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

Respiratory syncytial virus (RSV) remains a leading cause of lower respiratory tract infection and hospitalization in infancy worldwide. Historically, prevention relied on monthly palivizumab administration for selected high-risk infants, despite evidence that a substantial proportion of severe RSV disease occurs in previously healthy term infants. The recent introduction of maternal RSV vaccination and long-acting monoclonal antibodies has transformed the prevention landscape. Clesrovimab (MK-1654; Enflonsia) is a long-acting monoclonal antibody designed to provide season-long protection following a single dose. In the pivotal phase 2b/3 CLEVER trial, clesrovimab reduced RSV-associated medically attended lower respiratory tract infection and hospitalization among 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, corresponding to an estimated number needed to treat of 51 infants over 150 days of follow-up. In this policy-focused clinical perspective informed by a narrative review, we examine the emerging role of clesrovimab within contemporary RSV prevention strategies. We discuss efficacy, safety, implementation challenges, economic considerations, and remaining evidence gaps, including the absence of head-to-head comparisons with nirsevimab, limited post-licensure data, and uncertainties regarding long-term effectiveness and affordability. Future success will depend not only on efficacy but also on equitable access, sustainable implementation, and ongoing surveillance. CLINICAL RELEVANCE: The emergence of long-acting monoclonal antibodies has expanded preventive options for infants at risk of RSV-associated lower respiratory tract disease during their first RSV season. For clinicians, the key shift is that RSV prevention is increasingly being considered within a broader population-health framework rather than solely as a risk-based intervention for selected high-risk groups. Clesrovimab, alongside nirsevimab and maternal RSV vaccination, represents one component of an evolving prevention strategy aimed at reducing RSV-associated morbidity and hospitalization during early infancy. From a practical perspective, successful implementation will depend on timely administration, integration into neonatal discharge planning and well-child care pathways, and coordination with maternal immunization programs. As RSV prevention moves into routine clinical practice, equitable access, sustained coverage, affordability, and ongoing post-licensure surveillance will be as important as efficacy demonstrated in clinical trials. Ultimately, the greatest reductions in RSV-related hospitalization are likely to result from effective delivery of preventive strategies to the infants at highest risk during the RSV season. KEY POINTS: RSV continues to impose a substantial burden on infants worldwide despite decades of clinical recognition and supportive care. Most RSV hospitalizations occur in infants without traditional high-risk conditions, highlighting the limitations of selective prophylaxis strategies. Long-acting monoclonal antibodies and maternal RSV vaccination have transformed prevention from a niche intervention into a population-level public health strategy. Clesrovimab demonstrated significant protection against RSV-associated medically attended lower respiratory tract infection and hospitalization in healthy infants entering their first RSV season. Future research should focus on comparative effectiveness, cost-effectiveness, long-term safety, implementation in low-resource settings, and optimization of delivery strategies to maximize population impact.