Elsevier

The Lancet Oncology

Volume 6, Issue 5, May 2005, Pages 271-278
The Lancet Oncology

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Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

https://doi.org/10.1016/S1470-2045(05)70101-7Get rights and content

Summary

Background

A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11).

Methods

277 young women (mean age 20·2 years [SD 1·7]) were randomly assigned to quadrivalent HPV (20 μg type 6, 40 μg type 11, 40 μg type 16, and 20 μg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20·0 years [1·7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol.

Findings

Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71–97, p<0·0001) in those assigned vaccine compared with those assigned placebo.

Interpretation

A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Published online April 7, 2005 DOI 10.1016/S1470-2045(05)70101-7

Introduction

Up to 70% of sexually active women will become infected with human papillomavirus (HPV) during their lifetime.1 HPV infection causes about 470 000 cases of cervical cancer per year.2 Although most cases of cervical cancer arise in the developing world where organised screening programmes with the Pap test have not been implemented, about 35 000 women die from this disease every year in the USA and Europe.2 Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions,3 which need careful follow-up and often need excision.4 Moreover, HPV infections that manifest as genital warts arise in 1–2% of young adults,5 for which treatment is expensive and painful, and recurrences are common.6 A diagnosis of genital warts might also cause sexual dysfunction and emotional disruption.7

More than 35 types of HPV infect the genital tract.8 Of these, types 16 and 18 cause about 70% of cervical cancer and high-grade cervical intraepithelial neoplasia (CIN);1 HPV 6 and 11 cause 90% of anogenital warts.6 A prophylactic vaccine that targets these types should thus substantially reduce the burden of HPV-associated clinical diseases.

HPV is a non-enveloped, encapsulated, double-stranded DNA virus.9 Expression of the L1 protein in heterologous systems (eg, yeast cells) generates non-infectious virus-like-particles (VLP) that resemble HPV virions.9 In a placebo-controlled study,10 a yeast-produced HPV 16 L1 VLP vaccine was 100% efficacious in prevention of CIN caused by HPV 16 infection 17 months after vaccination in women who were HPV 16 naive at the time of vaccination, and results from studies11, 12, 13, 14, 15 have also shown HPV 11 or 18 L1 VLP vaccines to be highly immunogenic. These trials thus served as the basis for assessment of a quadrivalent HPV vaccine that targets HPV 6, 11, 16, and 18.

Section snippets

Study design

A phase II randomised, multicentre, double-blind placebo-controlled study of a quadrivalent HPV (type 6, 11, 16, and 18) L1 VLP vaccine was done in two parts. Part A was a sequential dose-escalation safety assessment, in which participants, investigators, and staff were blinded as to assignment of vaccine or placebo, but not to assignment of doses in the active-treatment group. Part B was a fully blinded dose-ranging assessment of immunogenicity and efficacy. Study procedures for individuals in

Results

277 women were randomly assigned to quadrivalent HPV (types 6, 11, 16, and 18) L1 VLP vaccine (20, 40, 40, 20 μg, respectively) and 275 to placebo (figure 1). 431 (78%) were included in the per-protocol efficacy analyses for HPV types 6/11, 404 (73%) for type 16, and 456 (83%) for type 18 (table 1, figure 1). 275 (99%) women assigned low-dose vaccine and 275 (100%) assigned placebo were included in the safety analyses. The main reasons for exclusion from the per-protocol cohort were

Discussion

We have shown that a multivalent vaccine is efficacious against HPV types that cause cancer and genital warts. Over 35 months' follow-up, incidence of persistent infection associated with HPV 6, 11, 16, or 18 decreased by 89% in women allocated active vaccine who had at least one dose (ie, the modified intention-to-treat population) compared with those allocated placebo. Vaccine efficacy was 90% in the per-protocol efficacy population, suggesting that the vaccine was protective even during the

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