Nirsevimab Resistance Detected in RSV-B Breakthrough Infections

August 10, 2026 Dr. Michael Lee – Health Editor Health

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According to a multicentre observational study published in The Lancet Infectious Diseases by Professor Slim Fourati and colleagues, resistant viral variants demonstrated significant genetic diversity, though overall clinical impact requires ongoing monitoring.

  • Researchers analyzed full-length viral genomes from 858 infants out of 1,023 total participants in the POLYRES-2 project across French hospital settings.
  • Resistance-associated substitutions (RASs) were detected in RSV-B breakthrough infections among infants who had received nirsevimab prophylaxis.
  • Substitutions at residue 208 of the viral fusion (F) protein accounted for over half of the resistant RSV-B variants identified, with some cases emerging nearly a year after prophylaxis administration.

Epidemiological Scope and Study Design of the POLYRES-2 Project

As detailed in The Lancet Infectious Diseases, the POLYRES-2 project was structured as a multicentre, national, observational study conducted during the 2024–25 RSV season. Investigators evaluated infants aged one year or younger who presented with RT-PCR-confirmed RSV infections in routine hospital inpatient and outpatient care. The study design balanced nirsevimab-exposed breakthrough cases against nirsevimab-naive infections to accurately map viral susceptibility.

Out of 1,023 infected infants enrolled, researchers successfully sequenced full-length RSV genomes for 858 participants. This cohort comprised 419 samples from nirsevimab-treated breakthrough infections—split nearly evenly between 212 RSV-A and 207 RSV-B cases—and 439 samples from nirsevimab-naive infants. To maintain strict analytical reliability, the team restricted phylogenetic and mutational examinations to high-quality sequences achieving greater than or equal to 90% genome coverage alongside complete reads across the specific nirsevimab-binding site (site Φ) on the prefusion F protein.

Genotypic and Phenotypic Resistance Profiles in RSV-A versus RSV-B

The observational data revealed a distinct divergence in how RSV-A and RSV-B strains developed escape mutations against the long-acting monoclonal antibody. Resistance-associated substitutions (RASs) appeared in only two out of 195 RSV-A breakthrough infections, representing a small fraction of that subgroup. The singular RAS identified in RSV-A was the F:K209E substitution, which confers intermediate resistance.

Conversely, resistance proved notably more frequent and structurally diverse within the RSV-B lineage. Among 184 RSV-B breakthrough infections analyzed for resistance, 23 cases harbored RASs, translating to a substantial resistance prevalence. Within this resistant RSV-B subset, 12 of the 23 viruses (52.2%) carried a substitution at residue 208, specifically identifying F:N208D, F:N208I, F:N208K, F:N208S, or F:N208Y variants. Furthermore, investigators documented novel substitutions including F:I64V, F:K65E, F:K68I, F:L204S, and F:P205S mediating resistance through fusion inhibition assays. Notably, no resistant RSV strains were detected in the control group of nirsevimab-naive infants.

Clinical Implications and Long-Term Prophylaxis Monitoring

The detection of resistant variants long after initial administration highlights the biological adaptability of viral pathogens under passive immunoprophylaxis pressure. Specifically, researchers flagged the identification of a resistant RSV-B variant carrying the F:N208S substitution nearly one full year after the infant received prophylaxis. While these findings establish that real-world escape variants do emerge in clinical settings, the authors emphasize that current clinical impact remains constrained and requires continued longitudinal observation.

Healthcare systems managing pediatric respiratory infections must maintain rigorous diagnostic surveillance to track shifting susceptibility patterns. Clinicians managing complex infant populations or investigating atypical infection courses are encouraged to consult with specialized <[Relevant Clinic/Professional/Service]> and utilize advanced diagnostic laboratories for comprehensive molecular testing. Ensuring rapid identification of viral variants supports institutional infection control and informs future updates to immunization guidelines.

Disclaimer: The information provided in this article is for educational and scientific communication purposes only and does not constitute medical advice. Always consult with a qualified healthcare provider regarding any medical condition, diagnosis, or treatment plan.

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