FDA-approved RSV vaccine activated by work of UT molecular biologist

AUSTIN, Texas — The first-ever Food and Drug Administration-approved vaccine to treat respiratory syncytial virus (RSV) uses research from a team that includes Jason McLellan, a professor of molecular biosciences at the University of Texas at Austin.

“It is one of the most important viral pathogens for which we still lacked a vaccine. This milestone also means a lot to me and Barney Graham,” McLellan said, referring to a colleague he worked with at the National Institutes of Health where McLellan was a postdoctoral fellow at the time. “This is the first example where we have successfully made structure-based vaccine design work.”

People get RSV at all stages of life, but it is most dangerous in young and old people. The virus causes pneumonia, bronchiolitis and other lower respiratory diseases. Every year, millions of people contract RSV and more than 100,000 die from it, mostly in areas that lack access to modern medical care. For infants under the age of one, RSV is second only to malaria in deaths from infectious diseases.

Scientists have searched for decades for an effective vaccine. McLellan, Graham, and Peter Kwong of the National Institute of Allergy and Infectious Diseases Vaccine Research Center showed in 2013 that a then-novel approach, called structure-based vaccine design, could lead to an effective RSV vaccine. McLellan, Graham and others later used the same approach to design a key component of FDA-approved COVID-19 vaccines.

We already knew that a certain part of RSV, called the F protein, is responsible for the infection. But the F protein is a shapeshifter – before it infects and fuses with a cell, its shape (what scientists call its “prefusion conformation”) is different from that after it enters the cell. If the immune system encounters an RSV virus with the F protein in this prefusion form, it makes strong antibodies. But in its post-fusion conformation, the antibody response is weak and therefore not suitable for a vaccine.

This is where the structure-based approach comes in. First, McLellan and the team used a technique called X-ray crystallography to determine the atomic level structure of the F protein. Then they developed ways to conserve protein F shapeshifting, locking it into the conformation that elicits the right antibodies.

In 2013, the team tested several versions as a vaccine in mice and non-human primates. These protein variants elicited high levels of neutralizing antibodies and protected animals against RSV infection.

“The first time we tested these stabilized molecules in animals, the response was 10 times greater than anything anyone had ever seen before,” said McLellan, Robert A. Welch Chair in Chemistry. “And then we think, ‘This is it. We have it.’ It was exciting.

Approved May 3, GSK’s Arexvy vaccine showed a 94% reduction in severe disease and was nearly 83% effective against lower respiratory tract disease in human trials; it was recommended in March for approval by an advisory committee to the FDA. Based on work by McLellan, Graham, and Kwong at NIH, Arexvy contains a recombinant subunit prefusion version of RSV F and has been approved for use in the elderly.

A second RSV vaccine – developed by pharmaceutical company Pfizer – also contains a stabilized prefusion F protein based on the research team’s lessons. An interim analysis last summer showed that the vaccine was approximately 86% effective against severe RSV disease. The FDA should consider approving it soon for the elderly, and perhaps in a few months, also for pregnant women, since vaccines for this population would also have been proven to be safe and effective. With this population, the goal is to protect vulnerable infants through the natural transfer of antibodies from mother to child.

The University of Texas at Austin is committed to transparency and disclosure of all potential conflicts of interest. The university researcher involved in this research, Jason McLellan, submitted the required financial disclosure forms to the university. McLellan is an inventor on several patent applications related to this research filed by the National Institutes of Health, from which he receives royalties.