In the past few months, the respiratory syncytial virus (RSV) has been sending children under the age of 5 to hospital at alarming rates in the United States and Europe. As paediatric units fill beyond capacity, and physicians contend with a ‘tripledemic’ of RSV, influenza and COVID-19, some have been calling for a state of emergency to be declared.
RSV, which inflames the smallest airways of the lungs, is the only one of the three respiratory illnesses for which there are not yet any approved vaccines — but that could soon change. Last week, the pharmaceutical company Pfizer announced that the US Food and Drug Administration (FDA) had agreed to review its RSV vaccine, to be administered to adults over the age of 60, as a priority. If approved — which might happen as soon as May — it could be the first sanctioned jab for RSV. The same vaccine has also shown positive results against RSV in a clinical trial in pregnant people, and Pfizer has said it will seek approval for this group by the end of the year.
Nature looks back at how vaccines for RSV emerged, and ahead to how they are about to change the public-health landscape.
RSV has been a problem for decades. Why are vaccines only emerging now?
Efforts to develop an RSV vaccine were set back substantially after a particularly notable failure in the 1960s. Researchers had developed a vaccine containing RSV particles that were chemically inactivated so that the virus couldn’t replicate. But when they tested the shot in infants in a clinical trial, it ended in tragedy: two babies died. At first, the infants tolerated the vaccine well, says Jason McLellan, a structural biologist at the University of Texas at Austin. But during the next cold and flu season, 80% of the children who had received a shot and then subsequently caught RSV became so ill they were hospitalized1. By comparison, only 5% of children who received the placebo and then caught RSV ended up in hospital.
The failure halted efforts to develop an RSV vaccine, as scientists worked to understand what had happened.
How did researchers overcome this failure?
Rather than continue trying to make a vaccine from inactivated virus, researchers attempted to make a protein-based vaccine, in which an isolated component of the virus, such as a surface protein, is used to trigger a protective immune response. A major breakthrough came when scientists, including McLellan, characterized the different conformations of protein F, a molecule found on the surface of RSV. Protein F helps to bring together the membranes of the virus and the host cell, so that the virus can infect the cell.
Protein F exists in two forms: a postfusion form, which is highly stable, and a prefusion form, which is not. The protein takes on the prefusion form during infection, when the virus and host cell are coming together, and transitions to the second form once infection has taken hold.
Prefusion F is “a very unstable protein”, but “that is what is fully active, and induces the most robust immune response”, so it was what was needed to make an effective vaccine, says Pedro Piedra, a virologist at Baylor College of Medicine in Houston, Texas, whose research focuses on reducing the burden of illness caused by respiratory viruses in infants.
McLellan and a number of collaborators eventually characterized the structure of the prefusion form and then worked out how to stabilize it2. This enabled vaccine development, as well as opening the door to potential antibody-based therapies. A number of companies now have RSV vaccines in the pipeline, with versions from Pfizer and GSK being the closest to approval by government regulators.
Will those vaccines succeed?
Pfizer, which has headquarters in New York City, announced successful phase III results from two trials of its vaccine candidate earlier this year. In one trial, the firm gave the vaccine to pregnant people to boost their total antibody numbers, the idea being that those antibodies would then get transferred to their infants.
Pfizer reported in a press release that this strategy had an efficacy of 81.8% against severe cases of RSV in the infants for the 90 days after birth.
In the United States, RSV usually sends an average of 58,000–80,000 kids under the age of 5 to hospital each year, according to the US Centers for Disease Control and Prevention (CDC). Infants are most likely to be hospitalized with RSV around two and a half months of age, when their lungs are still developing, McLellan says. The major risk for infants and young children catching RSV “has a lot to do with having smaller airways”, says Helen Chu, an infectious-disease specialist at the University of Washington in Seattle.
RSV can also be dangerous for adults over the age of 65, resulting in an average of 60,000–120,000 hospitalizations per year in the United States, says the CDC. In Pfizer’s other phase III trial, the vaccine was reported to have an efficacy of 85.7% at preventing severe disease in adults over the age of 60. GSK, which has global headquarters in London, has also reported successful phase III results for an RSV vaccine tested in adults over the age of 60, which had an efficacy of 94.1% at preventing severe disease.
Pfizer and GSK will now race for approval; GSK announced last month that the FDA will give its vaccine priority review. As with Pfizer, approval could come as early as May.
But the vaccines are “not going to make RSV go away”, warns Barney Graham, a virologist and immunologist at Morehouse School of Medicine in Atlanta, Georgia, who collaborated with McLellan on prefusion F. What the vaccines will do, he adds, is protect some of the most vulnerable groups, including very young and very old people.
In the meantime, can any other treatments curb RSV?
Before this month, there was only one drug to tackle RSV. The monoclonal antibody palivizumab, originally developed by the pharmaceutical firm MedImmune, in Gaithersburg, Maryland, can be administered monthly as a prophylactic to reduce the severity of illness in infants and young children. Given the cost, necessary frequency of doses and the fact that it must be injected, physicians give palivizumab only to high-risk infants and children. Another monoclonal antibody, called nirsevimab and developed by companies AstraZeneca in Cambridge, UK, and Sanofi in Paris, finished phase III trials successfully earlier this year3. Its advantage is that one dose offers five months of protection against severe disease in infants. The European Commission approved it last month, and the FDA is reviewing it.
A number of tools could soon be available to help combat a disease that has haunted parents for decades, Graham says. “This is a major breakthrough.”