The frontline protection infants now receive against RSV rests largely on a single monoclonal antibody — nirsevimab — administered to millions of newborns across Europe and North America. Understanding whether RSV can evolve around that shield in real-world conditions, not just in laboratory settings, is one of the more consequential questions in pediatric infectious disease right now. This French multicentre study provides the most substantive real-world evidence to date that resistance is not merely theoretical.
The POLYRES-2 project enrolled infants aged one year or younger with RT-PCR-confirmed RSV infections across French hospital networks during the 2024–25 season, a period when RSV-B was the dominant circulating genotype — an unusual epidemiological window that allowed large-scale examination of RSV-B specifically. The study compared nirsevimab-exposed infants who experienced breakthrough infections against nirsevimab-naive infected infants, applying both genotypic sequencing of full-length F protein genes and phenotypic susceptibility testing. Escape variants were identified in the nirsevimab-exposed group at the prefusion F protein site Φ — the conserved epitope the antibody targets — with specific mutations reducing in vitro neutralization capacity.
This finding carries weight beyond a single season. Nirsevimab's therapeutic rationale rests heavily on targeting a structurally conserved region presumed to carry high fitness costs for mutational escape. The detection of viable escape variants in circulating RSV-B strains challenges that assumption and echoes evolutionary dynamics previously observed with influenza neuraminidase inhibitors when deployed at population scale. Importantly, this is an observational study — it characterizes emergence but cannot yet establish prevalence trajectories, transmission fitness of resistant strains, or clinical severity gradients between resistant and susceptible infections. The balanced inclusion design between exposed and unexposed infants strengthens internal comparisons, but generalizability beyond France's 2024–25 season requires caution. For public health planning, the findings argue strongly for sustained genomic surveillance integrated into RSV prophylaxis programs — a systems-level need this study makes harder to dismiss.