In 2013, Jason McLellan and colleagues determined the molecular structure of the RSV F glycoprotein in the pre-fusion conformation (the shape before the virus infects the cell). This allows them to redesign proteins reasonably, thus creating a powerful new vaccine against RSV. Image source: University of Texas at Austin
respiratory syncytial virus (RSV) experimental vaccine is one of the main causes of death from infectious diseases in infants and has shown early hope in phase 1 human clinical trials. A team of researchers, including Jason McLellan, a University of Texas at Austin, reported today in the journal " Science " that their dose of vaccine candidate caused a massive increase in RSV neutralizing antibodies, which lasted for months.
People will receive RSV at all stages of their lives, but this is the most dangerous among young people and older people. The virus causes pneumonia, bronchiolitis and other lower respiratory tract diseases. Millions of people suffer from RSV each year and more than 100,000 people die, most in areas with a lack of modern medical services. For infants under 1 year old, RSV is second only to malaria in deaths in infectious diseases.
Barney Graham and Peter Kwong from the National Center for Vaccine Research (VRC), the National Center for Allergy and Infectious Diseases Research, as well as McLellan, a former VRC postdoctoral fellow and current associate professor at UT Austin, have pioneered the development of the candidate vaccine DS-CAV1.
50 years ago, scientists have tried to use traditional methods to make RSV vaccines - so far, no one has worked. Instead, McLellan and his colleagues adopted a new approach called structure-based vaccine design.
already knows that a certain part of RSV, called F protein, triggers the human immune system to produce antibodies. But F protein is a shape shifter - before it infects the cell, it takes one shape, and then during infection, it turns into a second shape. If the immune system encounters the first form of the F protein RSV virus, it produces effective antibodies. But if the proteins are in the second shape, fewer antibodies are triggered and they are not very effective. Production of RSV vaccines using traditional methods usually results in poor responses to the second form of F protein and antibody.
This is where the structure-based approach comes in. First, the researchers used a technique called X-ray crystallography to determine the atomic structure of the first-shaped F protein. Next, they redesigned the F protein to eliminate its shape-switching ability, locking it in the shape that triggers the best antibody. Color scanning electron micrographs of human respiratory syncytial virus (RSV) virions (blue) and labeled with anti-RSV F protein/gold antibody (yellow) shed from the surface of human lung epithelial cells. Image source: NIAID
In 2013, they tested several versions of the vaccine in mice and nonhuman primates. These protein variants trigger high levels of neutralizing antibodies and protect the animals from RSV infection.
"For the first time we tested these stable molecules in animals, the reaction was 10 times higher than anyone before," McLellan said. “At that time, we were thinking, ‘That’s it. We’ve got it.’ That’s exciting.”
The most promising DS-Cav1 of these vaccine candidates was selected for clinical evaluation, which was subsequently made by VRC.
in science data reported from the top 40 healthy adult volunteers included in the trial, and the interim analysis began at the National College of Health Clinical Center in 2017. The researchers found that vaccine candidates can increase RSV neutralizing antibodies more than 10 times compared to the number of antibodies a person naturally produces after RSV exposure in early life.
results are promising, but McLellan carefully sets them aside.
"The first phase is just asking: Is it safe, does it trigger the type of antibodies and reactions we want to see?" he said. "It also needs to go through phases 2 and phase 3, focusing on efficacy, for example, will it reduce the severity of the disease or will it reduce hospitalization?"
Many drugs have not been completed through clinical trials. But if this or others are based on the same F protein structure he helped find, McClellan said it could be a game-changer.
"If it works quite well, we can prevent 70 to 80% of all deaths, then think about all the little babies and toddlers we are going to save," McClellan said. "There aren't that many vaccines in the world, so it would be great if we can really get involved in making a vaccine that works and saves lives."
