Half a century of research has failed to thwart respiratory syncytial virus (RSV), which causes severe disease in the lower airways and lungs of some 3 million newborn children and kills more than 100,000 worldwide each year. But now, two different approaches have had success. One gives a monoclonal antibody against RSV to the babies, whereas the other vaccinates their mothers against the virus, presumably leading to antibodies that protect their children.
Although more studies are needed before either product comes to market, the results, both published today in The New England Journal of Medicine, have given a boost to a beleaguered field. “These two studies provide encouraging data that prevention of this common infection in young infants is feasible,” says pediatrician Kathryn Edwards of Vanderbilt University School of Medicine, who was not involved in the studies.
A monoclonal antibody against RSV, palivizumab, has been on the market since 1998. Made by AstraZeneca, palivizumab has limited potency and degrades relatively quickly, meaning infants must receive five monthly shots—which, all told, cost several thousands of dollars—to ward off the disease. That’s why it’s only given to babies at highest risk of developing severe disease from RSV, such as those born prematurely with underlying heart or lung diseases. It is given just before and then throughout the RSV season, which in temperate regions is from fall through spring. In the United States, about 2% of babies receive palivizumab prophylactically.
Pediatrician Cody Meissner, an RSV researcher at Tufts University, says there’s “no question” that palivizumab works. But, he adds, some doctors “pushed the envelope and tried to imply that it had more beneficial effect, than, in fact, could be documented.” He notes that more than 80% of infants who develop severe RSV disease are full-term, healthy babies at birth, making an RSV monoclonal that is safe, effective, and easy to administer the real goal. But so far, monoclonals that sought to improve on palivizumab’s modest success have failed to win regulatory approval.
Nirsevimab, a new monoclonal developed by AstraZeneca in collaboration with Sanofi Pasteur, may fit the bill. It has a higher potency and more than three times the half-life of palivizumab, meaning a single shot can last for an entire RSV season. In a trial among 1500 preterm infants in 23 countries, researchers have shown that babies who received a single shot of nirsevimab within 2 months of the start of RSV season were 78.4% less likely to end up in the hospital with RSV-associated lower respiratory disease than those who received a placebo.
“They’re beautiful results,” says Barney Graham, an RSV researcher at the U.S. National Institute of Allergy and Infectious Diseases who was not involved with the study. Meissner agrees that nirsevimab “looks like a pretty interesting product.”
Study author Tonya Villafana of AstraZeneca says the company isn’t planning to seek regulatory approval for nirsevimab yet. The two companies first hope to show that nirsevimab proves safe and effective for all babies; to that end, they have a placebo-controlled study underway in 3000 healthy infants born either “late preterm” or full-term. “We would always want to see—and the regulators would want us to have—a bigger data safety base,” Villafana says. Another study is comparing nirsevimab with palivizumab in the highest risk babies. Both studies are slated to be completed in 2023 but could end earlier if nirsevimab yields stronger than expected signals of success or failure.
The companies have yet to disclose pricing plans. “It’s a little premature for us to talk about that,” Villafana says. Edwards says the question is key. “Whether this product will be priced to make it accessible to premature infants with an acceptable cost/benefit ratio remains to be seen,” she says. Merck also has a monoclonal antibody against RSV in late-stage development, and Graham says competition likely could drive down price.
As for RSV vaccines, the field has a troubled past. In the 1960s, a vaccine given to babies increased the likelihood that they developed severe disease, probably because it tilted their immune systems in the wrong direction. Several other candidate vaccines have failed, in part because it is difficult to trigger strong responses in babies’ immature immune systems. But the biotechnology company Novavax appears to have had some success with a different approach: Vaccinate the pregnant mother—in this case with RSV’s surface protein in a nanoparticle formulation—and hope her antibodies pass to the baby.
For that study, researchers administered Novavax’s vaccine or a placebo to more than 4500 pregnant women in 11 countries who were between 28 and 37 weeks of gestation and expected to deliver at the start of RSV season. Then, they analyzed the health of the children for 180 days after birth. Ideally, a vaccine would reduce pediatric or emergency room visits for RSV-related disease that is worrisome but not severe. The study did not find any statistically significant drop in “medically significant” lower respiratory disease in babies whose mothers received the vaccine, the trial’s primary endpoint. But the babies of vaccinated mothers did have a 44.4% reduction in hospitalization for RSV-related lower respiratory tract infections, suggesting the vaccine does limit disease severity. “It is a step in the right direction,” Edwards says.
For reasons that remain unclear, the vaccine appeared to work better in children in lower middle-income countries, including Bangladesh, Mexico, the Philippines, and South Africa.
If maternal vaccines and monoclonal antibodies in babies both prove safe and effective, there will be a niche for each, says Graham, who is working with Pfizer to develop an RSV vaccine. Some women may seek care too late in a pregnancy for their babies to benefit from the vaccine, he says. It could also be that a vaccine or a monoclonal antibody may not find wide acceptance. “Some cultures may not want you to immunize a pregnant woman, and some cultures may not want you to touch a baby,” Graham says. “There are a lot of things that are going to determine how they’re used, and I think they will be complementary.”