Fast track — ArticlesProphylactic 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
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
References (29)
- et al.
The cervical cancer epidemic that screening has prevented in the UK
Lancet
(2004) - et al.
Classification of papillomaviruses
Virology
(2004) - et al.
Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles
Virology
(1991) - et al.
Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine
Vaccine
(2004) - et al.
Dose-ranging studies of the safety and immunogenicity of human papillomavirus type 11 and type 16 virus-like particle candidate vaccines in young healthy women
Vaccine
(2004) - et al.
A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine
Vaccine
(2004) - et al.
Monoclonal antibodies to HPV-6 L1 virus-like particles identify conformational and linear neutralizing epitopes on HPV-11 in addition to type-specific epitopes on HPV-6
Virology
(1996) - et al.
Surface conformational and linear epitopes on HPV-16 and HPV-18 L1 virus-like particles as defined by monoclonal antibodies
Virology
(1996) - et al.
Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection of human papillomavirus type 16 and 18 in young women: a randomised controlled trial
Lancet
(2004) - et al.
The health care costs of cervical human papillomavirus-related disease
Am J Obstet Gynecol
(2004)
Sexual behavior in Britain: early heterosexual experience
Lancet
Sexual behavior in Britain: partnerships, practices, and HIV risk behaviors
Lancet
Chapter 1: Human papillomavirus and cervical cancer-burden and assessment of causality
J Natl Cancer Inst Monogr
GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide. IARC CancerBase No 5. Version 2.0
Cited by (1457)
Stimulation of the immune system by a tumor antigen-bearing adenovirus-inspired VLP allows control of melanoma growth
2023, Molecular Therapy Methods and Clinical DevelopmentPrimary prevention of cervical cancer in women: Human papillomavirus vaccine
2023, European Journal of Obstetrics and Gynecology and Reproductive BiologySingle-dose HPV vaccine immunity: is there a role for non-neutralizing antibodies?
2022, Trends in ImmunologyBioinspired and biomimetic micro- and nanostructures in biomedicine
2022, Journal of Controlled Release