A LARGE-scale genomic surveillance study in France has found that resistance to nirsevimab, a monoclonal antibody used to prevent respiratory syncytial virus (RSV) in infants, remains rare despite widespread use.
The multicentre, national observational study aimed to characterise RSV strains in breakthrough infections following nirsevimab administration and assess potential resistance-associated mutations. Conducted during the 2023–24 RSV season, it included infants under 1 year of age who were either treated with nirsevimab or untreated before their first RSV season. Respiratory samples from infected infants were collected for full-length RSV RNA sequencing, focusing on mutations in the nirsevimab binding site Ø. Clinical RSV isolates were tested for neutralisation by nirsevimab, and candidate substitutions in the fusion protein were analysed using a fusion-inhibition assay. Infants with insufficient treatment information or without parental consent were excluded.
Of 695 RSV-infected infants, 545 full-length RSV genome sequences were analysed, with 260 (48%) from nirsevimab-treated breakthrough infections and 285 (52%) from untreated infants. RSV-A was the predominant strain in both groups (91% in treated and 83% in untreated infants), with no resistance-associated mutations detected at site Ø. Among the 24 RSV-B breakthrough cases, resistance-associated mutations were found in two infants (8%), including the F:N208D substitution, which conferred dominant resistance, and a newly identified F:I64M plus F:K65R combination, which demonstrated high resistance levels in fusion-inhibition assays.
These findings confirm that nirsevimab-resistant variants remain infrequent despite widespread administration in infants. However, the emergence of resistance-associated mutations in RSV-B highlights the need for continued molecular surveillance to monitor potential resistance development.
Ada Enesco, EMJ
Reference
Fourati S et al. Genotypic and phenotypic characterisation of respiratory syncytial virus after nirsevimab breakthrough infections: a large, multicentre, observational, real-world study. Lancet Infect Dis. 2025;25(3):301-311.
