Background Nirsevimab, a long-acting monoclonal antibody, has been approved for the prevention of respiratory syncytial virus (RSV) infection in infants. In France, more than 210 000 single doses were administered in infants younger than 1 year during the 2023-24 season. In this context, the selection and spread of escape variants might be a concern. Here, we aimed to characterise RSV associated with breakthrough infection. Methods We did a multicentre, national, observational study in France during the 2023-24 RSV season in RSV-infected infants (aged <1 year) who either received or did not receive a dose of nirsevimab before their first RSV season. We excluded infants with insufficient information about nirsevimab treatment or without parental consent. We used respiratory samples collected in each laboratory for full-length RSV RNA sequencing to analyse changes in the nirsevimab binding site circle divide. We tested clinical RSV isolates for neutralisation by nirsevimab. We analysed F candidate substitutions by fusion-inhibition assay. Findings Of the 695 RSV infected infants, we analysed 545 (78%) full-length RSV genome sequences: 260 (48%) from nirsevimab-treated breakthrough infections (236 [91%] RSV-A and 24 [9%] RSV-B) and 285 (52%) from untreated RSV-infected infants (236 [83%] RSV-A and 49 [17%] RSV-B). Analysis of RSV-A did not reveal any substitution in site circle divide known to be associated with resistance to nirsevimab. Two (8%) of 24 RSV-B breakthrough infections had resistance-associated substitutions: F:N208D (dominant resistance-associated substitution) and a newly described F:I64M plus F:K65R combination (minority resistance-associated substitution), both of which induced high levels of resistance in the fusion-inhibition assay. Interpretation This study is, to the best of our knowledge, the largest genotypic and phenotypic surveillance study of nirsevimab breakthrough infections to date. Nirsevimab breakthrough variants remain very rare despite the drug''s widespread use. The detection of resistance-associated substitutions in the RSV-B F protein highlights the importance of active molecular surveillance. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
[1]Hop Univ Henri Mondor, AP HP, Dept Virol, Creteil, France.
[2]Univ Paris Est Creteil, Creteil, France.
[3]INSERM, U955, Team Viruses, Hepatol,Canc, Creteil, France.
[4]Univ Paris Saclay, Univ Versailles St Quentin, INSERM, M3P,UMR 1173 2I, Paris, France.
[5]Univ Paris Cite, Inst Pasteur, M3P Ctr Natl Reference Virus Infect Resp, Paris, France.
[6]Hosp Civils Lyon, Hop Croix Rousse, Inst Agents Infect, Lab Virol,Ctr Biol & Pathol Nord, Lyon, France.
[7]Ctr Hosp Intercommunal Toulon, Lab Biol Med, Toulon, France.
[8]CHU St Etienne, Hop Nord, Serv Agents Infect & Hyg Plateau Biol, St Etienne, France.
[9]CHU Toulouse, Lab Virol, Toulouse, France.
[10]Normandie Univ, CHU Caen, Dept Virol, Normandie,INSERM,DYNAMICURE,UMR1311, Caen, France.
[11]Hop Ambroise Pare, Virol Dept, Paris, France.
[12]Univ Paris Cite, Hop St Louis, INSIGHT, Virol Dept,INSERM,U976, Paris, France.
[13]CHU Nantes, Virol Dept, Nantes, France.
[14]CHU Clermont Ferrand, Virol Dept, Clermont Ferrand, France.
[15]Univ Grenoble Alpes, Ctr Hosp Univ Grenoble Alpes, Inst Biol Pathol, Lab Virol, Grenoble, France.
[16]Normandie Univ, Univ Caen Normandie, Univ Rouen Normandie, INSERM,DYNAMICURE,UMR 1311,CHU Rouen,Dept Virol, Rouen, France.
[17]Sorbonne Univ, Paris Ile De France, France.
[18]APHP Virol Pitie Salpetriere, Paris Ile De France, France.
[19]Sorbonne Univ, APHP Virol St Antoine, Trousseau, Paris Ile De Fr, France.
[20]Hop Necker Enfants Malad, Virol Dept, Paris, France.
[21]Univ Montpellier, CHU Montpellier, Pathogenesis & Control Chron & Emerging Infect, INSERM,Etab Francais Sang, Montpellier, France.
[22]Univ Hosp Tours, Virol Unit, Dept Bacteriol Virol & Hosp Hyg, Tours, France.
[23]CH Victor Dupouy, Lab Biol Med, Microbiol, Argenteuil, France.
[24]CHRU Brest, Virol Dept, Brest, France.
[25]CHU Avicenne, AP HP, Serv Microbiol Clin, Bobigny, France.
[26]CHU Orleans, Virol, Orleans, France.
[27]CHU Bordeaux, Serv Virol, Bordeaux, France.
[28]CHU Angers, Lab Virol, Angers, France.
[29]CHU Rennes, Virol Dept, Rennes, France.
[30]CHU Poitiers, Virol Dept, Poitiers, France.
[31]CHU Reunion, Hop Felix Guyon, Lab Microbiol, CNR Associe Virus Resp, St Denis, La Reunion, France.
[32]Univ Paris Saclay, Hop Paul Brousse, AP HP, Virol Dept,INSERM,U1193, Paris, France.
[33]Univ Picardie Jules Verne, CHU Amiens, Lab Virol, Ctr Biol Humaine, Amiens, France.
[34]Univ Lille, Lab Virol, CHU Lille, ULR3610, Lille, France.
[35]Univ Lorraine Vandoeuvre les Nancy, CHRU Nancy Brabois, Lab Virol, Vandoeuvre Les Nancy, France.
[36]CHU Limoges, Virol Dept, Limoges, France.
[37]CHU Strasbourg, Virol Dept, Strasbourg, France.
[38]CHU Martinique, Microbiol Dept, Fort De France, La Martinique, France.
[39]Univ Paris Cite, Inst Pasteur, Evolutionary Genom RNA Viruses, Paris, France.
[40]Univ Paris Cite, Inst Pasteur, Virus & Immun Unit, Paris, France.
[41]Univ Paris Cite, Inst Pasteur, Bioinformat & Biostat Hub, Paris, France.
[42]Hop Univ Henri Mondor, AP HP, Clin Res Unit Mondor, IMRB,INSERM,U955,Team CEpiA, Creteil, France.
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