Second season of clesrovimab for RSV well tolerated in high-risk kids

For respiratory syncytial virus (RSV) prevention, the long-acting monoclonal antibody clesrovimab (Enflonsia) was well tolerated among infants at increased risk for severe disease through two RSV seasons, a randomized clinical trial found.

In final results from the SMART trial, adverse events were generally comparable between infants who got a single 105-mg dose of clesrovimab or monthly palivizumab (Synagis) -- an older, short-acting monoclonal antibody that is now off the market -- in their first RSV season. The proportion with any adverse event was 75.3% versus 79.6%, respectively.

Adverse events in the subset of children who got an open-label second dose were comparable between those who had initially received clesrovimab versus palivizumab (66.7% vs 68.1%), reported Anushua Sinha, MD, MPH, of Merck in Rahway, New Jersey, and colleagues in JAMA Pediatrics. (Merck is the maker of clesrovimab.)

The SMART trial "adds to the growing body of evidence supporting [clesrovimab] in children under 2 years of age who remain at increased risk for severe RSV entering their second RSV season," Sinha said.

None of the trial participants discontinued due to an adverse event, and no serious adverse events were considered to be related to clesrovimab, the research team noted.

"Given the significant burden of RSV on infants, families and healthcare systems, it is important to have multiple options available to help protect infants from RSV," Sinha told MedPage Today in emailed remarks.

Additionally, "the single-dose [clesrovimab] regimen reduces the number of injections, potentially improving adherence, an important advantage for this vulnerable population," Sinha and colleagues further noted in JAMA Pediatrics.

"All infants are at risk for RSV disease, particularly in the first 6 months of life," the research team noted. However, "[p]reterm infants and those with comorbidities such as chronic lung disease of prematurity, congenital heart disease, or other certain conditions are at an increased risk for severe RSV disease," they noted. And "children with these comorbidities continue to be at increased risk in their second year of life."

"For decades, the standard of care for RSV prevention in high-risk infants was the short-acting monoclonal antibody palivizumab (Synagis)," they noted. But more recently, long-acting monoclonal antibodies have come to the clinic, including clesrovimab in June 2025 and nirsevimab (Beyfortus) in 2023.

The phase IIb/III CLEVER trial "demonstrated that clesrovimab was well tolerated and efficacious in reducing RSV associated disease and hospitalization in healthy infants," Sinha and colleagues noted. The group previously reported prespecified interim results from the phase III SMART trial evaluating clesrovimab efficacy against palivizumab in infants at increased risk for severe RSV disease.

The current work details SMART end-of-study results through two RSV seasons among 997 infants. Ultimately, 276 children requiring ongoing RSV prevention in their second RSV season received 210 mg of clesrovimab (in two 105-mg doses).

Incidence of RSV-associated medically attended lower respiratory infection (MALRI) was comparable between clesrovimab (3.2%, 95% CI 1.8-5.2) and palivizumab (3.4%, 95% CI 2.0-5.6) in infants' first RSV season.

In infants dosed for a second RSV season, total RSV-associated MALRI incidence at day 180 was 7.3% (95% CI 4.4-11.4).

Overall, the research team examined a wide range of adverse events, such as solicited (injection site and systemic) events with daily body temperature checks to assess fever from day 1 to 5 after any dose; adverse events of special interest (anaphylaxis, hypersensitivity, and rash) through 42 days from first dose; nonserious adverse events from day 1 to 42 after first dose and 14 days after each subsequent dose; and serious adverse events throughout the RSV season.

No anaphylaxis or hypersensitivity was reported in either season, and rash was reported in just a few children.

There were 14 deaths; however, none were considered related to treatment. Rather, all deaths were attributable to underlying conditions or comorbidities or another clearly identifiable cause, Sinha and colleagues noted.

RSV testing was performed for six of the 14 descendants, with all testing negative.

Sinha and colleagues conducted their study at 110 sites in 27 countries and territories between Nov. 30, 2021, and Nov. 20, 2025. The population encompassed palivizumab-eligible infants, including those with prematurity, chronic lung disease of prematurity, or hemodynamically significant congenital heart disease.

Limitations included the lack of a comparator arm in infants' second RSV season and the inability to assess noninferiority of clesrovimab compared with palivizumab, "as that would require a prohibitively large sample size," Sinha and colleagues noted.

Additionally, the potential impact on clesrovimab on long-term RSV associated morbidity (i.e., recurrent lower respiratory infection, wheezing, asthma, or lung function impairment) was not an objective of the study and was not assessed, "but it is important among these high-risk groups," they further noted.