Efficacy, immunogenicity and safety of the AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years: End-of-study results from a phase II/III, randomised, controlled trial

Abstract

Background: Cervical cancer is a major public health concern in China. We report the end-of-study results of a phase II/III trial to assess the efficacy, immunogenicity, and safety of the AS04-human papillomavirus (HPV)-16/18 vaccine in Chinese women aged 18-25 years followed for up to 72 months after first vaccination. Results of approximately 57 months following first vaccination have been previously reported.

Methods: Healthy 18-25-year-old women (N = 6051) were randomized (1:1) to receive three doses of AS04-HPV-16/18 vaccine or Al(OH)3 (control) at Months 0-1-6. Vaccine efficacy against HPV-16/18 infection and cervical intraepithelial neoplasia (CIN), cross-protective vaccine efficacy against infections and lesions associated with nonvaccine oncogenic HPV types, immunogenicity, and safety were assessed. Efficacy was assessed in the according-to-protocol efficacy (ATP-E) cohort (vaccine N = 2888; control N = 2892), total vaccinated cohort for efficacy (TVC-E; vaccine N = 2987; control N = 2985) and TVC-naïve (vaccine N = 1660; control N = 1587).

Results: In initially HPV-16/18 seronegative/DNA-negative women, vaccine efficacy against HPV-16/18-associated CIN grade 2 or worse was 87.3% (95% CI: 5.5, 99.7) in the ATP-E, 88.7% (95% CI: 18.5, 99.7) in the TVC-E, and 100% (95% CI: 17.9, 100) in the TVC-naïve. Cross-protective efficacy against incident infection with HPV-31, HPV-33 and HPV-45 was 59.6% (95% CI: 39.4, 73.5), 42.7% (95% CI: 15.6, 61.6), and 54.8% (95% CI: 19.3, 75.6), respectively (ATP-E). At Month 72, >95% of initially seronegative women who received HPV vaccine in the ATP cohort for immunogenicity (N = 664) remained seropositive for anti-HPV-16/18 antibodies; anti-HPV-16 and anti-HPV-18 geometric mean titers were 678.1 EU/mL (95% CI: 552.9, 831.5) and 343.7 EU/mL (95% CI: 291.9, 404.8), respectively. Serious adverse events were infrequent (1.9% vaccine group [N = 3026]; 2.7% control group [N = 3025]). Three and zero women died in the control group and the vaccine group respectively. New onset autoimmune disease was reported in two women in the vaccine group and two in the control group.

Conclusions: This is the first large-scale randomized clinical trial of HPV vaccination in China. High and sustained vaccine efficacy against HPV-16/18-associated infection and cervical lesions was demonstrated up to Month 72. The vaccine had an acceptable safety profile. Combined with screening, prophylactic HPV vaccination could potentially reduce the high burden of HPV infection and cervical cancer in China.

Trial registration: NCT00779766.

Keywords: AS04-HPV-16/18 vaccine; China; efficacy; human papillomavirus; immunogenicity; safety.

Conflict of interest statement

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf and declare the following potential conflicts of interest: The institutions of Fang‐Hui Zhao, Shang‐Ying Hu, Ying Hong, Yue‐Mei Hu, Xun Zhang, Yi‐Ju Zhang, Qin‐Jing Pan, Wen‐Hua Zhang, Cheng‐Fu Zhang, Xiaoping Yang, Jia‐Xi Yu, Jiahong Zhu, Yejiang Zhu, Feng Chen, Qian Zhang, Hong Wang, Changrong Wang, Jun Bi, Shiyin Xue, Lingling Shen, Yan‐Shu Zhang, Feng‐Cai Zhu received grants/investigator fees from the GSK group of companies for the conduct of this study. Fang‐Hui Zhao, Feng‐Cai Zhu and Yue‐Mei Hu received support for travel to meetings related to the study from the GSK group of companies. Haiwen Tang, Naveen Karkada, Dan Bi and Frank Struyf are employees of the GSK group of companies. Haiwen Tang, Dan Bi, and Frank Struyf hold shares in the GSK group of companies. Pemmaraju Suryakiran and Yunkun He were employees of the GSK group of companies at the time the study was conducted.

© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1

Participant disposition. The TVC‐naïve included 1660 women in the vaccine group and 1587 women in the control group. AE, adverse event; ATP‐E, according to protocol cohort for efficacy; N, number of women in the analysis; n, number of cases; SAE, serious adverse event; TVC‐E, total vaccinated cohort for efficacy; TVC‐naïve, total vaccinated naïve cohort; TVC, total vaccinated cohort

Figure 2

Clinical diagnosis and biopsy PCR results of CIN2+ cases associated with HPV‐16/18 (TVC‐E). Cases were from women in the TVC‐E who were HPV‐16/18 DNA‐negative at baseline regardless of initial serostatus. ‖Case 1 was also part of the ATP‐E cohort. *All samples taken by punch biopsy except case 9 which was taken by endocervical curettage. CIN1, cervical intraepithelial neoplasia grade 1; CIN2, cervical intraepithelial neoplasia grade 2; CIN3, cervical intraepithelial neoplasia grade 3; HPV, human papillomavirus; LSIL, low‐grade squamous intraepithelial lesion; PCR, polymerase chain reaction; TVC‐E, total vaccinated cohort for efficacy

Figure 3

Number of cases of CIN2+ and CIN3+ associated with vaccine and nonvaccine types (TVC‐naïve). The incidence rate of CIN2+ irrespective of HPV was 0.13 per 100 person‐years in the vaccine group and 0.20 per 100 person‐years in the control group. The incidence rate of CIN3+ irrespective of HPV was 0.02 per 100 person‐years in the vaccine group and 0.05 per 100 person‐years in the control group. Oncogenic HPV types detected in CIN2+ cases in the vaccine group: no HPV detected (n = 2); HPV‐33 (n = 2); HPV‐35 (n = 1); HPV‐39 (n = 2); HPV‐51 (n = 1); HPV‐52/58 (n = 1); HPV‐58 (n = 1); HPV‐58/66 (n = 1). Oncogenic HPV types detected in CIN2+ cases in the control group: HPV‐16 (n = 4); HPV‐16/31/39 (n = 1); HPV‐16/66 (n = 1); HPV‐33 (n = 3); HPV‐35 (n = 1); HPV‐35/52 (n = 1); HPV‐45 (n = 1); HPV‐52 (n = 1); HPV‐58 (n = 3). Oncogenic HPV types detected in CIN3+ cases in the vaccine group: HPV‐58 (n = 1); HPV‐39 (n = 1). Oncogenic HPV types detected in CIN3+ cases in the control group: HPV‐16 (n = 2); HPV‐16/31/39 (n = 1); HPV‐58 (n = 1) CIN2+: cervical intraepithelial neoplasia grade 2 or worse. CIN3+, cervical intraepithelial neoplasia grade 3 or worse; HPV, human papillomavirus; TVC‐naïve, total vaccinated naïve cohort

Figure 4

Immunogenicity in initially seronegative women receiving the HPV‐16/18 vaccine (ATP cohort for immunogenicity). Numbers above bars show the percentage seropositivity. Solid line shows the level of antibodies observed following clearance of a natural infection ie GMTs observed in women who were HPV‐16/18 DNA‐negative and seropositive at baseline in a phase III efficacy study (29.8 EL.U/mL for HPV‐16 and 22.6 EL.U/mL for HPV‐18).34 ATP, according to protocol; CI, confidence interval; EL.U, ELISA units; GMT, geometric mean titer; HPV, human papillomavirus; M, month; Pre, prevaccination

Figure 5

Study highlights