Efficacy of a bivalent L 1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women : a randomised controlled trial

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 470 000 new cases and 230 000 deaths every year; almost 80% of the cases occur in developing countries, where in many regions it is the most common cancer among women. 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. 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. The odds ratio for cervical cancer associated with highrisk HPV infection has been estimated as greater than 150 in case-control studies. 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. 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%. HPV vaccines based on L1 virus-like particles have shown promise in protecting against infection and development of lesions. Recently, a monovalent HPV-16 virus-like particle vaccine showed protection against persistent infection with HPV-16 and its associated cervical intraepithelial neoplasia (CIN). 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. Lancet 2004; 364: 1757–65