Elsevier

The Lancet

Volume 373, Issue 9679, 6–12 June 2009, Pages 1949-1957
The Lancet

Articles
Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-blind trial

https://doi.org/10.1016/S0140-6736(09)60691-7Get rights and content

Summary

Background

Although the peak incidence of human papillomavirus (HPV) infection occurs in most populations within 5–10 years of first sexual experience, all women remain at risk for acquisition of HPV infections. We tested the safety, immunogenicity, and efficacy of the quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like-particle vaccine in women aged 24–45 years.

Methods

Women aged 24–45 years with no history of genital warts or cervical disease were enrolled from community health centres, academic health centres, and primary health-care providers into an ongoing multicentre, parallel, randomised, placebo-controlled, double-blind study. Participants were allocated by computer-generated schedule to receive quadrivalent HPV vaccine (n=1911) or placebo (n=1908) at day 1, and months 2 and 6. All study site investigators and personnel, study participants, monitors, and central laboratory personnel were blinded to treatment allocation. Coprimary efficacy endpoints were 6 months' or more duration of infection and cervical and external genital disease due to HPV 6, 11, 16, 18; and due to HPV 16 and 18 alone. Primary efficacy analyses were done in a per-protocol population, but intention-to-treat analyses were also undertaken. This study is registered with ClinicalTrials.gov, number NCT00090220.

Findings

1910 women received at least one dose of vaccine and 1907 at least one dose of placebo. In the per-protocol population, efficacy against the first coprimary endpoint (disease or infection related to HPV 6, 11, 16, and 18) was 90·5% (95% CI 73·7–97·5, four of 1615 cases in the vaccine group vs 41/1607 in the placebo group) and 83·1% (50·6–95·8, four of 1601 cases vs 23/1579 cases) against the second coprimary endpoint (disease or infection related to HPV 16 and 18 alone). In the intention-to-treat population, efficacy against the first coprimary endpoint was 30·9% (95% CI 11·1–46·5, 108/1886 cases vs 154/1883 cases) and against the second coprimary endpoint was 22·6% (−2·9 to 41·9, 90/1886 cases vs 115/1883 cases), since infection and disease were present at baseline. We recorded no vaccine-related serious adverse events.

Interpretation

The quadrivalent HPV vaccine is efficacious in women aged 24–45 years not infected with the relevant HPV types at enrolment.

Funding

Merck (USA).

Introduction

Studies of the natural history of human papillomavirus (HPV) infection and disease have shown that the peak incidence of HPV infection occurs in most populations within 5–10 years of first sexual experience (age 15–25 years). Women older than 25 years clearly remain at substantial risk for acquisition of HPV infections, although the extent to which infections occurring in mid-adult life are associated with subsequent risk of precancer and cancer is unclear.1, 2, 3 In a cohort of 1600 women from Bogota, Colombia, the 5-year cumulative risk of cervical HPV infection of any type decreased from 42·5% in women aged 15–19 years to 22·0% in those aged 30–44 years,4 showing a reduced, but not insignificant risk in the older cohort. A second peak in HPV DNA prevalence has been recorded in women in the fourth and fifth decades of life.5 Whether this second peak is due to reactivation of latent infections, a cohort effect, or new HPV infections is not clear; however, the cohort study from Colombia lends support to the possibility of new HPV infections. The curve of incident HPV infections in these women showed a first peak in those younger than 25 years and a second peak after menopause.4

Changes in sexual behaviour during the past 30 years, characterised by rising age at first marriage and an increase in divorce rates, have led to more widespread premarital sexual intercourse and acquisition of new sexual partners around middle age, respectively.6 Published work suggests that in the USA, nearly 40% of men and women have married and divorced by 55 years of age, and that more than 25% of these people have remarried at least once.7 As the potential for HPV infection and disease exists in women in their third, fourth, and fifth decades of life, these women could benefit from prophylactic HPV vaccination.

Recent phase III trials (FUTURE I and II) undertaken in about 15 000 women aged 16–26 years from North America, Latin America, Asia, and Europe have shown that a prophylactic quadrivalent HPV (types 6, 11, 16, and 18) L1 virus-like-particle (VLP) vaccine adjuvanted with amorphous aluminium hydroxyphosphate sulphate to be highly effective in prevention of cervical, vulvar, or vaginal intraepithelial neoplasia related to HPV 6, 11, 16, or 18, as well as adenocarcinoma in situ in women who were naive to the respective HPV types at enrolment.8, 9 A high efficacy against genital warts related to HPV 6 and 11 was also seen.8 Data from these trials indicated that women who were naive to all four vaccine HPV types (negative by both serological and DNA testing) before vaccination derive full benefit (ie, protection from disease caused by all four vaccine HPV types), whereas women who are infected with one or more vaccine HPV types before vaccination will derive partial benefit (ie, protection from the types that the participants were not infected with at time of vaccination).10

We undertook a phase III trial to assess the efficacy, safety, and immunogenicity of the prophylactic quadrivalent HPV vaccine in women aged 24–45 years.

Section snippets

Study design and participants

Between June, 18, 2004, and April 30, 2005, 3819 women between the ages of 24 years and 45 years were enrolled from 38 international study sites into an ongoing randomised, placebo-controlled, double-blind safety, immunogenicity, and efficacy study. Participants were enrolled from community health centres, academic health centres, and primary health-care providers in Colombia, France, Germany, Philippines, Spain, Thailand, and the USA. For all women enrolled, the duration of the study will be

Results

Figure 1 shows the trial profile. Of the 4082 participants who were screened for eligibility, 3819 were enrolled into the study and were randomly assigned to receive either quadrivalent HPV vaccine (n=1911) or placebo (n=1908). 263 women were screened and not randomly assigned to a group (figure 1). Two women were randomly assigned but not vaccinated. 85% of all vaccinated participants were included in the PPE analysis specific to one or more HPV vaccine type (n=1631). 94 women (3%)

Discussion

The PPE analysis for the use of a prophylactic quadrivalent HPV vaccine in adult women aged 24–45 years shows that vaccine efficacy against infection of at least 6 months' duration and cervical and external genital disease is high (mostly due to efficacy against infection). Differences in efficacy in younger and older women are probably due to more HPV infections occurring in younger women. The quadrivalent HPV vaccine already has a proven benefit in women and girls aged 9–26 years.8, 9 The

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