Inter-assay variability in anti-JC virus serology in the era of natalizumab biosimilars: implications for PML risk...

Anti-John Cunningham virus (JCV) serological testing constitutes a cornerstone of progressive multifocal leukoencephalopathy (PML) risk assessment in patients receiving natalizumab for multiple sclerosis (MS). Existing PML risk stratification algorithms were originally developed and validated within a single-assay framework based on the STRATIFY JCV™ DxSelect™ platform. The recent introduction of natalizumab biosimilars in Europe has coincided with implementation of IMMUNOWELL™ JCV IgG assay, creating a multi-assay environment in which quantitative antibody index values and binary serostatus classifications may not be directly interchangeable. We conducted a structured narrative review of comparative studies evaluating STRATIFY and IMMUNOWELL performance in natalizumab-treated cohorts. Outcomes included seroprevalence, qualitative concordance, quantitative index distribution, reclassification across established PML risk categories, and reported changes in clinical management. Across analytical validation datasets and real-world populations, IMMUNOWELL classified a higher proportion of individuals as JCV-positive than STRATIFY. Reported binary discordance ranged from approximately 6% to 38%, with a predominance of IMMUNOWELL-positive/STRATIFY-negative classifications. Longitudinal studies further showed that many low-positive IMMUNOWELL results fluctuated or reverted over time. The available evidence suggests that the transition from a mono-assay to a multi-assay testing environment introduces a previously underrecognized source of variability in PML risk stratification. In the absence of a biological gold standard for latent JCV infection, interpretation of discordant results should integrate antibody magnitude, longitudinal persistence, and clinical context rather than relying on binary thresholds.