Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study.
Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study.
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DOI：
10.1136/bmj.f5906
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发表时间：
2013-10-09
期刊：
影响因子：
--
通讯作者：
Hviid A
中科院分区：
文献类型：
--
作者：
Arnheim-Dahlström L;Pasternak B;Svanström H;Sparén P;Hviid A
目的评估青少年女性接种四价人乳头瘤病毒（qHPV）疫苗后发生严重不良事件的风险。基于设计注册的队列研究。设置丹麦和瑞典，2006年10月至2010年12月。参与者997 585名10 - 17岁的女孩，其中296 826人共接种了696 420剂qHPV疫苗。主要结局指标：每次qHPV疫苗接种后180天内，医院诊断出自身免疫性、神经系统和静脉血栓栓塞事件（53种不同结局）。仅考虑对至少5例疫苗暴露病例的事件进行进一步评估。根据年龄、国家、日历年和父母出生国、教育和社会经济地位调整的比率进行了估计，比较了接种疫苗和未接种疫苗的人的时间。对于率比显著增加的结局，我们将三个标准视为信号加强：基于20例或更多疫苗暴露病例的分析（可靠性），率比3.0或以上（强度），以及国家特定分析中率比显著增加（一致性）。我们还评估了事件的时间聚集，并估计了从第181天开始的风险期的比率。 结果在53例结局中，29例发生至少5例疫苗暴露病例，并对这些病例进行了进一步分析。尽管23例自身免疫性事件中有20例的比率没有显著增加，但qHPV疫苗暴露与白塞氏综合征、雷诺氏病和1型糖尿病显著相关。这三个结果中的每一个仅满足三个预定义的信号增强标准中的一个。此外，所有三种疫苗接种后时间分布模式均为随机分布，从接种后第181天起，这些结局的率比与主要风险期的率比相似。五种神经系统事件的比率没有显著增加，与癫痫（比率0.66，95%置信区间0.54 - 0.80）和瘫痪（0.56，0.35 - 0.90）呈负相关。qHPV疫苗暴露与静脉血栓栓塞之间没有相关性（0.86，0.55 - 1.36）。结论：这项大型队列研究没有发现任何证据支持qHPV疫苗暴露与自身免疫性、神经系统和静脉血栓栓塞不良事件之间的相关性。尽管最初观察到三种自身免疫事件的相关性，但在进一步评估时，这些相关性较弱，与疫苗暴露无时间相关性。此外，需要考虑评估的多种结果来解释调查结果。
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.
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