Infectious Disease · Medical Literature
[Articles] Real-world emergence of nirsevimab resistance in breakthrough infections with respiratory syncytial virus-B: a multicentre observational study in France
Abstract
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.
Clinical relevance
In real-world settings during the 2024–25 RSV season in France, at what frequency and with what molecular diversity do resistance-associated substitutions (RASs) emerge in RSV-B breakthrough infections among nirsevimab-treated infants, and what is their phenotypic and clinical impact? __SNAPSHOT__ {"studyDesign":"Prospective multicentre observational cohort study (POLYRES-2 project)","setting":"32 tertiary care and university-affiliated hospitals across France (inpatient and outpatient); RSV season September 16, 2024 to April 23, 2025","sampleSize":"n=1,023 RSV-infected infants total; 858 (83.9%) had full-length RSV genome sequences — 419 (48.8%) from nirsevimab-treated breakthrough infections (212 RSV-A; 207 RSV-B) and 439 (51.2%) from untreated infants (192 RSV-A; 247 RSV-B); RAS analysis conducted on a subset of high-quality sequences (195 RSV-A and 184 RSV-B breakthrough cases)","population":"Infants younger than 1 year with RT-PCR–confirmed RSV infection, admitted or managed at participating centres during the 2024–25 RSV season; both nirsevimab-treated and untreated infants included","intervention":"Nirsevimab (long-acting monoclonal antibody targeting the prefusion RSV F protein site Φ/Ø) administered as part of France's national RSV immunisation programme (~420,000 doses in the 2024–25 season, representing ~60% coverage of infants <1 year). Virological assessment included full-length RSV genome sequencing, phylogenetic analysis, identification of F protein binding-site amino acid substitutions, fusion inhibition assays, and plaque reduction neutralisation tests.","comparator":"Untreated (non-nirsevimab-immunised) RSV-infected infants serving as a virological comparator arm for RAS prevalence","primaryOutcome":"Prevalence and molecular diversity of resistance-associated substitutions (RASs) in the RSV F protein among nirsevimab-treated infants with breakthrough RSV-B infection; phenotypic impact on nirsevimab susceptibility; virological and clinical factors associated with resistance emergence","followUp":"Duration of follow-up for individual infants not reported; study surveillance window September 16, 2024 to April 23, 2025 (approximately 7 months)","fundingSource":"ANRS Maladies Infectieuses Emergentes (government/non-profit); French Ministry of Higher Education and Research (EMERGEN Consortium)"}
Key findings
Among 1,023 RSV-infected infants with full-length genome sequencing available in 858 (83.9%), RAS analysis performed on high-quality sequences identified resistance-associated substitutions in 2 of 195 RSV-A breakthrough infections (1.0%) and in 23 of 184 RSV-B breakthrough infections (12.5%). No resistant RSV was detected in any untreated infant, consistent with selection pressure driving emergence. In RSV-B, resistance was both more frequent and more molecularly diverse than previously recognised: 12 of 23 (52%) resistant RSV-B viruses harboured substitutions at F 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 — were also found to mediate resistance. In RSV-A, the sole RAS identified was F:K209E, conferring only intermediate resistance. A particularly notable finding was the detection of a resistant RSV-B variant (F:N208S) almost one year after nirsevimab prophylaxis, indicating that the window of selective pressure and clinical relevance may extend well beyond the expected duration of antibody activity. The phenotypic impact of identified substitutions was confirmed via fusion inhibition assays and plaque reduction neutralisation tests. Absolute and relative effect sizes (e.g., odds ratios, confidence intervals, p-values) for resistance risk factors and clinical outcomes are not reported in the available abstract; NNT/NNH cannot be calculated from the provided data.
Practice implications
This study establishes that nirsevimab resistance in RSV-B can emerge under real-world programmatic conditions, affecting approximately 12.5% of RSV-B breakthrough infections in a high-coverage national immunisation setting — a substantially higher proportion than observed in Phase 2/3 trial data, where only 4 resistant variants were identified among 56 RSV-B breakthrough infections. The molecular diversity of RSV-B RASs is greater than previously characterised, with multiple novel substitution positions identified beyond the well-known residue 208 hotspot. The complete absence of RASs among untreated infants strongly implies nirsevimab-mediated selection pressure as the driver of resistance emergence. However, the study does not yet establish whether resistant variants result in more severe clinical illness, increased hospitalisation rates, or altered transmission dynamics — the abstract explicitly states that 'the clinical impact remains constrained by available evidence.' Findings are most applicable to full-term and near-term infants <1 year of age in high-coverage national immunisation programmes during RSV-B–predominant seasons. Premature infants, immunocompromised patients, and older children eligible for second-season dosing are not specifically characterised. Critically, this summary is based on the published abstract only; the full dataset, multivariate resistance risk factors, clinical severity analyses, and phenotypic IC50/IC90 data are not available for review and may substantially affect interpretation. Overall programme effectiveness against hospitalisation was approximately 70–85% in prior real-world studies, and no large-scale population-level emergence of resistance has yet been observed despite two seasons of widespread use. Practice should not change at this time, but the data provide a compelling rationale for strengthening integrated genomic and clinical surveillance. __LIMITATIONS__ Only an abstract was available for this summary; full methodology, statistical analyses, clinical severity data, and phenotypic resistance thresholds are not reviewable.,Observational design precludes causal inference regarding risk factors for resistance emergence or clinical outcomes associated with resistant variants.,Selection bias is possible: infants captured at hospital-affiliated centres (inpatient and outpatient) may not represent the full spectrum of nirsevimab breakthrough infections occurring in the community, likely overrepresenting more severe cases.,RAS analysis was restricted to a subset of high-quality full-length sequences (195 RSV-A and 184 RSV-B breakthrough infections), introducing potential ascertainment bias if sequencing success was non-random.,The study was conducted exclusively in France during a single RSV season with RSV-B predominance; generalisability to RSV-A–predominant seasons, other geographic settings, or lower-coverage programmes is uncertain.,Clinical outcomes data (severity, hospitalisation duration, mechanical ventilation, mortality) associated with resistant versus susceptible strains are not reported in the abstract, precluding assessment of clinical significance.,The detection of a resistant variant nearly one year after prophylaxis raises questions about prolonged viral persistence versus community transmission, which cannot be distinguished from the available data.,No p-values, confidence intervals, or effect sizes for resistance risk factors are reported, limiting quantitative interpretation.,Phenotypic resistance thresholds (IC50/IC90 fold-changes) for individual novel substitutions are not detailed in the abstract.,The study enrolled only infants <1 year; findings do not address resistance dynamics in children receiving second-season nirsevimab dosing. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ During the 2024–25 RSV-B–predominant season in France, nirsevimab resistance-associated substitutions were detected in approximately 12.5% of RSV-B breakthrough infections — substantially higher than prior trial-era estimates — with greater molecular diversity than previously recognised, including novel substitution sites and a case of resistance detected nearly one year post-prophylaxis. No resistant variants were identified among untreated infants, strongly implicating immunological selection pressure. While current evidence does not demonstrate a measurable adverse clinical impact from resistant variants and overall programme effectiveness remains robust, these findings mandate integrated genomic and clinical surveillance systems as a prerequisite for sustaining the long-term effectiveness of national nirsevimab immunisation programmes.