Worldwide, an estimated 470,000 new cases of cervical cancer and 230,000 deaths from the disease occur annually. In many parts of the world, cervical cancer is the most common cancer among women and the leading cause of reduced life expectancy for women. Because the human papillomavirus (HPV) types 16 and 18 are believed to cause around 70 percent of cases, vaccines against these oncogenic viruses could provide protection against cervical cancer. Harper and colleagues conducted a double-blind, multi-center, randomized controlled trial of a bivalent HPV-16/18 vaccine to assess prevention of infection with these viruses and subsequent development of cytologic abnormalities associated with cervical cancer.
The researchers recruited 1,113 women 15 to 25 years of age in North America and Brazil by advertising and by contacting participants of a previous epidemiologic study of HPV. Eligibility for the trial depended on good general health and negative testing by cytology and serology for HPV-16 and HPV-18. Participants also were required to have had no more than six sexual partners and to have no history of abnormal Papanicolaou smears, ablative or excisional cervical treatment, hysterectomy, or treatment for condylomata.
After extensive intake screening, including cervical cytology and serology testing, participants were randomly assigned to receive three doses of bivalent HPV-16/18 vaccine or an identical placebo at intake, one month, and six months. At baseline, six months, and every three months thereafter, participants obtained cervicovaginal swabs for HPV and cytologic testing. Colposcopy was performed after two reports of atypical squamous cells of undetermined significance, one report of atypical glandular cells of undetermined significance, low- or high-grade squamous intraepithelial lesions, or any form of carcinoma. Specimens were reviewed by a panel of three pathologists and were tested for HPV DNA. Serum was tested for antibodies to HPV-16 and HPV-18 at months zero, 1, 6, 7, 12, and 18. Information was collected on symptoms during the first week after vaccination. Participants also reported any adverse effects within 30 days. Serious adverse events and pregnancies were monitored throughout the study.
The 560 women who received the vaccine were similar in all significant variables to the 553 who received placebo. The average age of the participants was 20 years; about 70 percent were white, and about one half smoked. The groups had similar risk profiles for HPV infection and cervical cancer. In the study population, the vaccine efficacy was 95.1 percent against persistent HPV-16/18 infection and 92.9 percent against related cytologic abnormalities. Cervical abnormalities associated with HPV were detected in 27 women in the placebo group and two in the vaccinated group. Six of the women in the placebo group developed cervical intraepithelial neoplasia; HPV-16 was present in all lesions. One woman in the vaccinated group was found to have HPV-51 on colposcopy of a suspicious lesion. No serious adverse effects were associated with vaccination.
The authors conclude that the bivalent HPV-16/18 vaccine is highly effective in preventing HPV infection and subsequent cervical abnormalities. They project that a vaccination program targeting young women could be highly cost-effective in reducing morbidity and mortality from cervical disease, generating substantial savings in medical treatment.