Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
J Intern Med. 2018 Feb;283(2):154-165. doi: 10.1111/joim.12694. Epub 2017 Oct 18.
Since 2006, human papillomavirus (HPV) vaccines have been introduced in many countries worldwide. Whilst safety studies have been reassuring, focus has been on the primary target group, the young adolescent girls. However, it is also important to evaluate safety in adult women where background disease rates and safety issues could differ significantly.
We took advantage of the unique Danish and Swedish nationwide healthcare registers to conduct a cohort study comparing incidence rate ratios (RRs) of 45 preselected serious chronic diseases in quadrivalent HPV (qHPV)-vaccinated and qHPV-unvaccinated adult women 18-44 years of age.
We used Poisson regression to estimate RRs according to qHPV vaccination status with two-sided 95% confidence intervals (95% CIs).
The study cohort comprised 3 126 790 women (1 195 865 [38%] Danish and 1 930 925 [62%] Swedish) followed for 16 386 459 person-years. Vaccine uptake of at least one dose of qHPV vaccine was 8% in the cohort: 18% amongst Danish women and 2% amongst Swedish. We identified seven adverse events with statistically significant increased risks following vaccination-Hashimoto's thyroiditis, coeliac disease, localized lupus erythematosus, pemphigus vulgaris, Addison's disease, Raynaud's disease and other encephalitis, myelitis or encephalomyelitis. After taking multiple testing into account and conducting self-controlled case series analyses, coeliac disease (RR 1.56 [95% confidence interval 1.29-1.89]) was the only remaining association.
Unmasking of conditions at vaccination visits is a plausible explanation for the increased risk associated with qHPV in this study because coeliac disease is underdiagnosed in Scandinavian populations. In conclusion, our study of serious adverse event rates in qHPV-vaccinated and qHPV-unvaccinated adult women 18-44 years of age did not raise any safety issues of concern.
自 2006 年以来，人乳头瘤病毒（HPV）疫苗已在全球许多国家推出。虽然安全性研究结果令人安心，但重点一直放在年轻的青少年女孩这一主要目标群体上。然而，评估成年女性的安全性也很重要，因为这些女性的背景疾病发病率和安全性问题可能有显著差异。
我们利用丹麦和瑞典独特的全国性医疗登记系统，开展了一项队列研究，比较了 18-44 岁接种四价 HPV（qHPV）疫苗和未接种 qHPV 疫苗的成年女性中 45 种预先选定的严重慢性疾病的发病率比值（RR）。
我们使用泊松回归根据 qHPV 疫苗接种状态估计 RR，并采用双侧 95%置信区间（95%CI）。
研究队列包括 3126790 名女性（1195865 名[38%]来自丹麦，1930925 名[62%]来自瑞典），随访时间为 16386459 人年。该队列中至少接种一剂 qHPV 疫苗的人数占 8%：丹麦女性占 18%，瑞典女性占 2%。我们发现接种疫苗后有 7 种不良事件的风险显著增加，包括桥本甲状腺炎、乳糜泻、局限性红斑狼疮、寻常性天疱疮、艾迪生病、雷诺病和其他脑炎、脊髓炎或脑脊髓炎。在考虑多次检测并进行自身对照病例系列分析后，乳糜泻（RR 1.56 [95%置信区间 1.29-1.89]）是唯一剩余的关联。
在该研究中，qHPV 相关风险增加可能是由于在疫苗接种时发现了未确诊的疾病，因为在斯堪的纳维亚人群中，乳糜泻的漏诊率较高。总之，我们对 18-44 岁接种 qHPV 疫苗和未接种 qHPV 疫苗的成年女性严重不良事件发生率的研究没有发现任何值得关注的安全问题。
