Efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine in Chinese women aged 18-25 years: event-triggered analysis of a randomized controlled trial

Abstract

We previously reported the results of a phase II/III, double-blind, randomized controlled study in Chinese women (NCT00779766) showing a 94.2% (95% confidence interval: 62.7-99.9) HPV-16/18 AS04-adjuvanted vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or higher (CIN1+) and/or 6-month (M) persistent infection (PI) with a mean follow-up of <2 years, and immunogenicity until 7 months post-dose 1. Here, we report efficacy and safety results from an event-triggered analysis with ~3 years longer follow-up, and immunogenicity until M24. Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of HPV-16/18 vaccine or Al(OH)3 (control) at M0, 1, 6. VE against HPV-16/18-associated CIN2+, and cross-protective VE against infections with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. In the according-to-protocol efficacy cohort, in initially seronegative/DNA-negative women (vaccine group: N = 2524; control group: N = 2535), VE against HPV-16/18-associated CIN2+ was 87.3% (5.3-99.7); VE against incident infection or against 6-month persistent infection associated with HPV-31/33/45 was 50.1% (34.3-62.3) or 52.6% (24.5-70.9), respectively. At least, 99.6% of HPV-16/18-vaccines remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and -18 geometric mean titers were 1271.1 EU/mL (1135.8-1422.6) and 710.0 EU/ml (628.6-801.9), respectively. Serious adverse events were infrequent (1.7% vaccine group [N = 3026]; 2.5% control group [N = 3026]). Of the 1595 reported pregnancies, nine had congenital anomalies (five live infants, three elective terminations, one stillbirth) that were unlikely vaccination-related (blinded data). VE against HPV-16/18-associated CIN2+ was demonstrated and evidence of cross-protective VE against oncogenic HPV types was shown. The vaccine was immunogenic and had an acceptable safety profile.

Keywords: Efficacy; HPV-16/18 AS04-adjuvanted vaccine; human papillomavirus; immunogenicity; safety.

© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1

Study design. M, month; B, blood sampling; CS, cervical sample. A1:event‐triggered analysis with a mean follow‐up of ~21 months post‐dose 1 30. A2:current analysis: event‐triggered analysis with a mean follow‐up time of ~57 months post‐dose 1 (total vaccinated cohort for efficacy). *only for immunogenicity subset.

Figure 2

Participant flow. N, number of subjects included in each group; *n*, number present in one group only and duplicated to avoid unblinding of ongoing study; ATP, according‐to‐protocol; TVC, total vaccinated cohort. aStudy vaccine dose not administered but subject number allocated. bAtypical squamous cells cannot exclude high‐grade squamous intraepithelial lesions, high‐grade squamous intraepithelial lesions, atypical glandular cells, or malignancy. cSubjects may have more than one elimination code assigned ATP cohort for efficacy included participants who were seronegative (by ELISA) at Month 0 and DNA negative (by polymerase chain reaction [PCR]) at Month 0 and 6 for the HPV type considered in the analysis.

Figure 3

Pre‐ and postvaccination (A) anti‐HPV‐16 and (B) anti‐HPV‐18 geometric mean titers in initially seronegative women from the vaccine group (ATP cohort for immunogenicity). GMT, geometric mean titer; EU, ELISA units; Pre, prevaccination; M, month; ATP, according‐to‐protocol. Plateau level: GMTs of women aged 15–25 years at months 45–50 after the first vaccine dose (total vaccinated cohort) from a previous long‐term efficacy study (HPV‐007); GMTs were (A) 397.8 EU/mL and (B) 297.3 EU/mL 24. Natural infection level: GMTs of women who were (A) HPV‐16 or (B) HPV‐18 DNA‐negative and seropositive at baseline (i.e., who had cleared a natural infection); GMTs were (A) 29.8 EU/mL and (B) 22.6 EU/mL 15, 16. At the time of this event‐triggered analysis, immunogenicity results were only available up to the M24 timepoint. The percentages of seropositive women for the respective HPV type at each timepoint of assessment are indicated within each graph bar. The numbers indicated above each graph bar represent the number of women with prevaccination results available/number of women with titer ≥ the ELISA cut‐off (8 EU/mL for anti‐HPV‐16 or 7 EU/mL for anti‐HPV‐18). The error bars represent 95% confidence intervals.