OBJECTIVE To assess the benefits and harms of the human papillomavirus (HPV) vaccines. DATA SOURCES Clinical study reports obtained from the European Medicines Agency and GlaxoSmithKline from 2014 to 2017. ELIGIBILITY CRITERIA Randomised trials that compared an HPV vaccine with a placebo or active comparator in healthy participants of all ages. APPRAISAL AND SYNTHESIS Two researchers extracted data and judged risk of bias with the Cochrane tool (version 2011). Risk ratio (RR) estimates were pooled using random-effects meta-analysis. OUTCOMES Clinically relevant outcomes in intention to treat populations-including HPV-related cancer precursors irrespective of involved HPV types, treatment procedures and serious and general harms. RESULTS Twenty-four of 50 eligible clinical study reports were obtained with 58,412 pages of 22 trials and 2 follow-up studies including 95,670 participants: 79,102 females and 16,568 males age 8-72; 393,194 person-years; and 49 months mean weighted follow-up. We judged all 24 studies to be at high risk of bias. Serious harms were incompletely reported for 72% of participants (68,610/95,670). Nearly all control participants received active comparators (48,289/48,595, 99%). No clinical study report included complete case report forms. At 4 years follow-up, the HPV vaccines reduced HPV-related carcinoma in situ (367 in the HPV vaccine group vs. 490 in the comparator group, RR 0.73 [95% confidence interval, CI, 0.53 to 1.00], number needed to vaccinate [NNV] 387, P = 0.05, I2 = 67%) and HPV-related treatment procedures (1018 vs. 1416, RR 0.71 [95% CI 0.63 to 0.80], NNV 75, P < 0.00001, I2 = 45%). The HPV vaccines increased serious nervous system disorders (exploratory analysis: 72 vs. 46, RR 1.49 [1.02 to 2.16], number needed to harm [NNH] 1325, P = 0.040, I2 = 0%) and general harms (13,248 vs. 12,394, RR 1.07 [95% CI 1.03 to 1.11], NNH 51, P = 0.0002, I2 = 77%) but did not significantly increase fatal harms (45 vs. 38, RR 1.19 [95% CI 0.65 to 2.19], P = 0.58, I2 = 30%) or serious harms (1404 vs. 1357, RR 1.01 [95% CI 0.94 to 1.08], P = 0.79, I2 = 0%). CONCLUSION At 4 years follow-up, the HPV vaccines decreased HPV-related cancer precursors and treatment procedures but increased serious nervous system disorders (exploratory analysis) and general harms. As the included trials were primarily designed to assess benefits and were not adequately designed to assess harms, the extent to which the HPV vaccines' benefits outweigh their harms is unclear. Limited access to clinical study reports and trial data with case report forms prevented a thorough assessment. SYSTEMATIC REVIEW REGISTRATION CRD42017056093. Our systematic review protocol was registered on PROSPERO in January 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews in January 2018: https://doi.org/10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published in September 2018: https://doi.org/10.1136/bmj.k3694.

中文翻译：

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人乳头瘤病毒 (HPV) 疫苗的益处和危害：对临床研究报告中的试验数据进行系统评价和荟萃分析。


目的 评估人乳头瘤病毒 (HPV) 疫苗的益处和危害。数据来源 2014 年至 2017 年从欧洲药品管理局和葛兰素史克获得的临床研究报告。 资格标准 在所有年龄段的健康参与者中对 HPV 疫苗与安慰剂或活性比较剂进行比较的随机试验。评估与综合 两名研究人员提取数据并使用 Cochrane 工具（2011 版）判断偏倚风险。使用随机效应荟萃分析汇总风险比（RR）估计值。结果 意向治疗人群的临床相关结果，包括 HPV 相关癌症前兆，无论涉及的 HPV 类型、治疗程序以及严重和一般危害如何。结果 共获得 50 份符合条件的临床研究报告中的 24 份，共 58,412 页，共 22 项试验和 2 项随访研究，包括 95,670 名参与者：8-72 岁的女性 79,102 名，男性 16,568 名； 393,194 人年；平均加权随访时间为 49 个月。我们判断所有 24 项研究均存在高偏倚风险。 72% 的参与者 (68,610/95,670) 报告了严重伤害。几乎所有对照参与者都接受了积极的比较（48,289/48,595，99%）。没有临床研究报告包含完整的病例报告表。随访 4 年时，HPV 疫苗减少了 HPV 相关原位癌（HPV 疫苗组有 367 例，对照组有 490 例，RR 0.73 [95% 置信区间，CI，0.53 至 1.00]，接种疫苗 [NNV] 387，P = 0.05，I2 = 67%）和 HPV 相关治疗程序（1018 与 1416，RR 0.71 [95% CI 0.63 至 0.80]，NNV 75，P < 0.00001，I2 = 45% ）。 HPV 疫苗增加了严重的神经系统疾病（探索性分析：72 vs. 46，RR 1.49 [1.02 至 2.16]，造成伤害所需的数量 [NNH] 1325，P = 0.040，I2 = 0%）和一般伤害（13,248 与 12,394，RR 1.07 [95% CI 1.03 至 1.11]，NNH 51，P = 0.0002，I2 = 77%），但并未显着增加致命伤害（45 vs. 38，RR 1.19 [95% CI 0.65 to 2.19]，P = 0.58，I2 = 30%）或严重伤害（1404 vs. 1357，RR 1.01 [95%] CI 0.94 至 1.08]，P = 0.79，I2 = 0%）。结论 在 4 年随访中，HPV 疫苗减少了 HPV 相关癌症前兆和治疗程序，但增加了严重的神经系统疾病（探索性分析）和一般危害。由于纳入的试验主要旨在评估益处，而没有充分设计来评估危害，因此 HPV 疫苗的益处在多大程度上超过其危害尚不清楚。临床研究报告和试验数据与病例报告表的获取有限，无法进行彻底的评估。系统审查注册 CRD42017056093。我们的系统评价方案于 2017 年 1 月在 PROSPERO 上注册：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf。 2017 年 11 月，两项协议修正案在 PROSPERO 上注册：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf。我们的 HPV 疫苗研究索引于 2018 年 1 月发表在《系统评论》上：https://doi.org/10.1186/s13643-018-0675-z。 2018 年 9 月发布了获取数据挑战的描述：https://doi.org/10.1136/bmj.k3694。