RSV Immunoprophylaxis in Infants and Children: Old Standards, New Agents and the Complexities Therein

Every year, respiratory syncytial virus (RSV) causes an estimated 33 million lower respiratory tract infections in children under five years of age, driving millions of hospitalizations worldwide and substantial mortality in developing countries. For 28 years, the monoclonal antibody (mAb) palivizumab has been the principal agent for RSV immunoprophylaxis, reducing hospitalization in defined high-risk groups through monthly intramuscular dosing. The recent approval of two second-generation long-acting mAbs, nirsevimab and clesrovimab, and maternal preF vaccine has fundamentally changed the RSV prevention landscape. In contrast to palivizumab, the long-acting mAbs offer single-dose seasonal protection across a broader infant population, enabling universal immunization programmes for the first time. In this review, we conjointly examine nirsevimab and clesrovimab across their mechanisms of action, pharmacokinetics, efficacy, safety and cost-effectiveness, using palivizumab as the reference standard. Cross-trial efficacy comparisons are complicated by differences in study populations and endpoint definitions; however, when these factors are considered, the available evidence suggests that all three agents offer broadly comparable protection against severe RSV disease. All three agents also demonstrate favourable and comparable tolerability profiles. Nirsevimab is now supported by a substantial body of real-world evidence confirming effectiveness in routine immunization programmes that closely align with registrational studies. Clesrovimab, as the newest agent, currently lacks real-world effectiveness, and both long-acting monoclonals require further confirmatory evidence in high-risk groups. Overall, existing data support that both monoclonals have equivalent efficacy and safety profiles as palivizumab, and choice should be based on cost-effectiveness and local availability, with consideration given to optimal integration of infant immunoprophylaxis alongside maternal RSV vaccination programmes.