Abstract and Introduction
Abstract
Persistent infection with oncogenic human papillomavirus (HPV)-16 and -18 accounts for over 70% of all cases of cervical cancer. Vaccination against these HPV types has become a reality. This article discusses the latest data available for Cervarix™ (GlaxoSmithKline Biologicals), an AS04-adjuvanted HPV-16/18 vaccine, and considers immunological factors important in vaccine effectiveness. High and sustained HPV-16 and -18 antibody levels have now been observed together with 100% vaccine efficacy in preventing HPV-16/18-related persistent infections and cervical intraepithelial neoplasia grade 2 and above, up to 6.4 years after first vaccination. Significant crossprotection against incident and persistent infection has been observed, notably against HPV-45, the third most prevalent HPV type in cervical cancer. An integrated safety summary of Phase II/III trials has shown that GlaxoSmithKline's HPV-16/18 AS04-adjuvanted vaccine is generally safe. Further studies will reveal the full duration and extent of the immune response and protection induced by Cervarix in broad populations and age ranges of women.
Cervical cancer is the second most common cancer in women worldwide with over 493,000 new cases occurring in 2002. Precancerous cervical lesions are also associated with significant morbidity. Human papillomavirus (HPV) has been conclusively demonstrated to be the causative agent of cervical cancer. Approximately 130 different HPV types have been identified and, of these, 30–40 HPV types infect the human genital tract. In total, 15 HPV types are classified as 'high-risk' (or oncogenic) for the development of cervical cancer. Together, HPV types 16 and 18 are responsible for over 70% of all cases of cervical cancer. Several other cancers, such as those of the vulva, vagina, anus, oropharynx and mouth, are also HPV related. Of the approximately 16,000 new cases of vulvar/vaginal cancer attributable to HPV in 2002, 80% were caused by HPV-16/18.
After HPV-16 and -18, types 45, 31, 33 and 52 are the next most prevalent Figure 1. HPV-45 is the third most prevalent type in both squamous cell carcinoma (SCC) and cervical adenocarcinoma. Endocervical adenocarcinoma is becoming increasingly important as it is not easily detected by cytological screening (even in countries with well-established screening programs) and is becoming more frequent in young women. In addition, adenocarcinoma is associated with a higher rate of relapse and poorer outcomes than SCC.
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Figure 1.
HPV type-specific distribution in cervical adenocarcinoma and SCC in eight combined multicenter, case–control studies. HPV X: denotes unknown HPV type. Studies conducted by the International Agency for Research on Cancer. Overall HPV prevalence among patients with cervical adenocarcinoma and SCC was 93.0 and 96.2%, respectively. Data for patients with SCC are from a subset of the studies in. HPV: Human papillomavirus; SCC: Squamous cell carcinoma. Reproduced from with permission of Oxford University Press.
Recently, vaccination against the HPV types responsible for most cases of cervical cancer has become a reality, with two prophylactic HPV vaccines now licensed in many countries worldwide. A HPV-16/18 L1 virus-like particle (VLP) vaccine formulated with the AS04 Adjuvant System (Cervarix™, GlaxoSmithKline Biologicals) showed efficacy in an initial Phase IIb trial (NCT00689741). An extended follow-up study (NCT00120848) reported vaccine-induced protection of up to 4.5 and 5.5 years.
However, a number of important questions regarding the long-term duration of vaccine-induced protection, vaccine efficacy and safety in large populations, the potential for crossprotection against other oncogenic HPV types and the age range of women who are likely to benefit from vaccination need to be addressed in order to maximize the impact of vaccination. Recent clinical studies with Cervarix have gone some way to address these important issues and are described below.