how a human monoclonal antibody isolated at Vanderbilt in 2021 can prevent infection by the potentially lethal Sin Nombre virus.

Their findings, published June 15 in the journal Nature Microbiology, provide a “molecular-level blueprint” for understanding the antibody’s neutralizing response, an important step toward development of the first effective protection against this emerging pathogen.

“Studies of the three-dimensional structures of antibodies bound to their viral targets show us how these molecules recognize and inhibit viruses in the body,” said James Crowe Jr., MD, Ann Scott Carell Professor and director of the Vanderbilt Vaccine Center. “They also reveal the extreme beauty in natural phenomena.”

Crowe, also professor of Pediatrics and Pathology, Microbiology and Immunology at VUMC, is the paper’s co-corresponding author with Thomas Bowden, DPhil, professor of Structural Biology at Oxford’s Wellcome Center for Human Genomics.

“It has been very exciting to study these hantavirus antibodies with Bowden and his team,” Crowe said.

New World hantaviruses, including Sin Nombre, are primarily transmitted by rodents, but evidence suggests they also may be spread through close human contact. There is no effective treatment for hantavirus infection, which can cause the lungs to fill with fluid. The fatality rate approaches 40%.

Since the Sin Nombre virus was first isolated in the Four Corners region of the Colorado Plateau in 1993, 800 cases have been reported in the United States, including a 2012 outbreak at Yosemite National Park that killed three campers.

In 2021, Crowe and his colleagues isolated broad and potently neutralizing monoclonal antibodies from the blood of people who had survived New World hantavirus infections. Four of the antibodies, when injected into muscle in animal studies, showed therapeutic efficacy at clinically relevant doses.

In the latest study, Crowe’s team partnered with Bowden and his colleagues to evaluate a highly neutralizing monoclonal antibody, SNV2, that had been isolated from a survivor of a Sin Nombre infection.

Crystallographic analysis conducted by Bowden’s group revealed that the antibody targeted part of the viral envelope, thereby preventing the virus from fusing with and injecting its genetic material into the cells of its host.

While further study is needed, these findings suggest that SNV2 could provide the first effective protection against infection by the Sin Nombre virus, the researchers concluded.

VUMC co-authors were Nathaniel Chapman, Rachel Wolters, DVM, Laura Handal, Summer Diaz, and Taylor Engdahl, the paper’s co-first author with Oxford’s Robert Stass, PhD.

The research was supported in part by the Wellcome Trust, the National Institutes of Health, and the German science and technology company Merck KGaA. Crowe is a 2019 recipient of the company’s Future Insight Prize.


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