Newly identified protein structure could pave the way for RSV vaccines, drugs

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The alpha 3 helix region in an RSV protein could lead to the development of drugs or vaccines for people most at risk of severe RSV infection: infants and older adults.

A team led by Washington University in St. Louis has unraveled the structure of a protein that allows respiratory syncytial virus (RSV) to elude the immune system. This structure could be a target for researchers developing vaccines or treatments for RSV infection.

RSV is a common respiratory virus that tends to cause mild symptoms. But the infection can be serious in people with weakened immune systems, including infants and older adults. There is no RSV vaccine, nor is there a specific antiviral treatment, according to the CDC.

Scientists have long known that an RSV protein, known as NS1, is behind the virus’ ability to evade the immune response, but the protein’s structure has been unknown until now. Without understanding the structure, scientists couldn’t identify how NS1 affects the immune system.

Co-senior authors Daisy Leung and Gaya Amarasinghe used X-ray crystallography to visualize the structure of NS1. This method involves crystallizing the protein, aiming X-rays at it and analyzing the way the crystal causes the X-rays to diffract.

They landed on a piece of the protein, the alpha 3 helix, which the scientists suspected played a role in dampening the immune response. Along with colleagues from Georgia State University, Leung and Amarasinghe created different versions of the RSV virus, some with normal NS1 protein and others with a mutated alpha 3 helix.

When the team infected cells with these viruses, they found that viruses with a helix mutation did not suppress the immune response, while viruses with a normal helix region did. The findings are published in Nature Microbiology.

"One of the surprising things we found was that this protein does not target just one set of genes related to the immune response, but it globally modulates the immune response," Amarasinghe said in a press release. The alpha 3 helix is required for RSV to interfere with the immune response and cause disease, so a vaccine or treatment that targets it could be useful for people with compromised immune systems.

A number of pharma players have RSV vaccines in the pipeline, including Bavarian Nordic and AstraZeneca’s MedImmune. Novavax, which is racing to bring the first RSV vaccine to market, suffered a phase 3 failure in older adults last fall. Despite a drop in shares and the need to lay off 30% of its workforce, the Maryland-based biotech is pressing on, launching a new phase 2 study and continuing a trial evaluating the vaccine’s ability to protect infants through maternal immunization.

As for therapeutics, researchers at St. Jude Children’s Research Hospital discovered that a cancer drug prevents the flu virus from replicating by targeting its effects on cell metabolism. The drug blocked the virus’ ability to alter the glucose metabolism of the cells that line the lungs, decreasing the production of new virus. While their focus was flu, the team plans to study how cell metabolism is affected by other respiratory viruses, including RSV.