Clesrovimab: a single-dose antibody reshapes RSV prevention for infants

Respiratory syncytial virus, or RSV, has been a stubborn adversary of infant health for decades. It remains a leading cause of lower respiratory tract infection and hospitalization in babies worldwide, and for most of that history prevention was limited to a narrow, risk-based strategy: monthly injections of the monoclonal antibody palivizumab for a small group of preterm or otherwise high-risk infants. A new policy-focused clinical perspective published in Pediatric Research by Fajia Farhath and Sushil Kumar K of Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow, India, examines how the prevention landscape has now been transformed, with the long-acting antibody clesrovimab emerging as the latest addition to a rapidly expanding arsenal.

The central paradox that motivated the shift is well documented in the RSV literature. Although selective prophylaxis with palivizumab was effective for the infants who received it, a substantial proportion of severe RSV disease occurs in previously healthy term infants who would never qualify for risk-based treatment. Most RSV hospitalizations, in other words, happen in babies without traditional high-risk conditions. This epidemiological reality exposed the limits of a niche intervention and pushed pediatric researchers toward population-level strategies capable of protecting essentially all infants entering their first RSV season.

Three technological advances converged to make that possible. Maternal RSV vaccination, given in late pregnancy to boost transplacental antibody transfer, offers passive protection to newborns. Extended-half-life monoclonal antibodies, engineered to survive months rather than weeks in the infant circulation, allow season-long protection from a single dose. Clesrovimab, known during development as MK-1654 and marketed as Enflonsia, is one such long-acting antibody, designed to provide RSV season-long protection following a single intramuscular injection. Together with nirsevimab, the first extended-half-life antibody to reach clinical practice, and maternal immunization, clesrovimab represents a component of an evolving prevention strategy aimed at reducing RSV-associated morbidity and hospitalization during early infancy.

The clinical evidence base for clesrovimab rests primarily on the pivotal phase 2b/3 CLEVER trial. In that study, clesrovimab significantly reduced RSV-associated medically attended lower respiratory tract infection and hospitalization among healthy infants entering their first RSV season, with a safety profile comparable to placebo. The absolute risk reduction for RSV hospitalization was approximately 1.9 percentage points, which corresponds to an estimated number needed to treat of 51 infants over 150 days of follow-up. In practical terms, roughly one hospitalization was prevented for every 51 babies treated, a figure that reflects both the genuine protective effect of the antibody and the baseline probability that any given healthy infant will be hospitalized with RSV in a single season.

At the molecular level, clesrovimab works by binding a conserved site on the RSV F protein, the fusion glycoprotein the virus uses to enter respiratory epithelial cells. Sequence analyses of circulating RSV strains from 2019 through 2023, cited in the perspective, indicate that the clesrovimab binding site has remained conserved across circulating viruses, a reassuring finding for a prophylactic agent that will be deployed against a pathogen notorious for its antigenic variability. Resistance surveillance is nonetheless considered essential, and a prospective German pediatric cohort study has already begun mapping the prevalence of resistance-associated mutations in the RSV F protein before widespread implementation of the new antibodies.

The regulatory picture has moved quickly. In 2025, the Advisory Committee on Immunization Practices of the United States issued formal recommendations for the use of clesrovimab in preventing severe RSV-associated lower respiratory tract infections in infants, and the antibody received its first approval the same year. Earlier phase 1 studies, including a trial of clesrovimab in healthy preterm and full-term infants and an open-label safety study in healthy Chinese participants, established the tolerability and pharmacokinetic foundation for the later-stage program. Modeling studies have also begun comparing the cost-effectiveness of nirsevimab and clesrovimab in preventing RSV lower respiratory tract disease in infants in the United States, an early signal that economic evaluation will be as central to policy as efficacy data.

Yet the perspective is careful to emphasize the substantial evidence gaps that remain. There are no head-to-head comparisons between clesrovimab and nirsevimab, leaving clinicians without direct data on comparative effectiveness. Post-licensure data are limited, and uncertainties persist regarding long-term effectiveness, long-term safety, and affordability, particularly in low-resource settings where the RSV burden is heaviest. A network meta-analysis of monoclonal antibody prophylaxis and interim analyses of trials comparing maternal vaccination, infant nirsevimab, or both are beginning to fill these gaps, but the comparative landscape is still immature. Population-based studies, such as the Galicia universal nirsevimab program in Spain, have demonstrated that population-level prophylaxis can sharply reduce RSV hospitalizations, providing a template for what clesrovimab programs might achieve.

From a practical standpoint, the authors argue that successful implementation will depend on far more than the pharmacology of the antibody itself. Timely administration is critical, since protection must be in place before the RSV season begins. Integration into neonatal discharge planning and well-child care pathways, and coordination with maternal immunization programs, will determine whether eligible infants actually receive their dose. Because RSV prevention is increasingly considered within a broader population-health framework rather than solely as a risk-based intervention, delivery systems must be redesigned to reach the entire birth cohort, not just the infants who historically qualified for palivizumab. The greatest reductions in RSV-related hospitalization, the perspective concludes, are likely to result from effective delivery of preventive strategies to the infants at highest risk during the RSV season.

Equitable access, sustained coverage, affordability, and ongoing post-licensure surveillance will be as important as the efficacy demonstrated in clinical trials. Future research, the authors suggest, should focus on comparative effectiveness, cost-effectiveness, long-term safety, implementation in low-resource settings, and optimization of delivery strategies to maximize population impact. As RSV prevention moves into routine clinical practice, the arrival of clesrovimab marks a milestone in a decades-long effort to tame a virus that has shaped pediatric medicine for generations. Whether one dose and one season can translate into lasting population benefit will now depend on the unglamorous machinery of health systems, surveillance networks, and financing decisions that determine whether scientific breakthroughs reach the infants who need them most.

Subject of Research: Clesrovimab in the new era of RSV prevention: one season, one dose, one chance

Article Title: Clesrovimab in the new era of RSV prevention: one season, one dose, one chance

Article References: Clesrovimab in the new era of RSV prevention: one season, one dose, one chance. (n.d.). https://doi.org/10.1038/s41390-026-05586-0

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05586-0

Keywords: Clesrovimab, prevention, season, dose, chance, scientific research