Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial

doi:10.1016/S0140-6736(07)60946-5

The Lancet

Volume 369, Issue 9580, 30 June–6 July 2007, Pages 2161-2170

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https://doi.org/10.1016/S0140-6736(07)60946-5 Get rights and content

Summary

Background

The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women.

Methods

18 644 women aged 15–25 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpoint—vaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18—was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681.

Findings

Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14·8 (SD 4·9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90·4% (97·9% CI 53·4–99·3; p<0·0001). No clinically meaningful differences were noted in safety outcomes between the study groups.

Interpretation

The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2+ associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention.

Introduction

The necessary role of oncogenic human papillomavirus (HPV) infection in cervical cancer provides an opportunity to reduce disease burden through prophylactic vaccination.1, 2, 3 HPV types 16 and 18 account for 70% or more of cases of cervical cancer worldwide.⁴ Up to 15 oncogenic HPV types contribute to cervical cancer and several are members of either the A7 (HPV18, 39, 45, 59, 68, 70, and 85) or A9 (HPV16, 31, 33, 35, 52, 58, and 67) papillomavirus species.5, 6

An HPV16/18 L1 virus-like-particle candidate vaccine (GlaxoSmithKline Biologicals, Rixensart, Belgium), adjuvanted with 3-O-desacyl-4′-monophosphoryl lipid A and aluminium hydroxide (AS04), has shown complete prevention of 12-month persistent infections with the combined endpoint of HPV16 infection, HPV18 infection, or HPV16 and HPV18 co-infection (HPV16/18), and associated combined cervical intraepithelial neoplasia (CIN grades 1, 2, and 3) in fully vaccinated young women who were seronegative for HPV16 and HPV18 and negative for any cervical oncogenic HPV DNA at study entry.7, 8 High efficacy has been shown through 4·5 years of follow-up, together with sustained levels of antibodies against HPV16 and HPV18.⁸ The vaccine has also shown evidence of cross-protection against incident infection with HPV45 and HPV31, two non-vaccine HPV types that are phylogenetically related to HPV16 and HPV18,⁸ which together with HPV16 and HPV18, account for about 80% of cases of cervical cancer worldwide.4, 5

The aim of this prespecified interim analysis of a phase III double-blind, randomised controlled trial is to assess the efficacy of this vaccine against CIN2, CIN3, adenocarcinoma in situ, and invasive carcinoma associated with HPV16 or HPV18—a surrogate endpoint for cervical cancer—and against persistent infections with HPV16, HPV18, and other oncogenic HPV types.⁹

Section snippets

Patients

Women were recruited for the PApilloma TRIal against Cancer In young Adults (PATRICIA) study between May, 2004, and June, 2005, in 14 countries (Australia, Belgium, Brazil, Canada, Finland, Germany, Italy, Mexico, Philippines, Spain, Taiwan, Thailand, UK, and USA).

Healthy women aged 15–25 years who reported no more than six lifetime sexual partners before study enrolment (in some countries this criteria was not considered for minors), who agreed to adequate contraception (barrier methods in

Results

The demographic characteristics of women enrolled in this study are shown in table 1. 17 106 (92%) women complied with the full three-dose vaccination schedule and only 5% dropped out from the study; reasons for dropouts are shown in table 1. The baseline characteristics for vaccinated women are shown in table 2. 3753 (20%) women had cervical oncogenic HPV DNA at baseline.

Almost all women vaccinated (99·4%) were included in the total vaccinated cohort for efficacy. The figure shows the number

Discussion

This interim analysis shows that the adjuvanted HPV16/18 vaccine exhibits high prophylactic efficacy against CIN2+ associated with HPV16/18 in women who were uninfected with HPV16 or HPV18 but possibly infected with other oncogenic HPV types or who had current or previous low-grade cytological abnormalities before vaccination. No clinically meaningful differences were noted in safety outcomes between the study groups, although injection site symptoms and some solicited general symptoms were

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A total of 21,168 eligible VVS specimens were tested for HPV DNA. The prevalence of HPV16/18 in sexually active 16–18 year old females who were offered vaccination aged 12–13 years was <1% in the most recent years tested, compared to over 15% prior to the vaccination programme in 2008. The magnitude of these decreases also suggests reduced transmission is offering some herd protection to unvaccinated females. HPV31/33/45 prevalence also steadily decreased, providing evidence of cross-protection. HPV6/11 prevalence remained stable during the bivalent vaccine period, with more recent declines, as expected due to the use of the quadrivalent vaccine. There has been no substantive increase in the prevalence of other high-risk (HR) HPV types.
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The pichia pastoris-expressed bivalent HPV vaccine was safe and immunogenic in Chinese females aged 9–45 years. The low dosage (0.5 mL) was selected for further immunogenicity and efficacy study.
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A total of 40.8% of women were HPV DNA positive; 3.0% had cardiovascular diseases; and 9.0% of women received the HPV vaccine. The presence of vaginal HPV infection was associated with cardiovascular diseases (odd ratio [OR] = 1.66, 95% confidence interval [CI] 1.28-2.16), which remained significant (OR = 1.54, 95% CI 1.15-2.08) after adjustment for sociodemographic characteristics, lifestyle behaviors, medical history, family history of cardiovascular diseases, and antihypertensive drugs. The association was absent among those who were vaccinated against HPV (OR= 0.50, 95% CI 0.07-3.51) but present among those who were not (OR = 1.63, 95% CI 1.18-2.25).
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Fast track — ArticlesEfficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Virology

Lancet

Lancet

Vaccine

Virology

Vaccine

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

J Pathol

Prophylactic HPV vaccines: prospects for eliminating ano-genital cancer

Br J Cancer

The epidemiology of genital human papillomavirus infection

Vaccine

Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update

Int J Cancer

Epidemiologic classification of human papillomavirus types associated with cervical cancer

N Engl J Med

Fast track — Articles
Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial