Abstract 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. image
Vauloup‐Fellous et al. (Mon,) studied this question.