{ "abstract": "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.", "abstract_shown": true, "affiliations": [ "Department of Virology, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France; Université Paris-Est-Créteil (UPEC), Créteil, France; INSERM U955, Viruses, Hepatology, Cancer Team, Créteil, France. Electronic address: slim.fourati@aphp.fr", "M3P, Institut Pasteur, UMR 1173 (2I), INSERM, Université de Versailles St. Quentin, Université Paris Saclay, Université Paris Cité, Paris, France; M3P, Centre National de Référence Virus des Infections Respiratoires (CNR VIR), Institut Pasteur Université Paris Cité, Paris, France", "M3P, Centre National de Référence Virus des Infections Respiratoires (CNR VIR), Institut Pasteur Université Paris Cité, Paris, France", "Laboratoire de Virologie, Institut des Agents Infectieux, Centre de Biologie et Pathologie Nord, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France", "INSERM U955, Viruses, Hepatology, Cancer Team, Créteil, France", "Laboratoire de Biologie Médicale Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer, Toulon Cedex, France", "Laboratoire de Virologie, CHU de Toulouse, Toulouse, France", "Virology department, CHU de Nantes, Nantes, France", "Service des Agents Infectieux et d'Hygiène-Plateau de Biologie Hôpital Nord-CHU de Saint-Etienne, Saint-Etienne, France", "Virology department, Hôpital Necker - Enfants Malades, Paris, France", "Virology department, CHU Carémeau, Nîmes, France", "Laboratoire de Virologie et Mycobactériologie, CHU de Poitiers, Poitiers, France", "CHU de Bordeaux, Service de Virologie, CNRS UMR 5234, Fundamental Microbiology and Pathogenicity, Bordeaux University, Bordeaux, France", "Virology Department, Hôpital Paul Brousse, INSERM U1193, AP-HP, Université Paris Saclay, Paris, France", "Sorbonne Université, APHP Virologie Pitié-Salpêtrière, Paris Ile de France, France", "Sorbonne Université, APHP Virologie St Antoine-Tenon-Trousseau, Paris Ile de France, France", "Virology department, CHU de Rennes, Rennes, France", "Emergence Unit, Department of Bacteriology, Virology and Hospital Hygiene, University Hospital of Tours, Tours, France", "Virology department, CHU de Reims, Reims, France", "Virology department, CHU de Strasbourg, Strasbourg, France", "Université Grenoble Alpes, Laboratoire de Virologie, Institut de Biologie-Pathologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France", "Université Lille, CHU de Lille, Laboratoire de Virologie ULR3610, Lille, France", "Normandie, INSERM, Normandie Université, DYNAMICURE UMR1311, CHU Caen, Department of Virology, Caen, France", "Laboratoire de Biologie Médicale, Microbiologie, CH Victor Dupouy, Argenteuil, France", "M3P, Institut Pasteur, UMR 1173 (2I), INSERM, Université de Versailles St. Quentin, Université Paris Saclay, Université Paris Cité, Paris, France; Virology Department, Hôpital Ambroise Paré (AP-HP), Paris, France", "Laboratoire de Virologie, CHRU de Nancy Brabois, Vandœuvre-lès-Nancy, France; Université de Lorraine, CNRS, LCPME, Nancy, France", "Service de Microbiologie Clinique, CHU Avicenne, APHP, Bobigny, France", "Univ Rouen Normandie, Université de Caen Normandie, INSERM, Normandie Univ, DYNAMICURE UMR 1311, CHU Rouen, Department of Virology, Rouen, France", "CHU