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

@article{fourati2026realworld,
  title = {{Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France}},
  author = {Slim Fourati and Alawiya Reslan and Jérôme Bourret and Jean-sébastien Casalegno and Yannis Rahou and Laurent Softic and Lionel Chollet and Pauline Trémeaux and Berthe-Marie Imbert-Marcille and Sylvie Pillet and Nicolas Veyrenche and Agathe Boudet and Luc Deroche and Sonia Burrel and Lina Mouna and Théophile Cocherie and Aurélie Schnuriger and Charlotte Pronier and Lynda Handala and Véronique Brodard and Floriane Gallais and Sylvie Larrat and Alexandre Réguème and Nefert Candace Dossou and Amandine Henry and Elyanne Gault and Cédric Hartard and Ségolène Brichler and Alice Moisan and Véronique Avettand-Fènoël and Caroline Lefeuvre and Ilka Engelmann and Sandrine Castelain and Audrey Mirand and Maud Salmona and Marie-Christine Jaffar-Bandjee and Mohamed Ader and Sarah Seng and Pierre Cappy and Christophe Rodriguez and Arnaud Ly and Georges Dos Santos and Olivier Schwartz and Chloé Petiot and Delphine Planas and Samar Berreira Ibraim and Kévin Da Silva and Amélie Recoing and Jean–Michel Pawlotsky and Frédéric Lemoine and Étienne Audureau and Marie‐Anne Rameix‐Welti and Nael Zemali and Sonia Burrel and Pantxika Bellecave and Alice Moisan and Zakasoa-Mbololona Zavaoarisaina and Romain Legros and Boris Derman and Vincent Pargny},
  journal = {The Lancet Microbe},
  year = {2026},
  month = jun,
  doi = {10.1016/j.lanmic.2026.101353},
  url = {https://doi.org/10.1016/j.lanmic.2026.101353},
  note = {CC BY-NC},
}

TY  - JOUR
TI  - Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France
AU  - Slim Fourati
AU  - Alawiya Reslan
AU  - Jérôme Bourret
AU  - Jean-sébastien Casalegno
AU  - Yannis Rahou
AU  - Laurent Softic
AU  - Lionel Chollet
AU  - Pauline Trémeaux
AU  - Berthe-Marie Imbert-Marcille
AU  - Sylvie Pillet
AU  - Nicolas Veyrenche
AU  - Agathe Boudet
AU  - Luc Deroche
AU  - Sonia Burrel
AU  - Lina Mouna
AU  - Théophile Cocherie
AU  - Aurélie Schnuriger
AU  - Charlotte Pronier
AU  - Lynda Handala
AU  - Véronique Brodard
AU  - Floriane Gallais
AU  - Sylvie Larrat
AU  - Alexandre Réguème
AU  - Nefert Candace Dossou
AU  - Amandine Henry
AU  - Elyanne Gault
AU  - Cédric Hartard
AU  - Ségolène Brichler
AU  - Alice Moisan
AU  - Véronique Avettand-Fènoël
AU  - Caroline Lefeuvre
AU  - Ilka Engelmann
AU  - Sandrine Castelain
AU  - Audrey Mirand
AU  - Maud Salmona
AU  - Marie-Christine Jaffar-Bandjee
AU  - Mohamed Ader
AU  - Sarah Seng
AU  - Pierre Cappy
AU  - Christophe Rodriguez
AU  - Arnaud Ly
AU  - Georges Dos Santos
AU  - Olivier Schwartz
AU  - Chloé Petiot
AU  - Delphine Planas
AU  - Samar Berreira Ibraim
AU  - Kévin Da Silva
AU  - Amélie Recoing
AU  - Jean–Michel Pawlotsky
AU  - Frédéric Lemoine
AU  - Étienne Audureau
AU  - Marie‐Anne Rameix‐Welti
AU  - Nael Zemali
AU  - Sonia Burrel
AU  - Pantxika Bellecave
AU  - Alice Moisan
AU  - Zakasoa-Mbololona Zavaoarisaina
AU  - Romain Legros
AU  - Boris Derman
AU  - Vincent Pargny
PY  - 2026
DA  - 2026/06/02
JO  - The Lancet Microbe
DO  - 10.1016/j.lanmic.2026.101353
UR  - https://doi.org/10.1016/j.lanmic.2026.101353
AB  - BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Nirsevimab, a long-acting monoclonal antibody targeting a conserved epitope on the prefusion F protein (site Φ), has shown high efficacy in clinical trials and early real-world studies. Although widespread resistance has not been reported, concerns remain about the emergence of escape variants, particularly among RSV-B viruses. During the 2024-25 RSV season in France, RSV-B predominated, providing a unique opportunity to examine breakthrough infections with RSV-B and resistance at a large scale. The study aimed to characterise RSV escape from nirsevimab using genotypic and phenotypic methods. METHODS: This POLYRES-2 project was a multicentre, national, observational study conducted in hospital settings (inpatients and outpatients) across France during the 2024-25 RSV season. We included infants aged 1 year or under with a RT-PCR-confirmed RSV infection in routine care, regardless of whether they had received nirsevimab. Infants were identified through hospital virology laboratory databases. Each participating centre was requested to include a balanced number of nirsevimab-exposed and non-exposed infected infants throughout the study period. Clinical data were retrieved from electronic medical records. We compared RSV susceptibility to nirsevimab in infants who received nirsevimab with that in nirsevimab-naive infants. Respiratory samples were sequenced for full-length RSV genomes. To ensure reliability, phylogenetic and mutational analyses were restricted to high-quality sequences with greater than or equal to 90% genome coverage and complete reads across the nirsevimab-binding site. Clinical RSV isolates were tested for neutralisation by nirsevimab. We analysed F candidate substitutions using a fusion inhibition assay. The primary outcomes were presence of resistance-associated substitutions (RASs) in the RSV F protein (site Φ) and phenotypic resistance to nirsevimab. FINDINGS: Among 1023 RSV-infected infants, 858 (83·9%) had full-length RSV genome sequences: 419 (48·8%) from nirsevimab-treated breakthrough infections (212 [50·6%] RSV-A, 207 [49·4%] RSV-B) and 439 (51·2%) from nirsevimab-naive infants (192 [43·7%] RSV-A, 247 [56·3%] RSV-B). RASs were identified in two of 195 RSV-A breakthrough infections (1·0%) and in 23 of 184 RSV-B breakthrough infections (12·5%). In RSV-A, the only RAS was F:K209E, conferring intermediate resistance. In RSV-B, resistance was more frequent and diverse than in RSV-A: 12 of 23 (52.2%) resistant viruses carried a substitution at residue 208 (F:N208D, F:N208I, F:N208K, F:N208S, or F:N208Y). Additional novel substitutions, including F:I64V/F:K65E, F:K68I, F:L204S, and F:P205S, also mediated resistance. Notably, a resistant RSV-B variant (F:N208S) was detected almost 1 year after prophylaxis. No resistant RSV was detected in nirsevimab-naive infants. INTERPRETATION: Resistance to nirsevimab in RSV-B can emerge in real-world settings, affecting around 12% of breakthrough infections and showing greater diversity than previously recognised, although the clinical impact remains constrained by available evidence. Detection of resistant variants long after prophylaxis highlights the need for extended genomic surveillance. Integration of clinical and virological data will be essential to sustain the long-term effectiveness of RSV monoclonal antibody programmes. FUNDING: This study was supported by a grant from the Agence Nationale de Recherche sur le Sida et les hépatites virales - Maladies Infectieuses Emergentes and the French Ministry of Health and Prevention.
SN  - 2666-5247
ER  -