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Genotypic and Phenotypic Characterisation of Rsv after Nirsevimab Breakthrough Infections in a Large Multicentre Observational Real-World Study
30 Pages Posted: 16 Jul 2024
More...Abstract
Background: Nirsevimab, a long-acting monoclonal antibody has recently been approved for the prevention of RSV lower respiratory tract infection in infants. In France, more than 210,000 single doses were administered during 2023-24 season in infants aged less than 1 year. In this context, emergence and spread of escape variants might be a concern. Here, we characterize RSV viral breakthrough in a large observational real-life study.
Methods: Multicentre national observational study during RSV 2023-24 season was conducted in infants receiving or not receiving one dose of nirsevimab before their first RSV season. Full-length RSV RNA sequencing was performed and changes of F (nirsevimab-binding site Ø) relative to reference sequences were analysed. RSV clinical isolates were tested for neutralization by nirsevimab. F candidate mutations were analysed using fusion-inhibition assay.
Findings: Of the 695 RSV infected infants, 545 RSV full-length genome sequences were analysed: 260 from nirsevimab-treated breakthrough infections (236 RSV-A; 24 RSV-B) and 285 from untreated RSV-infected infants (236 RSV-A; 49 RSV-B). Analysis of RSV-A revealed no mutation in site Ø known to be associated with resistance to nirsevimab. Two of the 24 RSV-B breakthrough infections evidenced resistance-associated mutations: F:N208D (dominant variant) and a newly described F: I64M+ K65R combination (minority variant) both inducing high level of resistance in fusion-inhibition assay.
Interpretation: This study is the largest genotypic and phenotypic surveillance study of nirsevimab breakthrough infections conducted so far. Nirsevimab escape variants remain very rare despite its widespread use. Detection of mutations in RSV-B F highlights the importance of active molecular surveillance.
Funding: This work was supported by the EMERGEN consortium—ANRS Maladies Infectieuses Emergentes (ANRS EM). The investigators would like to acknowledge ANRS | Emerging infectious diseases for their scientific support, the French Ministry of Health and Prevention for their funding and support.
Declaration of Interest: S.F. has served as a speaker for GlaxoSmithKline, AstraZeneca, MSD, Pfeizer, Cepheid and Moderna; J.-M.P. has served as an advisor or speaker for Abbvie, Arbutus, Assembly Biosciences, Gilead and Merck; E.A. has received fees for lectures from Alexion, Sanofi, Gilead and Pfizer. Other authors and investigators have no conflict of interest to disclose.
Ethical Approval: The study was approved by the Comité d’éthique de la recherche/Institutional review board (Mondor IRB#00011558).
Keywords: RSV, breakthrough infection, monoclonal antibodies, nirsevimab, resistance
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