d'Orléans, Virologie, Université d'Orléans, LI2RSO, Orléans, France", "Laboratoire de Virologie, CHU Angers, Angers, France", "Pathogenesis and Control of Chronic and Emerging Infections, Université Montpellier, INSERM, CHU Montpellier, Montpellier, France", "AGIR, UR4294, Université Picardie Jules Verne, Laboratoire de Virologie, Centre de Biologie Humaine-CHU Amiens, Amiens, France", "Virology department, CHU de Clermont-Ferrand, Clermond-Ferrand, France", "Virology Department, Hôpital Saint Louis (AP-HP), U976UMR 1342, Biology and Pathogenesis of Viral Infection Team, INSERM, Université Paris Cité Paris, France", "CNR Associé des Virus Respiratoires, Laboratoire Microbiologie, Hôpital Félix Guyon CHU Réunion, La Réunion, France", "Department of Virology, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France", "Department of Virology, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France; INSERM U955, Viruses, Hepatology, Cancer Team, Créteil, France", "Department of Virology, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France; Université Paris-Est-Créteil (UPEC), Créteil, France; INSERM U955, Viruses, Hepatology, Cancer Team, Créteil, France", "Virology department CHU de Martinique, Fort de France, Martinique, France", "Virus and Immunity Unit, Institut Pasteur, Université Paris Cité, CNRS UMR3569, Paris, France" ], "article_type": null, "arxiv": null, "author_total": 100, "authors": [ { "affs": [ 0 ], "name": "Slim Fourati", "orcid": "0000-0002-1236-5467" }, { "affs": [ 1 ], "name": "Alawiya Reslan" }, { "affs": [ 2 ], "name": "Jérôme Bourret", "orcid": "0000-0003-2863-8818" }, { "affs": [ 3 ], "name": "Jean-sébastien Casalegno" }, { "affs": [ 1 ], "name": "Yannis Rahou" }, { "affs": [ 4 ], "name": "Laurent Softic", "orcid": "0000-0001-6040-5040" }, { "affs": [ 5 ], "name": "Lionel Chollet" }, { "affs": [ 6 ], "name": "Pauline Trémeaux", "orcid": "0000-0001-8783-9885" }, { "affs": [ 7 ], "name": "Berthe-Marie Imbert-Marcille" }, { "affs": [ 8 ], "name": "Sylvie Pillet", "orcid": "0000-0002-0882-3162" }, { "affs": [ 9 ], "name": "Nicolas Veyrenche", "orcid": "0000-0001-5948-5039" }, { "affs": [ 10 ], "name": "Agathe Boudet" }, { "affs": [ 11 ], "name": "Luc Deroche", "orcid": "0000-0002-9985-7375" }, { "affs": [ 12 ], "name": "Sonia Burrel" }, { "affs": [ 13 ], "name": "Lina Mouna", "orcid": "0000-0003-0749-769X" }, { "affs": [ 14 ], "name": "Théophile Cocherie", "orcid": "0000-0001-5895-6193" }, { "affs": [ 15 ], "name": "Aurélie Schnuriger", "orcid": "0000-0003-0931-8720" }, { "affs": [ 16 ], "name": "Charlotte Pronier", "orcid": "0000-0001-7873-2752" }, { "affs": [ 17 ], "name": "Lynda Handala", "orcid": "0000-0001-5033-4357" }, { "affs": [ 18 ], "name": "Véronique Brodard" }, { "affs": [ 19 ], "name": "Floriane Gallais", "orcid": "0000-0001-9727-9391" }, { "affs": [ 20 ], "name": "Sylvie Larrat", "orcid": "0000-0001-7817-6602" }, { "affs": [ 21 ], "name": "Alexandre Réguème", "orcid": "0000-0002-6358-7772" }, { "affs": [ 22 ], "name": "Nefert Candace Dossou", "orcid": "0000-0002-7361-8106" }, { "affs": [ 23 ], "name": "Amandine Henry", "orcid": "0000-0002-8935-8185" }, { "affs": [ 24 ], "name": "Elyanne Gault" }, { "affs": [ 25 ], "name": "Cédric