The first-ever vaccine approved by the Food and Drug Administration 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.
"This 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," said McLellan, referring to a colleague he worked with at the National Institutes of Health where McLellan was a postdoctoral scientist at the time. "This is the first example where we got structure-based vaccine design to work."
People contract RSV in all stages of life, but it's most dangerous in the young and the old. The virus causes pneumonia, bronchiolitis and other diseases of the lower respiratory tract. Every year, millions of people become sick with RSV, and more than 100,000 die, mostly in areas that lack access to modern medical care. For infants under one year of age, RSV is second only to malaria for infectious disease deaths.
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-new 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 element of the FDA-approved COVID-19 vaccines.
It was already known that a certain part of RSV, called the F protein, is responsible for infection. But the F protein is a shape shifter - before it infects and fuses with a cell, its shape (what scientists call its "presfusion conformation") is different from after it enters the cell. If the immune system encounters an RSV virus with the F protein in this prefusion shape, it makes potent antibodies. But in its postfusion 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. Next, they developed ways to keep the F protein from shape-shifting, locking it in the conformation that elicits the right antibodies.
In 2013 the team tested several versions as a vaccine in both mice and nonhuman primates. These protein variants elicited high levels of neutralizing antibodies and protected the animals against RSV infection.
"Our first time testing these stabilized molecules in animals, the response was 10-fold higher than anything anyone had ever seen before," said McLellan, who holds the Robert A. Welch Chair in Chemistry. "And at that point, we're thinking, 'This is it. We've got it.' That was exciting."
Approved on May 3, GSK's vaccine Arexvy showed a 94% reduction in severe illness and was nearly 83% effective against lower respiratory tract illness in human trials; it was recommended in March for approval by an advisory committee to the FDA. Based on the work by McLellan, Graham and Kwong at the NIH, Arexvy contains a recombinant subunit prefusion version of RSV F and was approved for use in older adults.
A second RSV vaccine - developed by pharmaceutical company Pfizer - also contains a stabilized, prefusion F protein based on the lesssons from the research team. An interim analysis last summer showed the vaccine was roughly 86% effective against severe RSV disease. The FDA is expected to consider approving it soon for older adults, and possibly within a matter of months, also for pregnant mothers, since vaccines for that population were also reportedly shown to be safe and effective. With that 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 investigator involved in this research, Jason McLellan, has submitted required financial disclosure forms with the university. McLellan is an inventor on several patent applications related to this research filed by the National Institutes of Health, from which he is receiving royalties.
