{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T12:08:34Z","timestamp":1785326914511,"version":"3.55.0"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Anti\u2013John 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\u2122 DxSelect\u2122 platform. The recent introduction of natalizumab biosimilars in Europe has coincided with implementation of IMMUNOWELL\u2122 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1818341","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:38:03Z","timestamp":1785325083000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Inter-assay variability in anti\u2013JC virus serology in the era of natalizumab biosimilars: implications for PML risk stratification"],"prefix":"10.3389","volume":"17","author":[{"given":"Ana Bel\u00e9n","family":"Caminero","sequence":"first","affiliation":[{"name":"Department of Neurology, Complejo Asistencial de \u00c1vila","place":["\u00c1vila, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Oreja-Guevara","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, IdISSC","place":["Madrid, Spain"]},{"name":"Department of Medicine, Faculty of Medicine, Complutense University of Madrid (UCM)","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107829","article-title":"Risk of natalizumab-associated progressive multifocal leukoencephalopathy","volume":"366","author":"Bloomgren","year":"2012","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24286","article-title":"Anti\u2013JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy","volume":"76","author":"Plavina","year":"2014","journal-title":"Ann Neurol"},{"key":"B3","volume-title":"Tyruko (Natalizumab): EPAR","year":"2023"},{"key":"B4","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1007\/s00415-025-13273-z","article-title":"STRATIFY and IMMUNOWELL JCV test performance in a real-world multiple sclerosis cohort: possible clinical implications of biosimilar natalizumab use","volume":"272","author":"Guerrieri","year":"2025","journal-title":"J Neurol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1177\/13524585251322683","article-title":"Beyond the switch to the biosimilar of natalizumab: what is the impact of changing the JCV test","volume":"31","author":"Vukusic","year":"2025","journal-title":"Mult Scler J"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2025.0337","article-title":"Accuracy of a new John Cunningham virus antibody assay in natalizumab-treated patients with multiple sclerosis","volume":"82","author":"Gelissen","year":"2025","journal-title":"JAMA Neurol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/13524585251346652","article-title":"A comparison of JC virus assay performance provided with originator and biosimilar natalizumab","volume":"31","author":"Varley","year":"2025","journal-title":"Mult Scler J"},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1177\/13524585251346652","article-title":"A comparison of JC virus assay performance provided with originator and biosimilar natalizumab","author":"Varley","year":"2025"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1101\/2025.02.05.25320428","article-title":"Real-world experience with switching from originator to biosimilar natalizumab","author":"H\u00f8gest\u00f8l","year":"2025","journal-title":"medRxiv"},{"key":"B10","article-title":"A new assay for detection of anti-JCV antibodies to support risk stratification and monitoring for progressive multifocal leukoencephalopathy in patients treated with natalizumab","author":"Adler","year":"2024"},{"key":"B11","article-title":"Correlation of IMMUNOWELL JCV IgG and STRATIFY JCV DxSelect assays for PML risk stratification using anti-JCV antibody indices","author":"Azevedo","year":"2025"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1177\/17562864251374972","article-title":"Comparative evaluation of STRATIFY JCV\u2122 and IMMUNOWELL\u2122 assays for anti-JCV antibody detection in natalizumab-treated patients with relapsing\u2013remitting multiple sclerosis","volume":"18","author":"Chisari","year":"2025","journal-title":"Ther Adv Neurol Disord"},{"key":"B13","article-title":"JCV serostatus discrepancy by two different tests: impact on clinicians' and patients' choices in natalizumab-treated multiple sclerosis","author":"Garelli","year":"2025"},{"key":"B14","article-title":"Comparison of STRATIFY JCV and IMMUNOWELL JCV assays for anti-JCV antibody detection: a multicenter study across Tuscan neurology centers","author":"Giovannini","year":"2025"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1177\/13524585241300972","article-title":"Challenges and implications of anti-JCV antibody serology variability among different assays in natalizumab treatment: a call for standardization and transparency in clinical practice","volume":"31","author":"Inojosa","year":"2024","journal-title":"Mult Scler J"},{"key":"B16","article-title":"Longitudinal variability between commercial anti-JCV antibody assays in patients with multiple sclerosis","author":"Oreja-Guevara","year":"2025"},{"key":"B17","article-title":"Reassessing PML risk in multiple sclerosis: the impact of anti-JCV antibody assay selection","author":"Polovina","year":"2025"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.2174\/011570159X372688250226110925","article-title":"STRATIFY JCV\u2122 DxSelect\u2122 and IMMUNOWELL\u2122 JCV IgG tests in relapsing\u2013remitting multiple sclerosis to assess PML risk","volume":"23","author":"Zangh\u00ec","year":"2025","journal-title":"Curr Neuropharmacol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2026.107023","article-title":"Inter-assay variability in anti-JC virus testing for natalizumab: A Spanish cohort","volume":"107","author":"Fern\u00e1ndez Espigares","year":"2026","journal-title":"Mult Scler Relat Disord"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2025.106541","article-title":"Approach to JCV testing with natalizumab biosimilar: a UK consensus statement","volume":"100","author":"Dobson","year":"2025","journal-title":"Mult Scler Relat Disord"}],"container-title":["Frontiers in 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