Respiratory syncytial virus (RSV) has been so far one of the leading causes of acute respiratory infection in infants. It has been estimated that worldwide each year there are 3.2 million hospitalisations caused by RSV in children younger than 5 years, the vast majority in low- and middle-income countries. The recent introduction of the long-acting monoclonal antibody nirsevimab marks a significant milestone in prevention. Nirsevimab is designed for broad, population-wide use, its efficacy and safety are well-established: as shown by a recent real-world meta-analysis, the risk of RSV-related hospitalisation was reduced by 83% in children less than one year of age.1
In addition, a consistent body of evidence shows that early-life RSV is associated with long-term respiratory sequelae and prevention or delay of the RSV infection might be an effective primary prevention for recurrent wheezing and asthma.2
Nonetheless the battle against RSV requires constant vigilance and we should remain alert to potential threats of RSV widespread immunisation. Among the most significant challenges, the development of monoclonal antibody escape mutants driven by evolutionary pressure represents a noteworthy risk.3
From this perspective the research conducted by Furgier et al. is a valuable contribution. This prospective multicentric test-negative study aims to assess the effectiveness of nirsevimab in preventing RSV hospitalisation during the second season (2024–2025) in France. A total of 1270 patients under 12 months of age hospitalised for bronchiolitis were enrolled. Nirsevimab immunization was received by 22.0% of RSV-positive cases and 64.1% of RSV-negative controls. The authors concluded that the second national campaign maintained a high level of effectiveness in reducing hospitalisation with an efficacy rate of 84.9% (95% CI: 80.0–88.6). Notably, nirsevimab was effective even during a season that was marked by a predominant circulation (60–70% of cases) of RSV-B.4 The primary limitation of this study is the undetermined prevalence of RSV-B versus RSV-A strains among the enrolled infants. The author's assumption of RSV-B predominance relies on data from an international surveillance repository, which may not be comprehensive.
Although extensive research has been conducted on RSV disease, there remains some outstanding questions regarding the seasonal genomic variability of RSV subgroups A and B, as well as their specific susceptibility to preventive therapies. RSV-A and -B differ primarily in the mucin-like domains of the G protein and in the surface epitopes of prefusion F trimer. Most prevention strategies target the RSV F in its prefusion conformation. Protein F is highly conserved between RSV subgroups, but its antigenic surface, especially site Ø, which has the strongest neutralizing effect, shows some variation.5
Prior to nirsevimab's approval, studies found that the antibodies binding site remained highly conserved over time. Wilkins et al. evaluated the stability of the nirsevimab target. They analysed nearly 6000 RSV-positive nasal samples collected worldwide between 2015 and 2021. The binding site for nirsevimab was found to be highly conserved. While a prevalent RSV-B polymorphism was identified in over 40% of sequences, variants associated with true resistance were uncommon, detected in less than 1% of cases.6 Similarly, a study of 322 samples from three European countries found that just two RSV-B isolates (0.8% of participants with no prior immunoprophylaxis) had a nirsevimab resistance-associated substitution.7
Additionally, recent studies conducted following the implementation of nirsevimab have demonstrated reassuring outcomes. Fourati et al. sequenced complete RSV genomes from 545 French samples, including 260 nirsevimab breakthrough cases. RSV-A was most common, with no resistance-associated mutations found. Of the 24 RSV-B breakthrough cases, resistance-associated mutations were identified in only two infants.8 A research study conducted in Western Australia following the introduction of nirsevimab found no evidence of nirsevimab escape mutations in either clinical (n = 382) or wastewater (n = 12) samples.9
However, as emphasised by Oraby et al., attention should not be limited solely to binding site sequencing. Through computational modelling, these researchers show that a single amino acid change at a site far from classical epitopes causes conformational shifts in antigenic sites Ø, II, and IV, significantly lowering the virus susceptibility to neutralizing antibodies.10
In conclusion, the potential of new monoclonal antibodies to change the RSV natural history is clear, with demonstrably public health benefits. However, despite the sparse occurrences of resistance, there is a possible risk of mutation related to the widespread use of long-acting monoclonal antibodies. Future key steps are to sustain genomic and epidemiologic surveillance, especially stratified by RSV subtypes and to promote real-time data sharing, building on the work of Furgier et al.4
Preserving the long-term efficacy of these interventions is a scientific and ethical responsibility, requiring foresight and investments.
Contributors
EP and EB jointly drafted and edited the comment.
Declaration of interests
EB has received fees for lectures from Sanofi and AstraZeneca and has received honoraria for advisory boards from Sanofi, AstraZeneca, and MSD. EB is a member of ReSViNET Network. EP has received honoraria for lectures from Sanofi.
References
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