Hartard", "orcid": "0000-0001-5942-2345" }, { "affs": [ 26 ], "name": "Ségolène Brichler", "orcid": "0000-0002-7336-7730" }, { "affs": [ 27 ], "name": "Alice Moisan", "orcid": "0000-0002-1162-720X" }, { "affs": [ 28 ], "name": "Véronique Avettand-Fènoël", "orcid": "0000-0002-7022-2990" }, { "affs": [ 29 ], "name": "Caroline Lefeuvre", "orcid": "0000-0003-4934-5926" }, { "affs": [ 30 ], "name": "Ilka Engelmann", "orcid": "0000-0001-7489-3786" }, { "affs": [ 31 ], "name": "Sandrine Castelain", "orcid": "0000-0002-2670-3148" }, { "affs": [ 32 ], "name": "Audrey Mirand", "orcid": "0000-0002-9638-2415" }, { "affs": [ 33 ], "name": "Maud Salmona", "orcid": "0000-0001-7985-6132" }, { "affs": [ 34 ], "name": "Marie-Christine Jaffar-Bandjee" }, { "affs": [ 35 ], "name": "Mohamed Ader" }, { "affs": [ 35 ], "name": "Sarah Seng" }, { "affs": [ 36 ], "name": "Pierre Cappy", "orcid": "0000-0001-8540-2196" }, { "affs": [ 37 ], "name": "Christophe Rodriguez", "orcid": "0000-0002-9817-5006" }, { "affs": [ 35 ], "name": "Arnaud Ly" }, { "affs": [ 38 ], "name": "Georges Dos Santos", "orcid": "0000-0001-7383-4522" }, { "affs": [ 39 ], "name": "Olivier Schwartz", "orcid": "0000-0002-0729-1475" }, { "affs": [ 39 ], "name": "Chloé Petiot" }, { "affs": [ 39 ], "name": "Delphine Planas", "orcid": "0000-0002-2509-9954" }, { "name": "Samar Berreira Ibraim" }, { "name": "Kévin Da Silva" }, { "name": "Amélie Recoing" }, { "affs": [ 37 ], "name": "Jean–Michel Pawlotsky", "orcid": "0000-0003-0745-7559" }, { "name": "Frédéric Lemoine", "orcid": "0000-0001-9576-4449" }, { "name": "Étienne Audureau", "orcid": "0000-0002-6166-149X" }, { "name": "Marie‐Anne Rameix‐Welti", "orcid": "0000-0002-5901-3856" }, { "name": "Nael Zemali" }, { "affs": [ 12 ], "name": "Sonia Burrel" }, { "name": "Pantxika Bellecave" }, { "affs": [ 27 ], "name": "Alice Moisan", "orcid": "0000-0002-1162-720X" }, { "name": "Zakasoa-Mbololona Zavaoarisaina" }, { "name": "Romain Legros" }, { "name": "Boris Derman" }, { "name": "Vincent Pargny", "orcid": "0000-0002-2768-9528" } ], "bibtex": "https://research.draconitic.com/paper/9sfmn0g6w6sh5.bib", "cited_by": 13, "doi": "10.1016/j.lanmic.2026.101353", "fulltext_url": null, "id": "9sfmn0g6w6sh5", "issns": [ "2666-5247" ], "landing_url": "https://doi.org/10.1016/j.lanmic.2026.101353", "language": "en", "licence": "CC-BY-NC", "licence_label": "CC BY-NC", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2713|Respiratory viral infections research" ] ], "openalex": "W7163223042", "pdf_url": null, "pmcid": null, "pmid": "42229496", "published": "2026-06-02", "publisher": "Elsevier BV", "ris": "https://research.draconitic.com/paper/9sfmn0g6w6sh5.ris", "sources": [ { "first_seen": "2026-10-30T13:26:54Z", "native_id": "W7163223042", "source": "openalex", "url": "https://doi.org/10.1016/j.lanmic.2026.101353" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2713|Respiratory viral infections research", "subfield": "epidemiology-public-health" } ], "title": "Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France", "title_text": "Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France", "type": "peer-reviewed", "updated_at": "2026-11-09T13:21:16Z", "url": "https://research.draconitic.com/paper/9sfmn0g6w6sh5", "venue": "The Lancet Microbe", "versions": [] }