Background

A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination.

Methods

In the randomised trial, unmarried girls aged 10–18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702.

Findings

Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2–9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0–99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3–99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5–99·7) in three-dose recipients (1460 women assessed).

Interpretation

A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses.

Funding

Bill & Melinda Gates Foundation.

中文翻译：

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印度女孩接种一剂、两剂和三剂四价 HPV 疫苗 10 年后针对持续性人乳头瘤病毒 (HPV) 16/18 感染的疫苗功效：一项多中心、前瞻性队列研究

 背景

印度政府暂停 HPV 疫苗接种试验后，一项旨在比较印度少女接种三剂和两剂四价人乳头瘤病毒 (HPV) 疫苗的随机试验转为队列研究。在本文中，队列研究的修订目标是比较单剂疫苗与三剂和两剂疫苗在接种疫苗 10 年后预防持续性 HPV 16 和 18 感染的效果。

 方法

在随机试验中，从印度各地的 9 个中心招募了 10-18 岁的未婚女孩，并随机分配接种两剂或三剂四价 HPV 疫苗（Gardasil [Merck Sharp & Dohme，Whitehouse Station，新泽西州，美国]； 0·5 mL 肌肉注射）。暂停招募和疫苗接种后，该研究默认成为一项纵向、前瞻性队列研究，参与者根据每个方案收到的疫苗剂量数被分配到四个队列：两剂队列（在第 1 天和第 1 天接受疫苗） 180 或更高）、三剂量队列（第 1、60 和 180 或更高天）、两剂量默认队列（第 1 和 60 或更高天）以及单剂量默认队列。每年对参与者进行随访。研究人员在婚后 18 个月或第一次分娩后 6 个月（以较早者为准）采集参与者的宫颈标本，以评估偶发性和持续性 HPV 感染。已婚参与者在年满 25 岁时接受宫颈癌筛查。招募与已婚疫苗接种参与者年龄匹配的未接种疫苗的女性作为对照。对单剂接种者针对持续性 HPV 16 和 18 感染（主要终点）的疫苗功效进行了分析，并在调整未接种疫苗组和接种疫苗组之间潜在混杂因素分布不平衡后与两剂和三剂接种者进行比较。该试验已在 ISRCTN（ISRCTN98283094）和 ClinicalTrials.gov（NCT00923702）注册。

 发现

接种疫苗的参与者是在 2009 年 9 月 1 日至 2010 年 4 月 8 日（疫苗接种暂停日期）之间招募的，并进行中位随访时间为 9·0 年（IQR 8·2–9·6）。 4348 名参与者接种了三剂疫苗，4980 名参与者接种了两剂疫苗（0 个月和 6 个月），4949 名参与者接种了单剂疫苗。在单剂量默认队列（评估的 2135 名女性）中，可评估终点的参与者针对持续性 HPV 16 和 18 感染的疫苗功效为 95·4%（95% CI 85·0–99·9），93·1%（两剂组（评估的 1452 名女性）为 77·3–99·8），三剂组（评估的 1460 名女性）为 93·3%（77·5–99·7）。

 解释

单剂 HPV 疫苗可提供与两剂或三剂类似的保护，防止 HPV 16 和 18（这两种基因型导致近 70% 的宫颈癌）的持续感染。

 资金

比尔及梅琳达·盖茨基金会。