Background

The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16–26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up.

Methods

The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16–23 years) or men who have sex with men (MSM; aged 16–26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov, NCT00090285.

Findings

Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1–11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0–6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0–8·7) versus 137·3 (83·9–212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0–7·7) versus 140·4 (89·0–210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5–114·4) versus 906·2 (553·5–1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10 000 person-years [95% CI 101·6–212·3] vs 0 cases per 10 000 person-years [0·0–13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10 000 person-years [108·0–215·7] vs 0 cases per 10 000 person-years [0·0–10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10 000 person-years [583·9–1289·1] vs 101·3 cases per 10 000 person-years [32·9–236·3]). No vaccine-related serious adverse events were reported.

Interpretation

The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination.

Funding

Merck Sharp & Dohme.

中文翻译：

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男性四价 HPV 疫苗的功效、免疫原性和安全性：一项随机、安慰剂对照、3 期试验的开放标签、长期扩展结果

背景

一项针对 16-26 岁男性的随机、安慰剂对照研究显示，四价人乳头瘤病毒 (HPV) 疫苗可预防与 HPV6、11、16 和 18 相关的感染和病变。我们在 10 年的随访中评估了与 HPV6 或 11 相关的外生殖器疣的发生率，以及与 HPV6、11、16 或 18 相关的外生殖器病变和肛门发育不良的发生率。

方法

这项为期 3 年的基础研究是一项国际、多中心、双盲、随机、安慰剂对照试验，在 18 个国家的 71 个地点进行。符合条件的参与者是异性恋男性（16-23 岁）或男男性行为者（MSM；16-26 岁）。筛查时临床可检测到肛门生殖器疣或生殖器病变提示感染非 HPV 性传播疾病或有此类发现史的男性被排除在外。符合条件的参与者被随机分配 (1:1) 在第 1 天、第 2 个月和第 6 个月接受三剂四价 HPV 疫苗或安慰剂，以 0·5 毫升的剂量注射到三角肌中。在 16 个国家的 46 个中心进行了 7 年、开放标签、长期随访扩展研究。在基础研究中接受一剂或多剂四价 HPV 疫苗的参与者有资格参加长期随访研究（早期疫苗接种组）。在基础研究结束时，向安慰剂接受者提供三剂四价 HPV 疫苗；接受一剂或多剂四价 HPV 疫苗的人有资格参加长期随访研究（补种接种组）。主要疗效终点是所有参与者中与 HPV6 或 11 相关的外生殖器疣的发生率和与 HPV6、11、16 或 18 相关的外生殖器病变的发生率以及肛门上皮内瘤变（包括肛门疣和扁平病变）的发生率) 或仅在 MSM 中与 HPV6、11、16 或 18 相关的肛门癌。在早期疫苗接种组的符合方案人群中进行了主要疗效分析，其中包括接受所有三种疫苗剂量的参与者，在 HPV 基础研究的第 1 天为血清阴性，从第 1 天到第 7 个月为 PCR 阴性被分析的类型，没有可能影响疫苗功效评估的方案违规，并且在长期随访研究期间参加了至少一次访问。对于补种疫苗组，在改良意向治疗人群中评估疗效，其中包括接受至少一剂疫苗的参与者，从基础研究的第 1 天开始分析的 HPV 类型呈血清阴性和 PCR 阴性到接受四价HPV疫苗之前的最后一次随访，并且至少进行了一次长期随访。在接受至少一剂疫苗的所有随机参与者中评估了安全性。该研究已在 ClinicalTrials.gov 注册，NCT00090285。

发现

2010 年 8 月 10 日至 2017 年 4 月 3 日，1803 名参与者参加了长期随访研究，其中 936 名（827 名异性恋男性和 109 名 MSM）被纳入早期疫苗接种组，867 名（739 名异性恋男性和 128 名 MSM）被纳入补种接种组。早期接种组参与者在接受第三剂四价HPV疫苗后的中位随访时间为9·5年（范围0·1~11·5），后续接种组参与者接受随访接受第三剂后的中位数为 4·7 年（0·0-6·6）。与基础研究中的安慰剂组相比，在长期随访期间的早期疫苗组参与者中，每 10 000 人年与 HPV6 或 11 相关的外生殖器疣的发病率为 0·0（95% CI 0·0 –8·7) 与 137·3 (83·9–212·1)，与 HPV6、11、16 或 18 相关的外生殖器病变为 0·0 (0·0-7·7) 与 140·4 (89·0-210·7)，肛门上皮内瘤变或肛门癌相关HPV6、11、16 或 18 在 MSM 中仅为 20·5 (0·5–114·4) 与 906·2 (553·5–1399·5)。与基础研究期间（即四价 HPV 疫苗接种前）相比，在长期随访期间，追加接种组的参与者没有新报告的与 HPV6 或 11 相关的外尖锐湿疣病例（149 ·每万人年6例[95% CI 101·6–212·3]与0 例/10 000 人年 [0·0–13·5]）或与 HPV6、11、16 或 18 相关的外生殖器病变（155·1 例/10 000 人年 [108·0–215 ·7] vs 0 例/10 000 人年 [0·0–10·2]），并且与 HPV6、11、16 或 18 相关的肛门上皮内瘤变或肛门癌的发生率较低（每 10 000 人年 886·0 例） 10 000 人年 [583·9–1289·1]与101·3 例/10 000 人年 [32·9–236·3]）。没有报告与疫苗相关的严重不良事件。

解释

四价 HPV 疫苗对与 HPV6、11、16 和 18 相关的肛门生殖器疾病提供持久保护。结果支持男性四价 HPV 疫苗接种，包括补种疫苗。

资金

默克夏普和多姆。