Children at risk for severe respiratory syncytial virus (RSV) disease may remain protected for a second year in a row with a higher dose of the long-acting monoclonal antibody clesrovimab, according to new phase 3 data published on July 20 in JAMA Pediatrics.

Results from the new trial showed for their second season, a single 210-mg dose of the long-acting monoclonal antibody was safe in children who remained vulnerable because of conditions such as chronic lung disease of prematurity.

Although clesrovimab is already FDA-approved as a fixed-dose injection for infants entering their first fall or winter, evidence for a second season has been limited.

For infants at highest risk, “for years, the only RSV antibody we had was palivizumab, which had to be given monthly,” said Vandana Madhavan, MD, MPH, clinical director of pediatric infectious diseases at Mass General Brigham in Boston, who was not involved in the study.

The new trial compared clesrovimab with the older drug, which is no longer on the market. Nirsevimab is the only product currently recommended by the CDC for infants and children aged 8-19 months at high risk for RSV-associated lower respiratory tract infections entering their second RSV season.

Because placebo-controlled trials are unlikely for ethical and practical reasons, “we need both next generation monoclonal antibodies to be available for use as soon as possible even without ideal data from randomized controlled trials,” said Christopher J. Harrison, MD, professor of pediatrics at the University of Missouri-Kansas City School of Medicine and Children’s Mercy Kansas City.

Merck is sharing the second-season data with the FDA and other global regulatory agencies as part of ongoing applications to expand clesrovimab’s indication to children younger than 2 years who remain at an increased risk for severe RSV disease entering their second RSV season, said Anushua Sinha, MD, lead study author and lead clinical director at Merck, which manufactures clesrovimab.

Comparable Safety

The international trial enrolled 997 infants eligible for palivizumab because of underlying conditions that put them at an increased risk for severe RSV disease, including those born preterm or those with chronic lung disease of prematurity or congenital heart disease.

Participants were randomized to receive either a single 105-mg dose of clesrovimab followed by placebo or monthly palivizumab (15 mg/kg body weight) during their first RSV season. Of those who remained eligible, 276 children received open-label clesrovimab 210 mg before their second RSV season. The trial was designed to evaluate safety rather than efficacy.

During the first RSV season, adverse events occurred in 75.3% of infants receiving clesrovimab and 79.6% receiving palivizumab (95% CI, -9.5 to 0.9).

Serious adverse events were reported in 24.5% and 27.5% of participants, respectively (95% CI, -8.4 to 2.5). No serious adverse events were treatment related in the clesrovimab group compared with two treatment-related serious adverse events in the palivizumab group (95% CI, -1.5 to 0.4).

Injection-site reactions were similar between groups (14.9% vs 17.2%; 95% CI, -6.9 to 2.2), as were systemic adverse events (39.2% vs 41.7%; difference, 95% CI, -8.5 to 3.6).

No cases of anaphylaxis or hypersensitivity were reported in either group.

During the second RSV season, adverse events occurred in 67.4% of children with serious adverse events in 18.5%; none were considered treatment related. Injection-site pain was the most common local reaction (4.3%). Fourteen deaths occurred during the study, but investigators determined none were related to treatment.

“These data are important to inform clinicians about potential RSV preventive options for these vulnerable children in their second year of life,” Sinha said.

RSV Illness Uncommon

Although the trial was not powered to assess efficacy, Sinha and colleagues found RSV-associated illness during the first season were similar between treatment groups.

Through 150 days, lower respiratory infections that resulted in a healthcare visit occurred in 3.2% of children receiving clesrovimab and 3.4% receiving palivizumab. RSV-associated hospitalization occurred in 1% and 1.7%, respectively.

Among children who received the second-season dose, lower respiratory infection occurred in 7.3% through 180 days, with no comparison arm.

The study relied on pharmacokinetic bridging to suggest second-season dosing is safe, which has long been used to validate updated vaccines, making it “reasonable to accept the process for a new RSV monoclonal antibody as well,” Harrison said.

Harrison said he would like to see head-to-head trials between nirsevimab and clesrovimab and postmarketing studies to evaluate long-term effectiveness after multiple RSV seasons.

While Merck has not conducted a head-to-head comparison with nirsevimab “we are confident in the strength of our clinical data, our product profile and the potential for clesrovimab (Enflonsia) to help reduce the burden of RSV on infants and families,” Sinha said.

Madhavan said future studies comparing clesrovimab directly with nirsevimab will be important as health systems determine which products to stock.

“There are some differences,” she said, noting that clesrovimab uses a single fixed dose rather than weight-based dosing and has a longer shelf life, factors that could simplify inventory management for pediatric practices.

Growing Complexity for Pediatricians

The study comes as pediatricians balance maternal RSV vaccination, infant monoclonal antibodies, and second-season prophylaxis for high-risk children.

“I think there is a lot of confusion,” Madhavan said. Families often ask whether maternal vaccination and infant monoclonal antibodies are “the same thing.”

While both aim to prevent severe RSV disease, they are different products used in different circumstances. She said successful implementation of various methods depends on communication across obstetric, newborn, and pediatric care teams.

“It does require a pause to check what time of year it is, whether mom received the vaccine, where it’s documented, and what happened in the nursery,” she said.

Madhavan said her greatest concern is ensuring that children who qualify for protection during a second RSV season are not missed because of fragmented care.

“I worry about children who are moving between practices or between states where there might be less cross-talk in terms of the electronic health record,” she said.

As RSV prevention becomes more routine, clinicians should build reminder systems similar to those already used for influenza and COVID vaccination, she said.

“We’re all thinking about, ‘It’s time for your flu shot. It’s time for your COVID shot,’” she said. “Making sure we’re all thinking about outreach for RSV prevention as well is important.”

The broader significance of the study is building on an already successful strategy for preventing severe pediatric RSV disease, said William Schaffner, MD, professor of medicine in the Division of Infectious Diseases at Vanderbilt University School of Medicine in Nashville, Tennessee.

“The data would indicate from many studies that serious hospital-requiring RSV infection has plummeted” since long-acting monoclonal antibodies were introduced, he said. “It’s a terrific success.”

Harrison said that having two long-acting monoclonal antibodies also provides options should RSV resistance emerge to one product.

“Our goal is 100% coverage for all eligibles as recommended by ACIP [Advisory Committee on Immunization Practices] and AAP [American Academy of Pediatrics],” said Harrison. “We could be entering the golden age of RSV prevention when surges of wheezing infants and toddlers are just a memory.”

The study was funded by Merck Sharp & Dohme. Harrison, Madhavan, and Schaffner reported having no relevant disclosures. Various study authors reported receiving grants, institutional grants, and personal fees, being members of data and safety monitoring boards, and employment from Merck Sharp & Dohme, Pfizer, Janssen, Novavax, the Bill and Melinda Gates Foundation, among others.

Lara Salahi is a health journalist based in Boston.