Detection of a Nirsevimab-Resistant RSV-B Variant (F:K68Q) in an Adult with Severe Infection

Respiratory syncytial virus (RSV) is recognized as a major cause of severe disease in adults, particularly those having cardiorespiratory comorbidities or immunosuppression. The recent deployment of monoclonal antibodies targeting the prefusion F protein could be used in the future to prevent RSV-associated hospitalization and critical illness in immunocompromised adult patients.

This report is part of the ongoing ARF-RSV study (NCT06197152), a prospective, multicenter observational cohort.

We report on the case of a 64-year-old man with a previous medical history of aggressive mantle cell lymphoma under active treatment who was admitted to the intensive care unit for severe sepsis in the setting of febrile aplasia. Clinical evolution was rapidly favorable, with resolution of hemodynamic failure within a few days. Two nasopharyngeal samples collected 7 days apart were positive for RSV-B. Genetic analysis identified a strain belonging to lineage B.D.E.1, with both samples harboring a dominant F:K68Q substitution in the fusion protein. In the first sample, the mean depth of coverage was over 180× and the F:K68Q substitution was detected at an allele frequency of 99%. In the second sample, collected 7 days later, the mean depth of coverage was 170×, with the same substitution detected with an allele frequency of 97%, consistent with persistence as a dominant variant over time. This substitution has been previously associated with high-level resistance to nirsevimab. More generally, F:K68Q appears to be rare among circulating RSV-B strains based on available global sequence surveillance data (GISAID). Its detection in a monoclonal antibody-naïve patient reinforces the hypothesis that this substitution may circulate independently of nirsevimab exposure.

The persistence of a resistant RSV variant in a patient who was immunocompromised without prior exposure to nirsevimab suggests that such variants may circulate and be transmitted. In this context, RSV vaccination of patients who are immunocompromised may not only provide individual protection but also help limit the dissemination of resistant strains.