Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical intraepithelial neoplasia and cervical infection in young Japanese women

Abstract

In this open, extended follow-up study (NCT00929526, Clinicaltrials.gov), we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy, immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20-25 years. In the initial randomized, double-blind study (NCT00316693), 1040 women received the study vaccine or hepatitis A control vaccine; 752 women were included in the follow-up study. In women from the according-to-protocol efficacy cohort (ATP-E), who were initially seronegative for the HPV type analyzed, no cervical intraepithelial neoplasia (CIN) grade 1 or greater (CIN1+) cases associated with HPV-16/18 were reported in the HPV group, while in the control group, 5 cases were identified in extended follow-up analyses (vaccine efficacy [VE] 100% [95% CI: -3.7-100]) and 8 cases in combined initial and follow-up studies analyses (VE 100% [42.2-100]). In the ATP-E, VE against CIN1+ and CIN2+ associated with high-risk HPV types reached 66.4% (21.6-87.1) and 83.0% (22.1-98.2) in extended follow-up analyses, and 63.4% (28.8-82.3) and 77.3% (30.4-94.4) in analyses of combined studies, respectively. During the 4-year period, protection against CIN1+ and CIN2+, irrespective of the HPV type, was 56.7% (32.8-72.6) and 54.9% (20.5-75.3) in women receiving ≥1 vaccine dose, regardless of baseline serostatus (total vaccinated cohort [TVC]) and 61.0% (11.8-84.2) and 73.9% (1.1-95.3) in women naïve to HPV infection at baseline (TVC-naïve), respectively. The high VE observed in Japanese women, accompanied by a sustained immune response and a clinically acceptable safety profile, support findings of large, international trials.

Keywords: HPV-16/18 AS04-adjuvanted vaccine; Japan; cervical cancer; efficacy; human papillomavirus; safety.

Figure 1. Study design (A) and flow of participants (B) throughout the study. ^aWomen who received ≥1 dose of HPV-16/18 vaccine were invited for follow-up at month 24. ^bNo women with high-grade cytology or missing cytology at baseline. ^cAdditional cytopathological examination could be performed per cytology management algorithm at month 42 if required. *Number of women eliminated from the analysis of the concerned cohort under the reason of “not participated in extended follow-up.” The other women who did not participate in the extended follow-up study were eliminated with other reasons indicated in the same box. †Non-compliance with study procedure includes protocol violation, or randomization code broken, or non-compliance with the vaccine dose/schedule in the initial study, or administration of vaccine(s)/medication(s) forbidden by the protocol. Abbreviations: ATP, according-to-protocol; HPV, HPV vaccine group; TVC, total vaccinated cohort; N, number of women; AE, adverse event.

Figure 2. Number of cases of CIN1+ (A and C) and CIN2+ (B and D) associated with vaccine and non-vaccine HPV types in the TVC (A and B) and TVC-naïve (C and D) over the combined 4-y study period. Number of cases is shown inside the bars. Women included in the analysis of the TVC-naïve cohort were HPV DNA negative for all 14 oncogenic HPV types tested, seronegative for HPV-16 and HPV-18, and had negative cytology at baseline. Oncogenic HPV types tested were HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66 and -68. Follow-up period started on the day after the first vaccine dose. Abbreviations: CIN1+, cervical intraepithelial neoplasia grade 1 or greater; CIN2+, cervical intraepithelial neoplasia grade 2 or greater; TVC, total vaccinated cohort.

Figure 3. Anti-HPV-16 and anti-HPV-18 antibody GMTs from month 0 in initial study to month 48 in the present study (ATP kinetic cohort [N = 232 for HPV-16 and N = 233 for HPV-18]). The kinetics of the immune responses were evaluated in women from the ATP-I who were seronegative for the corresponding HPV type at baseline and had data available for each time point (ATP kinetic cohort). Long dashed lines: antibody titers at the plateau level (months 45–50) in a previous study in which sustained protection with the HPV-16/18 AS04-adjuvanted vaccine was shown up to 6.4 y post-vaccination (i.e., 397.8 [344.7–459.1] EL.U/mL for HPV-16 and 297.3 [258.2–342.2] EL.U/mL for HPV-18). Short dashed lines: antibody titers in women (aged 15–25 y at time of enrolment) who were presumed to have cleared a natural infection prior to enrolment in a previous study (i.e., who were HPV DNA negative and seropositive at baseline for the HPV type analyzed; 29.8 [28.5–31.0] EL.U/mL for HPV-16 and 22.6 [21.6–23.6] EL.U/mL for HPV-18). Abbreviations: 95% CI, 95% confidence interval (lower limit-upper limit); EL.U, ELISA units; GMT, geometric mean titer; M, month.