Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection With Human Papillomavirus Types 16 and 18 in Young Women: A Randomized Trial

This double-blind, multicenter, randomized, placebo-controlled study was conducted to assess the efficacy of a bivalent human papillomavirus (HPV)-16/18 L1 virus-like particle vaccine in preventing cervical infection with HPV-16/18. The study participants were recruited among healthy women aged 15 to 25 years from 32 healthcare facilities in Brazil, Canada, and the United States. A total of 1113 women enrolled in the study. Enrollees had 6 or fewer lifetime sexual partners, no history of cervical abnormality, and were negative for high-risk HPV types. The subjects were randomized to receive placebo injections or the vaccine that contained 20 μg each of HPV-16 and HPV-18 virus-like particles. Women received 1 0.5-mL dose of vaccine or placebo at enrollment, 1 month, and 6 months. Cervical smears were taken at 6, 12, and 18 months. In addition, participants collected self-administered cervicovaginal samples at enrollment, 6 months, and every 3 months thereafter. Serologic testing for immunogenicity was performed at 0, 1, 6, 12, and 18 months. The women kept a diary of symptoms for 1 week after each injection, and symptoms were evaluated by telephone interview 1 month after each injection. Outcome results at 27 months were available for 81 women in the vaccine group and 59 in the placebo group. Study subject data were analyzed in two different cohorts. One analysis was performed including women who received all 3 injections and who had complete follow-up data. They comprised the ′according-to-protocol′ cohort (ATP). Another analysis was performed using data from the ′intention-to-treat′ cohort (ITT), which consisted of all enrolled participants who had at least one dose of vaccine or placebo and had any data available for analysis. There were 560 subjects randomized to receive vaccine and 553 randomized to receive placebo. The average age was 20 years. The two groups had similar patterns of risk factors for HPV infection. There were no cases of persistent HPV-16/18 among ATP women who received the vaccine. The vaccine was 100% effective against HPV-16, HPV-18, and HPV-16/18 (P < 0.0001). The effectiveness against HPV-18 infection was not significant until 27 months. In comparison, 13 (2.1%) women in the ATP group who received placebo developed a persistent HPV-16 infection, 4 (0.6%) had persistent HPV-18, and 16 (2.6%) had persistent HPV-16/18. In the ITT cohort, there were 4 women in the vaccine group who were positive for persistent HPV-16 (0.5%: efficacy 84.5%, P < 0.0001), 1 positive for persistent HPV-18 (0.1%: efficacy 91.1%, P = 0.003) and 4 with HPV-16/18 (0.5%: efficacy 87.5%, P < .0001). In the ITT placebo group, 25 women (3.2%) were positive for persistent HPV-16, 11 (1.4%) had persistent HPV-18, and 31 (4.0%) persistent HPV-16/18. Among the 560 women who received the vaccine, 2 developed cervical abnormalities associated with HPV types 16 or 18. One had atypical squamous cells of unknown significance (ASGUS) and 1 had a low-grade squamous intraepithelial lesion (LSIL). Of the 553 women who received placebo, 27 developed cervical abnormalities, including 15 ASCUS, 14 LSIL, and 1 high-grade squamous intraepithelial lesion (HSIL). The vaccine had an efficacy of 95.2% against HPV-16 (P < 0.0001), 91.2% against HPV-18 (P = 0.003), and 92.9% against HPV-16/18 (P < 0.0001). Cervical intraepithelial neoplasia (CIN) 1 or 2 was seen in 7 women, including 1 CIN 1 in the vaccine group, and 3 each CIN 1 and CIN 2 in the placebo group.