Elsevier

The Lancet

Volume 369, Issue 9574, 19–25 May 2007, Pages 1693-1702
The Lancet

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Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials

https://doi.org/10.1016/S0140-6736(07)60777-6Get rights and content

Summary

Background

Vulval and vaginal cancers among younger women are often related to infection with human papillomavirus (HPV). These cancers are preceded by high-grade vulval intraepithelial neoplasia (VIN2–3) and vaginal intraepithelial neoplasia (VaIN2–3). Our aim was to do a combined analysis of three randomised clinical trials to assess the effect of a prophylactic quadrivalent HPV vaccine on the incidence of these diseases.

Methods

18 174 women (16–26 years) were enrolled and randomised to receive either quadrivalent HPV6/11/16/18 L1 virus-like-particle vaccine or placebo at day 1, and months 2 and 6. Individuals underwent detailed anogenital examination at day 1, 1 month after dose three, and at 6–12-month intervals for up to 48 months. Suspect genital lesions were biopsied and read by a panel of pathologists and vaccine HPV type-specific DNA testing was done. The primary endpoint was the combined incidence of VIN2–3 or VaIN2–3 associated with HPV16 or HPV18. Primary efficacy analyses were done in a per-protocol population.

Findings

The mean follow-up time was 3 years. Among women naive to HPV16 or HPV18 through 1 month after dose three (per-protocol population; vaccine n=7811; placebo n=7785), the vaccine was 100% effective (95% CI 72–100) against VIN2–3 or VaIN2–3 associated with HPV16 or HPV18. In the intention-to-treat population (which included 18 174 women who, at day 1, could have been infected with HPV16 or HPV18), vaccine efficacy against VIN2–3 or VaIN2–3 associated with HPV16 or HPV18 was 71% (37–88). The vaccine was 49% (18–69) effective against all VIN2–3 or VaIN2–3, irrespective of whether or not HPV DNA was detected in the lesion. The most common treatment-related adverse event was injection-site pain.

Interpretation

Prophylactic administration of quadrivalent HPV vaccine was effective in preventing high-grade vulval and vaginal lesions associated with HPV16 or HPV18 infection in women who were naive to these types before vaccination. With time, such vaccination could result in reduced rates of HPV-related vulval and vaginal cancers.

Introduction

The female genital tract, a continuum of squamous epithelium from the vulva to the cervix, is commonly infected by human papillomavirus (HPV). The outcome of HPV infection depends on the viral genotype (low risk or high risk/carcinogenic) and the site of infection (the cervical squamocolumnar junction is more susceptible to HPV disease). Carcinogenic HPV can cause cervical, anal, vulval, and vaginal cancers.1, 2, 3, 4, 5, 6 Compared with cervical cancer, vulval and vaginal cancers develop less frequently. In the UK, vulval cancer is six times and vaginal cancer twenty times less common than cervical cancer.7 Nonetheless, vulval and vaginal cancer collectively account for about 6% of all gynaecological cancers. By contrast with secondary cancer prevention programmes for breast and cervical cancers, no screening programmes exist for vaginal and vulval malignancies.

As with cervical intraepithelial neoplasia grade 2–3, high-grade vulval and vaginal lesions—ie, vulval intraepithelial neoplasia grade 2–3 (VIN2–3) and vaginal intraepithelial neoplasia grade 2–3 (VaIN2–3)—are precursors to HPV-related invasive cancers of these areas.5, 6 Although the true incidence of vaginal intraepithelial neoplasia is unknown, the incidence of vulval carcinoma in situ (vulval intraepithelial neoplasia grade 3) increased more than 400% in the USA between 1973 and 2000; invasive vulval cancer increased by 20% during the same period.8 The rate of vulval carcinoma in situ has also been increasing worldwide and seems to be associated with HPV infection, especially with HPV16 and HPV18.9, 10, 11

The annual progression rate of untreated vulval carcinoma in situ to invasive cancer is at least 10%; by contrast, cervical intraepithelial neoplasia grade 3 progresses at a rate of about 2%.12 Patients with vaginal intraepithelial neoplasia have a 2% risk of developing invasive cancer.13 Treatment of vulval and vaginal intraepithelial neoplasia is challenging, can be disfiguring, and requires very long-term follow-up, since disease recurrence is common.14, 15, 16 Together, these data suggest that, as with cervical intraepithelial neoplasia grade 2–3, high-grade vulval and vaginal lesions are surrogate markers for potential development of HPV-related vulval or vaginal cancer.

Prophylactic administration of a quadrivalent HPV6/11/16/18 L1 virus-like-particle (VLP) vaccine has been shown to be 99% efficacious against cervical intraepithelial neoplasia grade 2–3 or adenocarcinoma in situ associated with HPV16 or HPV18 infection.17 The vaccine was also highly effective against disease caused by infection with HPV6 and HPV11, which are the cause of most anogenital warts and a proportion of low-grade neoplasias.18, 19, 20 We did a combined analysis of three randomised clinical trials of this vaccine to assess its effect on the rates of high-grade vulval and vaginal lesions associated with HPV16 and HPV18, as well as its effect on overall rates of such lesions, irrespective of whether or not HPV DNA was detected in the lesion.

Section snippets

Patients and procedures

18 174 women aged 16–26 years were enrolled in one of three double-blind placebo-controlled randomised trials.18, 21, 22 Participants were drawn from 157 sites in 24 countries in the Americas, Europe, and Asia. Most study sites were located in university settings and in urban clinics. In Finland, enrolment was population based. In Latin America, enrolment was based in neighbourhood health centres in many cases. Table 1 compares the design features of the three individual studies. Non-pregnant,

Results

Of the 18 174 women enrolled, 18 150 received at least one injection of quadrivalent vaccine or placebo. Baseline characteristics were much the same in the two randomised groups (table 2). The composition of the populations included in the efficacy analyses is shown in table 3.

In the per-protocol susceptible population, 15 women developed histologically confirmed VIN2–3 or VaIN2–3 that was associated with HPV16 or HPV18; all cases were in women who received placebo (vaccine efficacy 100%, 95%

Discussion

Our study provides evidence that this prophylactic quadrivalent HPV vaccine, developed to prevent cervical cancer, also prevents HPV-related vulval and vaginal precancers in 16–26-year-old women. The vaccine was 97% effective in preventing VIN2–3 and VaIN2–3 associated with HPV16 or HPV18 in a population that was naive to these viruses at the time of first vaccination, and 100% effective in a population that was naive through completion of the vaccination regimen. Vaccine efficacy in the

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