Clesrovimab Demonstrates Safety Through a Second RSV Season in High-Risk Infants

Clesrovimab (Enflonsia; Merck) was well tolerated in infants with an increased risk of severe respiratory syncytial virus (RSV) disease through their 2nd RSV season, according to a recent study published in JAMA Pediatrics.¹

Clesrovimab is a monoclonal antibody approved as a single fixed dose for neonates and infants born during or entering their first RSV season. The monoclonal antibody was added to the growing landscape of long-acting monoclonal antibodies preventing RSV in June 2025.² Although proven efficacious through neonates’ and infants’ first RSV season, there is limited data on its safety and tolerability for children who are at high risk for severe RSV disease. The study reported the end-of-study results of the SMART (NCT04938830) through 2 RSV seasons.¹

The phase 3 randomized, partially masked, active comparator-controlled trial was conducted between November 30, 2021, and November 20, 2025, across 110 sites in 27 countries and territories. Participants were infants recommended for palivizumab (Synagis; MedImmune), another long-acting monoclonal antibody, as standard of care prevention for RSV in high-risk infants.

Phase 3 Trial Supports Clesrovimab Safety Through a Second RSV Season

In RSV season 1, participants were randomized 1:1 to receive 105 mg of clesrovimab or 15 mg/kg body weight of palivizumab. On day 28, participants in the palivizumab group received a second dose, while those in the clesrovimab group received a placebo. In the open-label second-season phase, participants received 210 mg of clesrovimab 4 weeks before RSV season 2—aligned with Advisory Committee on Immunization Practices (ACIP) recommendations for nirsevimab in high-risk children entering their second RSV season.³

Infants at increased risk of severe RSV disease include those with comorbidities such as chronic lung disease (CLD) and congenital heart disease (CHD), among other certain conditions. ACIP recommendations note that older infants have greater body weight and require higher antibody exposure to maintain protective concentrations, consistent with second-season dosing principles used for other long-acting RSV monoclonal antibodies.

The study’s primary outcomes were safety and tolerability, specifically any participants who experienced solicited adverse events (AEs), and solicited daily body temperature to assess fever. Adverse events of special interest (AESIs) were also evaluated. They included anaphylaxis and/or hypersensitivity and rash through 42 days after the dose and other nonserious AEs and serious AEs throughout season 1.

Secondary outcomes evaluate incidence of RSV-associated disease outcomes like RSV-associated medically attended lower respiratory infection or severity and incidence of RSV-associated hospitalization.

There were 1003 participants enrolled in RSV season 1, of whom 997 received study treatment. Of them, 498 received 105 mg of clesrovimab, and 499 received palivizumab. The median age was 2.6 months, and the median weight was 3.3 kg.

How Clesrovimab Compared With Palivizumab in High-Risk Infants

In RSV season 2, there were 276 patients who received 210 mg of clesrovimab. The median age at dosing was 14.4 months, and the median weight was 8.4 kg. Researchers noted the proportion of participants with adverse events in RSV season 2 was comparable between those who received clesrovimab or palivizumab in RSV season 1 (92 of 138 [66.7%] with ≥1 AE among participants who received clesrovimab vs 94 of 138 [68.1%] among participants who received palivizumab).

There were 374 of 497 [75.3%] with ≥ 1 AE in the clesrovimab 105 mg group when compared with 397 of 499 [79.6%] in the palivizumab group in RSV season 1.

Solicited injection-site AEs were observed among 18 of 276 children (6.5%) receiving a 210-mg dose (administered as two 105-mg injections) in season 2, the most common being injection-site pain.

The majority of AEs were grade 1 or 2. Rash AESI was reportedly low in both seasons (3 [0.6%] in the clesrovimab group and 1 [0.2%] in the palivizumab group in season 1; 3 [1.1%] after 210 mg of clesrovimab in season 2; all grade 1).

“The safety profile of a 210-mg second season dose of clesrovimab was comparable between children receiving clesrovimab over 2 consecutive RSV seasons and those who had received palivizumab in their first RSV season,” the study authors wrote.

The study was limited by the absence of a comparator arm in season 2. Additionally, participant sample size limited the study’s power to assess noninferiority of clesrovimab when compared with palivizumab.

“The single-dose regimen reduces the number of injections, potentially improving adherence, an important advantage for this vulnerable population,” the study authors concluded.

References

1. Zar HJ, Bont LJ, Manzoni P, et al. Clesrovimab in infants at increased risk for severe disease during RSV seasons. JAMA Pediatr. Published online July 20, 2026. doi:10.1001/jamapediatrics.2026.2760

2. US FDA approves Merck’s ENFLONSIATM (Clesrovimab-CFOR) for prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in infants born during or entering their first RSV season. Merck. June 9, 2025. Accessed July 23, 2026. https://www.merck.com/news/u-s-fda-approves-mercks-enflonsia-clesrovimab-cfor-for-prevention-of-respiratory-syncytial-virus-rsv-lower-respiratory-tract-disease-in-infants-born-during-or-entering-their-fir/

3. ACIP evidence to recommendations for use of Nirsevimab in children 8–19 months of age at increased risk of severe disease entering their second RSV season | ACIP | CDC. Centers for Disease Control and Prevention. September 5, 2024. Accessed July 23, 2026. https://www.cdc.gov/acip/evidence-to-recommendations/nirsevimab-season2-rsv-infants-children-etr.html