Elsevier

The Lancet

Volume 364, Issue 9447, 13–19 November 2004, Pages 1757-1765
The Lancet

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Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(04)17398-4Get rights and content

Summary

Background

Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions.

Methods

We randomised 1113 women between 15–25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity.

Findings

In the according-to-protocol analyses, vaccine efficacy was 91·6% (95% CI 64·5–98·0) against incident infection and 100% against persistent infection (47·0–100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95·1% (63·5–99·3) against persistent cervical infection with HPV-16/18 and 92·9% (70·0–98·3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic.

Interpretation

The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.

Introduction

Cervical cancer is the most important manifestation of genital human papillomavirus (HPV) infection and is one of the leading causes of cancer mortality in women worldwide. The global disease burden of cervical cancer is estimated at 470000 new cases and 230000 deaths every year; almost 80% of the cases occur in developing countries, where in many regions it is the most common cancer among women.1, 2 Cervical cancer is also the leading cause of years-of-life-lost in women in south central Asia, Latin America, and sub-Saharan Africa, results in a greater reduction of a woman's life expectancy compared with AIDS, tuberculosis, or maternal conditions in Latin America and Europe.3

The causal role of some high-risk HPV types in cervical carcinogenesis has now been clearly established by studies that take into account the many molecular, epidemiological, virological, cytological, and histological complexities of the disease's natural history. Molecular studies show high-risk HPV DNA has been detected in 99·7% of an international series of cervical cancers with highly sensitive PCR, and, in 100% of cases, confirmed by expert histological review.4

The odds ratio for cervical cancer associated with high-risk HPV infection has been estimated as greater than 150 in case-control studies.5 Findings from case-control studies and cohort studies together with laboratory evidence of HPV oncogenic expression, have established that persistent infection with high-risk HPV types is the necessary cause of cervical cancer.6, 7, 8, 9 The most prevalent HPV types associated with cervical cancer are HPV-16 and HPV-18; HPV-16 accounts for more than 60% of cervical cancers, with HPV-18 adding about another 10%.5, 10, 11, 12, 13

HPV vaccines based on L1 virus-like particles have shown promise in protecting against infection and development of lesions.14, 15 Recently, a monovalent HPV-16 virus-like particle vaccine showed protection against persistent infection with HPV-16 and its associated cervical intraepithelial neoplasia (CIN).16 These data suggest that L1 virus-like particle vaccines have the potential to reduce worldwide cervical cancer rates.

We did a double blind, multi-centre, randomised, placebo-controlled clinical trial to assess the efficacy of a bivalent HPV-16/18 virus-like particle vaccine against incident and persistent infections with HPV-16 and HPV-18. We also assessed vaccine efficacy against cytological abnormalities and CIN, and vaccine immunogenicity, safety, and tolerability.

Section snippets

Study objectives and participants

The primary objective of this study was to assess vaccine efficacy in the prevention of infection with HPV-16, HPV-18, or both (HPV-16/18), between months 6 and 18 in participants who were initially shown to be seronegative for HPV-16/18 by ELISA and negative for HPV-16/18 DNA by PCR. Secondary objectives included: evaluation of vaccine efficacy in the prevention of persistent infection with HPV-16/18, and the evaluation of vaccine efficacy in the prevention of cytologically confirmed low-grade

Results

Based on the estimate of appropriate study sample size, 1113 women were enrolled and randomised. We administered the study vaccine to 560 women and the placebo to 553 women (figure). The average age of enrolled women was 20 years (SD 3). The demographic characteristics were similar between the vaccine and placebo groups in North America and Brazil (table 1; webtable 1 at http://image.thelancet.com/extras/04art10103webtable1.pdf). We noted similar patterns of risk factors for HPV acquisition

Discussion

The results of this trial show that the bivalent HPV-16/18 virus-like particle vaccine was highly efficacious in preventing incident and persistent HPV-16/18 infection in fully vaccinated healthy young women. The vaccine was also highly efficacious in the broader group of women, including those who did not fully comply with the protocol.

The incidence of HPV-16 infection in the placebo group was sufficient to detect significant differences compared with the vaccine arm in all cohorts. However,

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