Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France.

Summary

Among 858 high-quality RSV genomes from infants (419 nirsevimab-exposed; 439 unexposed), resistance-associated substitutions were found in 12.5% of RSV-B breakthrough infections versus 1.0% in RSV-A. Novel F-protein substitutions clustered at residue N208 and other Φ-site positions conferred reduced nirsevimab neutralization; no resistant viruses were detected in nirsevimab-naive infants. Resistant RSV-B variants were detected up to ~1 year after prophylaxis.

Key Findings

• Resistance-associated substitutions were detected in 23/184 (12.5%) RSV-B breakthrough cases but only 2/195 (1.0%) RSV-A.
• Novel F-protein mutations (e.g., N208D/I/K/S/Y; I64V+K65E; K68I; L204S; P205S) reduced nirsevimab susceptibility.
• No resistant RSV was identified among nirsevimab-naive infants.
• Resistant RSV-B variants were observed up to ~1 year post-prophylaxis, suggesting persistence/spread potential.

Clinical Implications

Sustained genomic surveillance should accompany nirsevimab rollout, with attention to RSV-B. Clinical algorithms may need contingency plans (e.g., alternative products, timing, or combined strategies) if resistant clusters emerge.

Limitations

• Observational design limits causal inference on clinical outcomes of resistance.
• Country-specific season; generalizability to other regions and seasons requires confirmation.

Future Directions

Integrate routine sequencing with real-time phenotyping to guide public health responses; assess clinical impact of resistant variants on hospitalization, severity, and transmission; evaluate next-generation antibodies or combinations to mitigate escape.