Prophylactic monoclonal antibodies against respiratory syncytial virus in early life: An in‐depth review of mechanisms of action, failure factors, and future perspectives

The burden of respiratory syncytial virus (RSV) remains a major global health concern in early childhood, responsible for substantial morbidity, hospitalizations, and deaths, particularly in infants under 6 months. For over two decades, palivizumab was the only monoclonal antibody (mAb) available for prophylaxis, restricted to high-risk groups due to cost and limited duration of protection. Recent advances in structural virology and antibody engineering have led to the emergence of long-acting mAbs, notably nirsevimab and clesrovimab, which offer single-dose seasonal protection and are now shifting RSV prevention strategies from high-risk targeting to universal infant immunization. These antibodies act by locking the RSV fusion (F) protein in its pre-fusion conformation, thereby preventing viral entry, with nirsevimab targeting site Ø and clesrovimab targeting site IV. Real-world implementation has demonstrated remarkable reductions in RSV hospitalizations, aligning with clinical trial results, while large-scale safety data support their favorable tolerance. However, the paradigm shift brings new challenges: understanding breakthrough infections, assessing long-term immune imprinting, and anticipating viral evolution under immunological pressure. The risk of antigenic escape and the consequences of passive immunization on long-term B-cell memory development-especially in breakthrough cases-remain critical and underexplored immunological frontiers. This review explores the molecular and immunological underpinnings of RSV-targeted mAbs, evaluates current real-world evidence, and outlines future directions-including bispecific antibodies and nanobody-based therapies-that could further transform RSV prophylaxis. Sustained genomic surveillance and a deeper understanding of host immunity will be crucial to preserve the long-term efficacy of these innovations in pediatric infectious disease prevention.