AstraZeneca’s nirsevimab (Beyfortus) is a highly effective monoclonal antibody (mAb) targeting the RSV F protein, first approved in the EU in 2022, for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in infants during their first RSV season and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. However, recent data presented at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global Conference demonstrated real-world evidence of resistance to this drug.
In the POLYRES-2 project, a multi-centre, national, observational study was conducted on infants under one year of age who were within a hospital setting (inpatient or outpatient) in France during the 2024–25 RSV season. RSV susceptibility was compared between infants who had received nirsevimab and those who were non-immunised. Respiratory samples were sequenced for full-length RSV genomes, only taking into account high-quality sequences for RSV lineages, and phylogenetic analysis and identification of RSV F protein binding site zero amino acid substitution was conducted. Fusion inhibition assays were utilised to assess the impact of identified substitutions. Furthermore, clinical RSV isolates were further analysed to assess the susceptibility of these isolates to nirsevimab by plaque reduction neutralisation tests.
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Co-circulation of several lineages of RSV-A and RSV-B samples were collected across multiple regions of France in 2024/2025. Among 1,023 RSV-infected infants, 858 (83.9%) had full-length RSV genome sequences: 419 (48.8%) from nirsevimab-treated breakthrough infections (with RSV-A and RSV-B accounting for 212 [50.6%] and 207 [49.4%], respectively) and 439 (51.2%) from non-immunised infants (with RSV-A and RSV-B accounting for 192 [43.7%] and 247 [56.3%], respectively). Resistance-associated substitutions (RAS) were identified in 2 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: 12 of 23 (52%) 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 one year after prophylaxis. No resistant RSV was detected in non-immunised infants.
This study has shown that RSV-B resistance to nirsevimab can emerge in real-world settings, affecting around 12% of breakthrough infections and displaying greater diversity than previously recognised. 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 programs. Key opinion leaders (KOLs) previously interviewed by GlobalData have expressed their concern regarding growing resistance to the prophylactic mAbs available, especially as their usage is increasing globally. Nonetheless, despite two years of widespread use of nirsevimab across major markets, including Europe and the US, no large-scale emergence of resistance has emerged, nor has there been an increasing trend in resistance. Further assessments as to whether the resistant variants are being spread to the community will be important to fully understand the burden of resistance.
