Yale study offers critical clues for future norovirus treatments

As the leading cause of viral gastroenteritis worldwide, norovirus is an all too familiar ailment. Its telltale digestive upset — not to mention its reputation for being notoriously contagious — has earned it the nicknames "winter vomiting bug" and "stomach flu."

Yet despite millions of dollars spent on research, there are still no vaccines or anti-viral drugs for norovirus.

A new Yale study, however, offers an important clue into where future treatments might be found: To beat the stomach flu, the researchers found, one should take the fight to the gut.

The findings, published in the journal Science Translational Medicine, upend traditional vaccine development efforts which to date have focused on creating norovirus-fighting antibodies that circulate in the blood rather than taking up residence in the gut.

According to findings, mucosal IgA (Immunoglobulin A) antibodies — which are found primarily in the body's mucosal surfaces, including the lungs, airway, the intestines, and gut — provide key immune defense against norovirus.

Therefore, the researchers say, the path to norovirus vaccines should focus on generating IgA, gut-based immunity.

One of the big challenges with norovirus is there are no drugs or vaccines, but that's not simply due to lack of investment. It's due to our limited understanding about the biology and the immunology of norovirus infection."

Craig Wilen, study senior author, associate professor of laboratory medicine and immunobiology, Yale School of Medicine (YSM)

"By using mouse models, we discovered that IgA was both necessary and sufficient for protection against norovirus."

This study was led by first author Arya ökten, who recently defended her Ph.D. in the labs of Wilen and of Joseph Craft, the Paul B. Beeson Professor of Medicine (Rheumatology) and Professor of Immunobiology at YSM.

For the study, the researchers first measured immune responses in cases of norovirus infection. They found that immunoglobin G (IgG) — the most common antibody in the blood which fights infections throughout the body — appeared quickly. Gut IgA, meanwhile, developed much more slowly.

Then, using genetically engineered mice, they discovered that B cells (which are immune cells that produce antibodies) and IgA were essential in fighting norovirus, while CD8 T cells (specialized immune cells that identify and destroy infected cells) were not.

They then examined reinfection with norovirus and found that mice with prior infection were largely protected, but engineered mice lacking IgA lost protection. Seeking a way to capitalize on IgA-mediated immunity, the researchers collaborated with Ted Kreider, assistant professor of medicine at the University of Pennsylvania. Together, they engineered mRNA lipid nanoparticles to produce anti-norovirus IgA.

This, they found, completely protected the mice from norovirus infection.

This discovery opens the door to potential norovirus treatment strategies that use mRNA technology to deliver protective IgA antibodies directly into the gut. In healthy adults, norovirus infection may need to persist for several weeks before the gut generates a strong protective IgA response on its own, the researchers noted. For chronically infected, immunocompromised patients, who can be infected for weeks to years, IgA could be a powerful therapeutic.

"We're now trying to figure out ways that we can test norovirus vaccine candidates that will elicit an IgA response," Wilen said. "It's a new immunological approach to the virus."