RSV-B Resistance to Nirsevimab Detected in Breakthrough Infections

Nirsevimab-resistant respiratory syncytial virus B (RSV-B) variants have been identified in infants with breakthrough infections during routine clinical use, according to a nationwide observational study from France. The findings provide the first large-scale real-world evidence that resistance to the long-acting monoclonal antibody can emerge following prophylaxis, although researchers emphasise that resistant viruses remain confined to breakthrough cases.

Nirsevimab, which targets a conserved region of the RSV prefusion F protein, has transformed prevention of severe RSV disease in infants since its introduction. Clinical trials and early implementation studies demonstrated high efficacy against RSV-associated hospitalisation, but concerns have persisted over whether widespread use could drive viral evolution.

Researchers analysed more than 1,000 infant RSV cases

The multicentre POLYRES-2 study examined RSV infections in 1,023 infants aged one year or younger who tested positive for RSV during the 2024–2025 season in France, when RSV-B predominated nationally.

Researchers successfully generated full-length viral genome sequences for 858 cases, including 419 breakthrough infections in infants who had received nirsevimab and 439 infections in infants who had not received the antibody. Viral sequencing was combined with laboratory neutralisation testing to determine whether identified mutations reduced susceptibility to nirsevimab.

Resistance was primarily detected in RSV-B

Resistance-associated substitutions were uncommon in RSV-A, occurring in just 1.0% of breakthrough infections. In contrast, resistant variants were identified in 12.5% of RSV-B breakthrough infections.

More than half of resistant RSV-B viruses carried mutations affecting amino acid residue 208 of the viral F protein, while researchers also identified several previously unreported mutations capable of reducing susceptibility to nirsevimab.

Importantly, no resistant RSV strains were detected in infants who had not received nirsevimab, suggesting these mutations emerged under selective pressure following prophylaxis rather than circulating widely in the community.

Some resistant variants persisted long after prophylaxis

One notable finding was the detection of an RSV-B variant carrying the F:N208S substitution almost one year after administration of nirsevimab.

The authors suggest this demonstrates that resistant viruses can persist longer than previously anticipated, highlighting the importance of monitoring viral evolution beyond the immediate RSV season.

Despite the emergence of resistance, the study does not suggest widespread treatment failure. Instead, resistance remained confined to a relatively small proportion of breakthrough infections, and the overall clinical effectiveness of nirsevimab remains high.

Genomic surveillance will be critical

The researchers conclude that integrating genomic sequencing with routine clinical surveillance will be essential as RSV immunisation programmes continue to expand.

Monitoring resistant variants in real-world settings could help identify emerging escape mutations early, inform future monoclonal antibody development, and ensure preventive strategies remain effective against evolving RSV strains.

While the findings warrant continued vigilance, the authors emphasise that the overall benefits of nirsevimab prophylaxis remain substantial, with resistance currently representing only a minority of breakthrough RSV-B infections.

Reference

Fourati S et al. Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France. The Lancet Microbe. 2026;DOI: 10.1016/j.lanmic.2026.101353.