Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study

Abstract

Objective: To assess the risk of serious adverse events after vaccination of adolescent girls with quadrivalent human papillomavirus (qHPV) vaccine.

Design: Register based cohort study.

Setting: Denmark and Sweden, October 2006 to December 2010.

Participants: 997,585 girls aged 10-17, among whom 296,826 received a total of 696,420 qHPV vaccine doses.

Main outcome measures: Incident hospital diagnosed autoimmune, neurological, and venous thromboembolic events (53 different outcomes) up to 180 days after each qHPV vaccine dose. Only events with at least five vaccine exposed cases were considered for further assessment. Rate ratios adjusted for age, country, calendar year, and parental country of birth, education, and socioeconomic status were estimated, comparing vaccinated and unvaccinated person time. For outcomes where the rate ratio was significantly increased, we regarded three criteria as signal strengthening: analysis based on 20 or more vaccine exposed cases (reliability), rate ratio 3.0 or more (strength), and significantly increased rate ratio in country specific analyses (consistency). We additionally assessed clustering of events in time and estimated rate ratios for a risk period that started on day 181.

Results: Among the 53 outcomes, at least five vaccine exposed cases occurred in 29 and these were analysed further. Whereas the rate ratios for 20 of 23 autoimmune events were not significantly increased, exposure to qHPV vaccine was significantly associated with Behcet's syndrome, Raynaud's disease, and type 1 diabetes. Each of these three outcomes fulfilled only one of three predefined signal strengthening criteria. Furthermore, the pattern of distribution in time after vaccination was random for all three and the rate ratios for these outcomes in the period from day 181 after vaccination were similar to the rate ratios in the primary risk period. The rate ratios for five neurological events were not significantly increased and there were inverse associations with epilepsy (rate ratio 0.66, 95% confidence interval 0.54 to 0.80) and paralysis (0.56, 0.35 to 0.90). There was no association between exposure to qHPV vaccine and venous thromboembolism (0.86, 0.55 to 1.36).

Conclusions: This large cohort study found no evidence supporting associations between exposure to qHPV vaccine and autoimmune, neurological, and venous thromboembolic adverse events. Although associations for three autoimmune events were initially observed, on further assessment these were weak and not temporally related to vaccine exposure. Furthermore, the findings need to be interpreted considering the multiple outcomes assessed.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; LAD and PS are and have been involved in other studies with unconditional grants from GlaxoSmithKline, Sanofi Pasteur MSD, and Merck; and no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1 Periods at risk for autoimmune and neurological events in adolescent girls after exposure to quadrivalent human papillomavirus (qHPV) vaccine. For venous thromboembolism, each period at risk was up to 90 days

Fig 2 Association between exposure to quadrivalent human papillomavirus (qHPV) vaccine and adverse events in adolescent girls in Denmark and Sweden, October 2006-December 2010. Rate ratios are adjusted for country, age in two year intervals, calendar year, and parental country of birth, parental education, and paternal socioeconomic status

Fig 3 Distribution of cases according to days since first dose of quadrivalent human papillomavirus (qHPV) vaccine. For type 1 diabetes case 1, vaccine doses 2 and 3 and event are not displayed (dose 2 was administered on day 425, dose 3 on day 609, and the event was on day 570). For type 1 diabetes case 2, event is not displayed (event was on day 460). For type 1 diabetes case 82, vaccine dose 3 is not displayed (dose was administered on day 455)