Genotypic and phenotypic characterisation of respiratory syncytial virus after nirsevimab breakthrough infections: a large, multicentre, observational, real-world study

Slim Fourati,Alawiya Reslan,Jérome Bourret,Jean-Sébastien Casalegno,Yannis Rahou,Lionel Chollet,Sylvie Pillet,Pauline Tremeaux,Nefert Candace Dossou,Elyanne Gault,Maud Salmona,Berthe-Marie Imbert-Marcille,Audrey Mirand,Sylvie Larrat,Alice Moisan,Stéphane Marot,Aurélie Schnuriger,Nicolas Veyrenche,Ilka Engelmann,Lynda Handala,Amandine Henry,Valentin Stephan,Ségolène Brichler,Véronique Avettand-Fenoel,Nael Zemali,Caroline Lefeuvre,Charlotte Pronier,Luc Deroche,Marie-Christine Jaffar-Bandjee,Lina Mouna,Catherine Francois,Alexandre Regueme,Cédric Hartard,Sylvie Rogez,Floriane Gallais,Arnaud Ly,Christophe Rodriguez,Georges Dos Santos,Etienne Simon-Loriere,Olivier Schwartz,Julian Buchrieser,Jean-Miichel Pawlotsky,Frédéric Lemoine,Etienne Audureau,Marie-Anne Rameix-Welti,Naël Zemali,Sonia Burrel,Alice Moisan,Zakasoa-Mbololona Zavaoarisaina,Romain Legros,Boris Derman,Vincent Pargny,Hortense Petat,Jean-Christophe Plantier,Véronique Avettand-Fenoel,Salim Ferrani,Jérome Guinard,Clémence Guillaume,Gilbert Mchantaf,Victoria Marie,Laurent Bret,Fabien Lesne,Anthony De Oliveira,Alexandre Regueme,Kazali Alidjinou,Lionel Chollet,Vincent Gardan,Ségolène Brichler,Loic De Pontual,Camille Aupiais,Stéphane Marot,Aurélie Schnuriger,Marine Perrier,Pierre Jatteau,Djeneba Fofana,Théophile Cocherie,Elisa Teyssou,Cathia Soulié,Vincent Calvez,Sylvie Larrat,Anne Faisant,Guillaume Mortamet,Caroline Tournegros,Mohamed Habib,Sylvie Pillet,Aymeric Cantais,Franck Zekre,Thomas Bourlet,Oulfa Boussetta-Charfi,Sara Chenafi-Adham,Eva Gleizes,Cédric Hartard,Caroline Lefeuvre,Elise Bouthry,Lina Mouna,Fairly Warnakulasuriya,Quentin Le Hingrat,Marie-Christine Jaffar,Diana Heaugwane,Benjamin Azemar,Nicolas Mnemosyme,Laurent Souply,Catherine François,Sandrine Castelain,Cinthia Rames,Arnaud Bécourt,Ilka Engelmann,Eric Jeziorski,Vincent Foulongne,Steven Henry,Léa Domitien,Lynda Handala,Catherine Gaudy-Graffin,Agathe Crémadés,Amandine Henry,Alessandra Pennisi,Maud Salmona,Jérôme Le Goff,Sarah Mafi,Audrey Gabassi,Marie-Laure Néré,Stéphane Bonacorsi,Naim Ouldali,Senhaji Rachik Abdeljalil,Marie-Anne Rameix-Welti,Alawyia Reslan,Yannis Rahou,Jérome Bourret,Frédérique Lemoine,Kévin Da Silva,Samar Berreira Ibraim,Emilie Yab,Vincent Enouf,Flora Donati,Matthieu Prot,Banujaa Jeyarajah,Etienne Simon-Loriere,Nefert Candace Dossou,Astrid Vabret,Slim Fourati,Christophe Rodriguez,Jean-Michel Pawlotsky,Pierre Cappy,Alexandre Soulier,Mohamed Ader,Sarah Seng,Arnaud Ly,Pierre-André Natella,Etienne Audureau,Georges Dos Santos,Laurence Fagour,Anne-Julie Schapira,Olivier Flechelles,Luc Deroche,Nicolas Leveque,Claire Morton Fauche,Berthe-Marie Imbert,Louise Castain,Audreay Rodallec,Justine Sourice,Christele Gras-Le Guen,Anne Chauvire-Drouard,Elyanne Gault,Frédérique Moreau,Claire Deback,Floriane Gallais,Morgane Solis,Valentin Stephan,Léa Pilorgé,Sophie Vallet,Léa Gaitan,Sylvie Rogez,Audrey Mirand,Cecile Henquell,Charlotte Pronier,Vincent Thibault,Pauline Trémeaux,Isabelle Claudet,Mélanie Pucelle,Laetitia Staes,Camille Vellas,Romain Carcenac,Nicolas Veyrenche,Jean-Sébastien Casalegno,Alexandre Gaymard,Jose Kombou,Antonin Bal,Stanislas Ogoudjobi

doi:10.1016/s1473-3099(24)00570-x

Abstract

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. 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 Ø. We tested clinical RSV isolates for neutralisation by nirsevimab. We analysed F candidate substitutions by fusion-inhibition assay. 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 Ø 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. 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. ANRS Maladies Infectieuses Emergentes and the French Ministry of Health and Prevention.

Full Text