AbstractBackground and purposeThis study was undertaken to retrospectively compare rates of John Cunningham virus (JCV) seroconversion in natalizumab‐treated patients before and during COVID‐19‐related community restrictions. Natalizumab is highly effective therapy for relapsing–remitting multiple sclerosis. Prolonged exposure to natalizumab in JCV‐positive patients can cause progressive multifocal leukoencephalopathy, a potentially fatal brain infection. Serial assessment of JCV status is required for patients receiving natalizumab.MethodsPatients receiving natalizumab at the Royal Melbourne Hospital were assessed for change in JCV serostatus and duration of exposure to natalizumab in two discrete time periods: from 1 February 2012 until 1 February 2017 (“pre‐COVID”; n = 128) and from 1 April 2020 until 12 October 2022 (“COVID”; n = 214). A Poisson regression model adjusted for age at natalizumab commencement and sex was used to model seroconversion rate between the two time periods.ResultsThe pre‐COVID JCV seroconversion rate among natalizumab‐treated patients at the Royal Melbourne Hospital was 9.08%. Conversely, we found a precipitous decline in JCV seroconversion during COVID lockdown. Annualized seroconversion during COVID‐19‐related restrictions was 2.01%. The annualized seroconversion rate was 4.7 times higher during the pre‐COVID‐19 period (95% confidence interval = 2.96–7.45, p < 0.0001) compared to the annualized seroconversion rate during COVID lockdown. Males had a 2× higher rate of seroconversion compared to females.ConclusionsJCV seroconversion among natalizumab‐treated patients was markedly lower during COVID‐19‐related community restrictions. Restrictions observed in Melbourne were among the longest and most comprehensive implemented worldwide. This suggests the presence of modifiable risk factors that could lower rates of JCV seroconversion among natalizumab‐treated patients.