Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study

Abstract

Background: Despite demonstrated effectiveness in real-world settings, concerns persist regarding the safety of the quadrivalent human papillomavirus (HPV4) vaccine. We sought to assess the risk of autoimmune disorders following HPV4 vaccination among grade 8 girls eligible for Ontario's school-based HPV vaccination program.

Methods: We undertook a population-based retrospective cohort study using Ontario's administrative health and vaccination databases from 2007 to 2013. The self-controlled case series method was used to compare the rate of a composite end point of autoimmune disorders diagnosed during days 7-60 post-vaccination ("exposed" follow-up) to that at any other time ("unexposed"). The analysis was repeated to assess the effect of a history of immune-mediated diseases and time since vaccination. We also conducted an exploratory analysis of individual autoimmune disorders. Rate ratios and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, adjusted for age, seasonality, concomitant vaccinations and infections.

Results: The study cohort consisted of 290 939 girls aged 12-17 years who were eligible for vaccination between 2007 and 2013. There was no significant risk for developing an autoimmune disorder following HPV4 vaccination (n = 681; rate ratio 1.12, 95% CI 0.85-1.47), and the association was unchanged by a history of immune-mediated disorders and time since vaccination. Exploratory analyses of individual autoimmune disorders found no significant risks, including for Bell palsy (n = 65; rate ratio 1.73, 95% CI 0.77-3.89), optic neuritis (n = 67; rate ratio 1.57, 95% CI 0.74-3.33) and Graves disease (n = 47; rate ratio 1.55, 95% CI 0.92-2.63).

Interpretation: We did not observe an increased risk of autoimmune disorders following HPV4 vaccination among teenaged girls. These findings should reassure parents and health care providers.

Figure 1:

Cohort flow diagram. *Cohort members could fulfill more than 1 exclusion criteria; therefore, criteria were not mutually exclusive. Note: HPV = human papillomavirus, HPV4 = quadrivalent HPV.

Figure 2:

Distribution of exposed and unexposed cases of autoimmune disorders after each dose of the quadrivalent human papillomavirus (HPV4) vaccine. *Counts of fewer than 5 cases were suppressed owing to data privacy guidelines.

Figure 3:

Adjusted rate ratios for individual autoimmune disorders diagnosed in the 7–60 days after quadrivalent human papillomavirus (HPV4) vaccination. *Autoimmune disorders with 10 or more vaccinated cases. ^†Adjusted for age at diagnosis, seasonality (Table 2), receipt of non-HPV vaccines (7–60 d before diagnosis) and recent infection (7–60 d before diagnosis), and implicitly adjusted for time-fixed confounders through the use of a self-matched analysis. ^‡Includes systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, dermatomyositis and polymyositis. Note: CI = confidence interval.