The objective of this study was to evaluate whether 9-valent human papillomavirus (HPV9) vaccination is associated with an increased risk of juvenile idiopathic arthritis (JIA), particularly during the coronavirus disease-2019 (COVID-19) pandemic. A retrospective cohort study was conducted using TriNetX U.S. Collaborative Network data from January 1, 2016, to December 31, 2023. Girls aged 9–13 years who received their first HPV9 dose in either the prepandemic period (2016–2019) or the pandemic period (2020–2023) were matched with unvaccinated controls. Exclusion criteria included a previous JIA diagnosis, prior antirheumatic drug use, or positive rheumatoid factor. The incidence of new-onset JIA was tracked over a period ranging from 8 days to 36 months. Cox regression and Kaplan-Meier survival analyses were applied to evaluate hazard ratios (HRs) and JIA-free survival.
Among 99,243 vaccinated individuals and 1.1 million unvaccinated controls, HPV9 recipients demonstrated a significantly reduced risk of JIA at 36 months in both study periods (HR 2016–2019, 0.207, P<.001; HR 2020–2023, 0.287, P<.001). No increased risk was observed during the early postvaccination period. The estimated cumulative probability of JIA did not differ significantly between vaccinated groups across the two periods (P=.9), nor among unvaccinated controls (P=.238), suggesting that COVID-19 did not modify the relationship. These findings indicate that HPV9 vaccination was associated with a lower risk of JIA, with this protective effect lasting for at least 3 years. Importantly, the COVID-19 pandemic did not alter this association, reinforcing the immunological safety of HPV9 and providing reassurance for adolescent vaccination programs even during pandemic contexts.
Human papillomavirus (HPV) is a double-stranded DNA virus implicated in a wide range of pathologies, including cervical cancer, genital warts, and potentially autoimmune disorders. Prophylactic vaccination, particularly with the 9-valent HPV (HPV9) vaccine approved by the U.S. Food and Drug Administration in 2014, has demonstrated high efficacy in preventing HPV-related diseases. Although the clinical benefits are well established, concerns about vaccine-associated autoimmunity continue, especially in pediatric populations. Juvenile idiopathic arthritis (JIA), the most common autoimmune rheumatic disease in children, is characterized by chronic joint inflammation with a multifactorial etiology involving both genetic predisposition and environmental triggers, including viral infections. Molecular mimicry between viral antigens and host tissues has been hypothesized as a mechanism linking infections to autoimmune disease onset.
Several observational studies have explored possible associations between HPV vaccination and autoimmune diseases. Analyses using the Vaccine Adverse Event Reporting System (VAERS) and inverse probability weighting models in Colombia reported increased risks of rheumatoid arthritis following HPV4 vaccination. However, these studies were limited by self-reported outcomes and lacked robust clinical validation. In contrast, large-scale electronic health record-based studies with clinically diagnosed endpoints found no significant association between HPV4 and autoimmune conditions. To date, no published studies have specifically assessed the long-term safety of HPV9 vaccination with respect to JIA onset. Furthermore, the COVID-19 pandemic disrupted health care access, vaccination schedules, and autoimmune disease surveillance, potentially influencing outcomes in ways yet to be fully characterized.
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