Abstract
‘Early results from human papillomavirus virus-like particle vaccination trials are extremely promising, suggesting that a prophylactic vaccine against high-risk HPV infection will be available soon.’
Cervical cancer kills approximately 270,000 women every year worldwide, being the second most common cancer in women. Cervical cancer is largely preventable through effective mass-screening programs. However, such programs are not feasible in developing countries, where approximately 80% of the almost 500,000 new cases of cervical cancer reported annually occur. Despite sufficient evidence for the excellent effectiveness of mass-screening programs in the prevention of cervical cancer, screening policies vary widely even among European countries [1]. Furthermore, the incidence of cervical cancer is increasing, particularly in younger women, due to the inability of the screening programs to tackle the rapidly increasing incidence of human papillomavirus (HPV) infections in adolescents [2]. The primary cause of cervical cancer is persistent high-risk HPV infection, which causes practically all such cases worldwide. Among the approximately 100 types of papillomaviruses characterized so far, approximately 40 types can infect the genital mucosa following sexual transmission. Of those, 16 are oncogenic or so-called high-risk HPV types. HPV-type distribution among women from different geographic populations varies, although HPV-16 is the most prevalent type worldwide [3]. Epidemiologic studies on the prevalence of HPV types in cervical cancer show that approximately 70% are related to HPV-16 and −18, and this is relatively consistent throughout the world [4].
The creation of HPV virus-like particle (VLP) vaccines has been an exceptionally rapid breakthrough. HPV VLPs were described in 1991, and Phase III HPV VLP vaccination efficacy trials have been underway since 1992. Results from Phase I trials have confirmed the safety and tolerability of the vaccine and shown excellent immunogenecity. Phase II trials have demonstrated uniform serologic immune responses and highly effective protection against persistent high-risk HPV infection caused by the vaccine types and also against HPV-associated cytologic atypia [5–7]. The initial interim results from combined Phase II and III efficacy trials using either monovalent HPV-16 VLP vaccine, quadrivalent HPV6/11/16/18 VLP vaccine, or placebo against cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) or adenocarcinoma in situ (AIS) have recently been reported at the European Cancer Conference in Paris, France (ECCO13, October 30-November 3, 2005) [8]. In total, 20,541 16–26-year-old women from the Americas, Europe and Asia were enrolled in different double-blind, placebo-controlled trials. The mean age of the study population was 20 years, 94% were non-virgins, the mean age of sexual debut was 17 years, the mean number of lifetime sex partners was two, 23% had past pregnancy, 58% were using oral contraceptive, 4% were positive for Chlamydia trachomatis at baseline, and 6% had cytologic atypia on Pap smears at baseline [9]. Vaccine or placebo was administered at day 1, and months 2 and 6. Liquid-based Pap smears and swabs for HPV DNA were taken at each visit. The primary end point was HPV-16/18-related CIN2/3 or AIS. The primary efficacy evaluation in the per-protocol population was based on women who received three vaccinations within 1 year, were HPV-16/18 seronegative at day 1, and remained HPV-16/18 DNA negative from day 1 throughout the vaccination period. The results were striking and showed that a three-dose regimen of HPV VLP vaccine was 100% effective in preventing HPV16/18-related CIN2/3 and AIS (Table 1). The administration of the VLP vaccine was generally well tolerated. Thus, implementation of a universal HPV vaccination may reduce the risk of cervical neoplasia. Further analyses are now underway to evaluate vaccine efficacy against any CIN, external genital lesions and the overall HPV disease burden. These recent results represent an important milestone for the introduction of a HPV vaccine [10]. If vaccines prove to be effective against not only persistent HPV infection, but also against high-grade CIN, it is likely that the vaccine also protects women against cervical cancer. There is a consensus that CIN2/3 represents a feasible surrogate end point in Phase III vaccination trials conducted for registration of the vaccine [11]. However, it is important to emphasize that the long-term efficacy of the vaccination against invasive cervical cancer can only be studied in Phase IV trials in countries with cancer registries, such as Nordic European countries. In addition, it is important to emphasize that existing cervical cancer screening programs must be maintained during the vaccination era. However, for the vaccinated birth cohorts, new screening strategies need to be implemented. In summary, the early results from HPV VLP vaccination trials are extremely promising, suggesting that a prophylactic vaccine against high-risk HPV infection and its sequelae will be available soon.
Primary analysis: results in per-protocol population.
AIS: Adenocarcinoma in situ; CI: Confidence interval; CIN: Cervical intraepithelial neoplasia; HPV: Human papillomavirus.
Modified from [8].