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Meta-Analysis
. 2020 Sep;29(9):1159-1167.
doi: 10.1002/pds.5063. Epub 2020 Jun 24.

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

Dominique Rosillon  1 , Corinne Willame  1 , Fernanda Tavares Da Silva  1 , Adrienne Guignard  1 , Sophie Caterina  1 , Sarah Welby  1 , Frank Struyf  1
Affiliations
Meta-Analysis

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

Dominique Rosillon et al. Pharmacoepidemiol Drug Saf. 2020 Sep.

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.

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Conflict of interest statement

A.G., C.W., D.R., F.T.D.S., S.C., S.W. are employees of the GSK group of companies. A.G., D.R., F.S., F.T.D.S., S.W. hold shares in the GSK group of companies as part of their employee remuneration. F.S. was an employee of the GSK group of companies at the time the study was performed and is currently an employee of Janssen, Pharmaceutical Companies of Johnson & Johnson. F.S. owns shares in the GSK group of companies.

Figures

FIGURE 1
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
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
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
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References

    1. European Medicines Agency . Cervarix. https://www.ema.europa.eu/en/medicines/human/EPAR/cervarix. Accessed January 10, 2019.
    1. European Medicines Agency . Gardasil. https://www.ema.europa.eu/en/medicines/human/EPAR/gardasil. Accessed January 10, 2019.
    1. European Medicines Agency . Gardasil 9. https://www.ema.europa.eu/en/medicines/human/EPAR/gardasil-9. Accessed January 10, 2019.
    1. Garcon N, Chomez P, Van Mechelen M. GlaxoSmithKline adjuvant systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines. 2007;6:723‐739. - PubMed
    1. Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon‐Levin N, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun. 2013;47:1‐16. - PubMed

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