Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Lancet. 2017 Nov 11;390(10108):2143-2159. doi: 10.1016/S0140-6736(17)31821-4. Epub 2017 Sep 5.
Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years.
We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543.
Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.
The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.
Merck & Co, Inc.
对年龄在 16-26 岁的年轻女性进行的一项研究的主要分析显示，九价人乳头瘤病毒（HPV 6、11、16、18、31、33、45、52 和 58）疫苗对 HPV 31、33、45、52 和 58 相关感染和疾病以及非劣效性 HPV 6、11、16 和 18 抗体反应具有疗效，与四价 HPV（HPV 6、11、16 和 18）疫苗相比。我们的目的是报告首次接种后长达 6 年的 9 价 HPV 疫苗的疗效以及 5 年的抗体反应。
我们在 18 个国家的 105 个研究地点进行了这项随机、双盲、疗效、免疫原性和安全性的 9 价 HPV 疫苗研究。年龄在 16-26 岁之间的健康女性，没有异常的宫颈细胞学史、没有异常的宫颈活检结果、性伴侣不超过 4 个，按中央随机化和 2 个和 2 个的分组大小，随机分配（1:1）接受三种肌内注射，每 6 个月一次，9 价 HPV 或四价 HPV（对照）疫苗。所有参与者、研究人员、研究现场人员、实验室工作人员、赞助商研究团队成员和裁决病理小组委员会成员都对疫苗组进行了盲法处理。主要结局是与 HPV 31、33、45、52 和 58 相关的高级别宫颈疾病（宫颈上皮内瘤变 2 级或 3 级、原位腺癌、浸润性宫颈癌）、外阴疾病（外阴上皮内瘤变 2/3 级、外阴癌）和阴道疾病（阴道上皮内瘤变 2/3 级、阴道癌）的发生率，以及 HPV 6、11、16 和 18 的几何平均滴度（GMT）的非劣效性（排除下降 1.5 倍）。组织样本经过组织病理学诊断和 HPV DNA 检测。血清抗体反应通过竞争性 Luminex 免疫测定法进行评估。疗效的主要评估是在符合方案的疗效人群中进行的优势分析，在修改后的意向治疗人群中进行了支持性疗效分析，免疫原性的主要评估是在非劣效性分析中进行的。该试验在 ClinicalTrials.gov 上注册，编号为 NCT00543543。
2007 年 9 月 26 日至 2009 年 12 月 18 日，我们招募并随机分配了 14015 名参与者接受 9 价 HPV（n=7106）或四价 HPV（n=7109）疫苗。在符合方案的人群中，与 HPV 31、33、45、52 和 58 相关的高级别宫颈、外阴和阴道疾病的发生率分别为每 10000 人年 0.5 例和每 10000 人年 19.0 例，9vHPV 组的疗效为 97.4%（95%CI 85.0-99.9）。从接种后 1 个月到 3 年，9vHPV 与 qHPV 组相比，HPV 6、11、16 和 18 的 GMT 非劣效性。研究组之间未观察到严重不良事件的临床意义差异。11 名参与者在研究随访期间死亡（9vHPV 疫苗组 6 名，qHPV 疫苗组 5 名）；没有死亡被认为与疫苗有关。
9 价 HPV 疫苗可预防 HPV 31、33、45、52 和 58 相关的感染、细胞学异常、高级别病变和宫颈手术。9 价 HPV 疫苗和四价 HPV 疫苗在 HPV 6、11、16 和 18 方面均具有相似的免疫原性。疫苗的疗效可维持长达 6 年。9 价 HPV 疫苗有可能提供更广泛的保护，预防全球 90%的宫颈癌病例。
默克公司。
