University of Alberta, 1000-8215 112 Street, Edmonton, AB, Canada, T6G 2C8.
Lancet. 2009 Dec 12;374(9706):1975-85. doi: 10.1016/S0140-6736(09)61567-1.
Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.
Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848.
For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred.
Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.
GlaxoSmithKline Biologicals (Belgium).
预防性人乳头瘤病毒（HPV）疫苗必须提供持续的保护。我们评估了 HPV-16/18 AS04 佐剂疫苗长达 6.4 年的疗效、免疫原性和安全性。
年龄在 15-25 岁之间、宫颈细胞学正常、HPV-16/18 血清阴性且筛查时 HPV 致癌 DNA 阴性（14 种）的女性参与了一项双盲、随机、安慰剂对照的初始研究（n=1113；560 例疫苗组与 553 例安慰剂组）和随访研究（n=776；393 例疫苗组与 383 例安慰剂组）。三个国家的 27 个地点参与了随访研究。每 6 个月对宫颈样本进行 HPV DNA 检测。异常细胞学的处理是预先规定的，并评估 HPV-16/18 抗体滴度。主要目的是评估 HPV-16 或 HPV-18 或两者同时感染的新发病例中疫苗的长期疗效。我们报告了该随访研究的 6.4 年分析结果，并与初始研究相结合。对于主要终点，疗效分析在按方案（ATP）队列中进行；CIN2+及以上的分析在总接种人群（TVC）中进行。该研究在 ClinicalTrials.gov 注册，编号为 NCT00120848。
对于初始和随访研究的联合分析，ATP 疗效队列包括疫苗组 465 名女性和安慰剂组 454 名女性；TVC 包括疫苗组 560 名女性和安慰剂组 553 名女性。HPV-16/18 新发病例的疫苗效力为 95.3%（95%CI 87.4-98.7），12 个月持续感染的疫苗效力为 100%（81.8-100）。针对与 HPV-16/18 相关的病变，疫苗对 CIN2+的疗效为 100%（51.3-100），针对 HPV DNA 无关的病变为 71.9%（20.6-91.9）。ELISA 检测的抗体浓度仍比自然感染后高 12 倍或更高（两种抗原）。两组间的安全性结果相似：在随访研究期间，疫苗组有 30 名（8%）参与者报告了严重不良事件，安慰剂组有 37 名（10%）。没有一个被认为与疫苗接种有关或可能有关，也没有死亡发生。
我们的研究结果表明，HPV-16/18 AS04 佐剂疫苗在长达 6.4 年的时间内具有优异的长期疗效、高且持续的免疫原性和良好的安全性。
葛兰素史克生物制品（比利时）。
