Elsevier

The Lancet

Volume 374, Issue 9686, 25–31 July 2009, Pages 301-314
The Lancet

Fast track — Articles
Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women

https://doi.org/10.1016/S0140-6736(09)61248-4Get rights and content

Summary

Background

The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis.

Methods

Women (15–25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681.

Findings

Mean follow-up was 34·9 months (SD 6·4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92·9% (96·1% CI 79·9–98·3) in the primary analysis and 98·1% (88·4–100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30·4% (16·4–42·1) in the TVC and 70·2% (54·7–80·9) in the TVC-naive. Corresponding values against CIN3+ were 33·4% (9·1–51·5) in the TVC and 87·0% (54·9–97·7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54·0% (34·0–68·4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC.

Interpretation

The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes.

Funding

GlaxoSmithKline Biologicals.

Introduction

Human papillomavirus (HPV) vaccines are now licensed in more than 100 countries. National and regional immunisation programmes aimed at young adolescent girls have been widely implemented, and include catch-up programmes in some countries up to the age of 18 years or older.1 The HPV-16/18 vaccine is adjuvanted with AS04 (consisting of aluminium hydroxide and 3-O-desacyl-4′-monophosphoryl lipid A), shown to enhance the vaccine's immunogenicity.2 This adjuvanted vaccine has been shown to be highly immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections and associated precancerous lesions, in an event-triggered interim analysis in our phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA),3 and other trials.4, 5, 6, 7 Additionally, the vaccine has been shown to protect not only against HPV-16 and HPV-18 but also against other non-vaccine oncogenic HPV types.3, 5, 8

We now present the final event-driven analysis, which includes cases accrued over a follow-up of about 3 years. As well as a further assessment of the vaccine efficacy against persistent infection and cervical intraepithelial neoplasia grade 2+ (CIN2+) associated with HPV-16/18 that was already noted in the interim analysis, we also assessed the efficacy of the vaccine against CIN3+ lesions, and infections and lesions caused by non-vaccine oncogenic HPV types in the final event-driven analysis. To further explore the potential public health effect of the HPV-16/18 AS04-adjuvanted vaccine, we did efficacy analyses in a broad population of sexually active young women that included a large proportion with evidence of current or previous HPV infection at the start of the trial. Additionally, we did analyses in a population with no evidence of exposure to 14 oncogenic HPV types that represents young adolescent girls before sexual debut (the primary target population for current public health vaccination programmes).

Section snippets

Participants

Healthy women aged 15–25 years at the time of first vaccination were enrolled in the trial between May, 2004, and June 2005, at 135 centres in 14 countries in Asia Pacific, Europe, Latin America, and North America. Women who reported no more than six lifetime sexual partners before study enrolment, agreed to using adequate contraception over the vaccination period, and had an intact cervix were eligible for inclusion. Women were excluded if they had a history of colposcopy, were pregnant or

Results

A total of 18 644 women were included in the TVC. Figure 2 shows the distribution of the participants. A total of 17 106 women (92%) completed the full vaccination schedule. Table 1 shows the demographic and baseline characteristics of the three cohorts. The characteristics of women in the TVC-E and ATP cohort for immunogenicity were similar (data not shown). A substantial proportion of women (n=4828, 26%) had evidence of past or current infection with HPV-16/18 at baseline (table 1), but only

Discussion

The final event-triggered analysis of our trial confirmed the high efficacy of the HPV-16/18 AS04-adjuvanted vaccine in the prevention of CIN2+ lesions associated with HPV-16/18. The present analysis adds important information about the prevention of CIN2+ associated with HPV-16 and HPV-18 individually, and also the prevention of CIN3+, the immediate precursor of invasive cervical cancer (ATP-E cohort analysis). We were also able to confirm and add to our previous findings of cross-protection

References (30)

  • T Verstraeten et al.

    Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines

    Vaccine

    (2008)
  • D Descamps et al.

    Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention. A pooled analysis of 11 clinical trials

    Human Vaccines

    (2009)
  • L-J van Doorn et al.

    Highly effective detection of human papillomavirus 16 and 18 DNA by a testing algorithm combining broad-spectrum and type-specific PCR

    J Clin Microbiol

    (2006)
  • FJ Dessy et al.

    Correlation between direct ELISA, single epitope-based inhibition ELISA and pseudovirion-based neutralization assay for measuring anti-HPV-16 and anti-HPV-18 antibody response after vaccination with the AS04-adjuvanted HPV-16/18 cervical cancer vaccine

    Human Vaccines

    (2008)
  • VRBPAC background document. Gardasil HPV quadrivalent vaccine. Vaccine and Related Biological Products Advisory Committee Meeting. Washington, DC, USA; May 18, 2006: 13

  • Cited by (0)

    View full text