Meta-analysis of the risk of autoimmune thyroiditis, Guillain-Barré syndrome, and inflammatory bowel disease following vaccination with AS04-adjuvanted human papillomavirus 16/18 vaccine

Abstract

Purpose: To assess the risk of three autoimmune diseases - autoimmune thyroiditis (AIT), Guillain-Barré syndrome (GBS), and inflammatory bowel disease (IBD) - in females following AS04-HPV-16/18 vaccination.

Methods: This meta-analysis included data from 18 randomized controlled trials, one cluster-randomized trial, two large observational retrospective cohort studies, and one case-control study. Following vaccination, a risk window of 2 years was defined for AIT and IBD and 42 days for GBS. Odds ratios (ORs) were estimated using three methods: meta-analysis inverse-variance with continuity correction (primary analysis), pooled estimate, and beta-binomial regression.

Results: In all studies apart from the case-control study, 154 398 exposed and 1 504 322 non-exposed subjects were included, among whom there were 141 and 1972 cases of (autoimmune) thyroiditis; 2 and 2 cases of GBS; and 43 and 401 cases of IBD, respectively. In the case-control study, there were 97 cases of AIT and 13 of GBS; matched with 802 and 130 controls, respectively. The primary analysis OR estimates were 1.46 (95% confidence interval [CI] 1.22-1.76), 11.14 (2.00-61.92), and 1.11 (0.75-1.66) for (autoimmune) thyroiditis, GBS, and IBD, respectively.

Conclusions: This meta-analysis did not show an increased risk of IBD following vaccination with AS04-HPV-16/18. The 1.5-fold increased risk of (autoimmune) thyroiditis does not allow us to conclude about a causal association. For GBS, the very low number of cases and wide 95% CIs negate any firm conclusion.

Keywords: Guillain-Barré syndrome; autoimmune thyroiditis; human papillomavirus vaccine; inflammatory bowel disease; pharmacoepidemiology.

FIGURE 1

Risk of (autoimmune) thyroiditis during 2 years following the first dose of AS04‐HPV‐16/18. There were partial events for the French cohort study ³³ due to the standardization of the follow‐up time to 2 years; and for the case‐control study ³⁵ , ³⁶ due to the continuity correction factor due to the “single‐zero” cases in the exposed arm. AIT, autoimmune thyroiditis; AS04‐HPV‐16/18, AS04‐adjuvanted human papillomavirus‐16/18 vaccine; CI, confidence interval; OR, odds ratio; RCTs, randomized controlled trials; UK, United Kingdom. *The case‐control study was not included in the pooled estimate

FIGURE 2

Risk of GBS during 42 days following each dose of AS04‐HPV‐16/18. There are partial events for the non‐exposed arm of the French cohort study ²⁹ , ³⁴ due to the standardization of the follow‐up time to 42 days; and for the other studies due to the continuity correction factor due to the “single‐zero” or “double‐zero” cases. AS04‐HPV‐16/18, AS04‐adjuvanted human papillomavirus‐16/18 vaccine; CI, confidence interval; GBS, Guillain‐Barré syndrome; OR, odds ratio; RCTs, randomized controlled trials; UK, United Kingdom.*The case‐control study was not included in the pooled estimate. ^†The beta‐binomial regression estimate is questionable because of convergence issues

FIGURE 3

Risk of IBD during 2 years following the first dose of AS04‐HPV‐16/18. There are partial events for the French cohort study ²⁹ , ³⁴ due to the standardization of the follow‐up time to 2 years. AS04‐HPV‐16/18, AS04‐adjuvanted human papillomavirus‐16/18 vaccine; CI, confidence interval; IBD, inflammatory bowel disease; OR, odds ratio; RCTs, randomized controlled trials; UK, United Kingdom