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）疫苗的利弊：对来自临床研究报告的试验数据进行荟萃分析的系统评价。

目的评估人乳头瘤病毒（HPV）疫苗的利弊。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。合格标准在所有年龄的健康受试者中比较HPV疫苗与安慰剂或活性比较剂的随机试验。评估与综合两名研究人员提取数据并使用Cochrane工具（版本2011）判断偏倚风险。使用随机效应荟萃分析汇总了风险比（RR）估计值。结果旨在治疗人群的临床相关结果，包括与HPV相关的癌症前体，无论涉及的HPV类型，治疗程序以及严重和一般的危害。结果50份合格的临床研究报告中有24份获得了58份 412页的22个试验和2个后续研究中，包括95,670名参与者：79,102名女性和16,568名男性，年龄在8-72岁之间；393,194人年 49个月平均加权随访。我们认为所有24项研究都有偏见的高风险。据报告，有72％的参与者受到严重伤害（68,610 / 95,670）。几乎所有控制参与者都收到了活跃的比较者（48,289 / 48,595，99％）。没有临床研究报告包括完整的病例报告表。在随访的4年中，HPV疫苗可减少与HPV相关的原位癌（HPV疫苗组为367例，而比较组为490例，RR为0.73 [95％置信区间，CI为0.53至1.00]，接种[NNV] 387，P = 0.05，I2 = 67％）和与HPV相关的治疗程序（1018对1416，RR 0.71 [95％CI 0.63至0.80]，NNV 75，P <0.00001，I2 = 45％） 。HPV疫苗会增加严重的神经系统疾病（探索性分析：72比46，RR 1.49 [1.02至2.16]，伤害[NNH] 1325所需的数字，P = 0.040，I2 = 0％）和一般伤害（13,248vs。 12,394，RR 1.07 [95％CI 1.03至1.11]，NNH 51，P = 0.0002，I2 = 77％），但没有显着增加致命伤害（45 vs. 38，RR 1.19 [95％CI 0.65至2.19]，P = 0.58，I2 = 30％）或严重伤害（1404对1357，RR 1.01 [95％CI 0.94至1.08]，P = 0.79，I2 = 0％）。结论在随访4年后，HPV疫苗减少了与HPV相关的癌症前体和治疗程序，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是为了评估收益，而没有适当地评估伤害，因此HPV疫苗的 收益大于危害尚不清楚。对临床研究报告和带有病例报告表的试验数据的访问受限，无法进行全面评估。系统审查注册CRD42017056093。我们的系统审核协议已于2017年1月在PROSPERO上注册：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf。2017年11月在PROSPERO上注册了两个协议修正案：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf。我们的HPV疫苗研究索引已于2018年1月发表在《系统评价》上：https：//doi.org/10.1186/s13643-018-0675-z。关于获取数据的挑战的描述于2018年9月发布：https：//doi.org/10.1136/bmj.k3694。对临床研究报告和带有病例报告表的试验数据的访问受限，无法进行全面评估。系统审查注册CRD42017056093。我们的系统审核协议已于2017年1月在PROSPERO上注册：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf。2017年11月在PROSPERO上注册了两个协议修正案：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf。我们的HPV疫苗研究索引已于2018年1月发表在《系统评价》上：https：//doi.org/10.1186/s13643-018-0675-z。关于获取数据的挑战的描述于2018年9月发布：https：//doi.org/10.1136/bmj.k3694。对临床研究报告和带有病例报告表的试验数据的访问受限，无法进行全面评估。系统审查注册CRD42017056093。我们的系统审核协议已于2017年1月在PROSPERO上注册：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf。2017年11月在PROSPERO上注册了两个协议修正案：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf。我们的HPV疫苗研究索引已于2018年1月发表在《系统评价》上：https：//doi.org/10.1186/s13643-018-0675-z。关于获取数据的挑战的描述于2018年9月发布：https：//doi.org/10.1136/bmj.k3694。uk / PROSPEROFILES / 56093_PROTOCOL_20170030.pdf。2017年11月在PROSPERO上注册了两个协议修正案：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf。我们的HPV疫苗研究索引已于2018年1月发表在《系统评价》上：https：//doi.org/10.1186/s13643-018-0675-z。关于获取数据的挑战的描述于2018年9月发布：https：//doi.org/10.1136/bmj.k3694。uk / PROSPEROFILES / 56093_PROTOCOL_20170030.pdf。2017年11月在PROSPERO上注册了两个协议修正案：https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf。我们的HPV疫苗研究索引已于2018年1月发表在《系统评价》上：https：//doi.org/10.1186/s13643-018-0675-z。关于获取数据的挑战的描述于2018年9月发布：https：//doi.org/10.1136/bmj.k3694。