Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years

Abstract

Immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in healthy Chinese females aged 9-45 years in 2 phase IIIB, randomized, controlled trials. Girls aged 9-17 years (ClinicalTrials.gov, NCT00996125) received vaccine (n = 374) or control (n = 376) and women aged 26-45 years (NCT01277042) received vaccine (n = 606) or control (n = 606) at months 0, 1, and 6. The primary objective was to show non-inferiority of anti-HPV-16 and -18 immune responses in initially seronegative subjects at month 7, compared with Chinese women aged 18-25 years enrolled in a separate phase II/III trial (NCT00779766). Secondary objectives were to describe the anti-HPV-16 and -18 immune response, reactogenicity and safety. At month 7, immune responses were non-inferior for girls (9-17 years) vs. young women (18-25 years): the upper limit of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio (women/girls) was below the limit of 2 for both anti-HPV-16 (0.37 [95% CI: 0.32, 0.43]) and anti-HPV-18 (0.42 [0.36, 0.49]). Immune responses at month 7 were also non-inferior for 26-45 year-old women vs. 18-25 year-old women: the upper limit of the 95% CI for the difference in seroconversion (18-25 minus 26-45) was below the limit of 5% for both anti-HPV-16 (0.00% [-1.53, 1.10]) and anti-HPV-18 (0.21% [-1.36, 1.68]). GMTs were 2- to 3-fold higher in girls (9-17 years) as compared with young women (18-25 years). The HPV-16/18 AS04-adjuvanted vaccine had an acceptable safety profile when administered to healthy Chinese females aged 9-45 years.

Keywords: China; HPV-16/18 AS04-adjuvanted vaccine; cervical cancer; female; human papillomavirus; immunogenicity; safety.

Figures

Figure 1. Overview of study design for each study. In each study, subjects were randomized in a 1:1 ratio to receive vaccine or control. In Study HPV-058, conducted in females aged 9–17 y, the control was Al(OH)3. In Study HPV-069, conducted in females aged 26–45 y, the control was hepatitis B virus (HBV) vaccine. N, number of subjects planned.

Figure 2. Flow of participants through each study. AE, adverse event; ATP, according-to-protocol.

Figure 3. Baseline seropositivity rate by age strata. Data are shown for the ATP cohort for immunogenicity for all subjects in HPV vaccine and control groups combined. Data for females aged 9–11, 12–14, and 15–17 y are from Study HPV-058. Data for females aged 18–25 y are from Study HPV-039. Data for females aged 26–35 and 36–45 y are from Study HPV-069. HPV-16 seropositivity defined as an ELISA concentration ≥ 8 EU/mL. HPV-18 seropositivity defined as an ELISA concentration ≥7 EU/mL. Numbers above each bar are the percentage of seropositive subjects per cohort.

Figure 4. Geometric mean antibody titers and associated 95% confidence intervals one month after the third vaccine dose, by age. Data are shown for the ATP cohort for immunogenicity. EU/mL, ELISA units per milliliter; GMT, geometric mean antibody titer; Initially seronegative, subjects who were seronegative at baseline; Total, all subjects regardless of baseline serostatus; y, years. Chinese data are from the following studies: females aged 9–11, 12–14, and 15–17 y from Study HPV-058; females aged 18–25 y from Study HPV-039; females aged 26–35 and 36–45 y from Study HPV-069. Global data are from the following studies: females aged 10–14 y from Study HPV-012 conducted in Europe (NCT00337818); females aged 15–25 y from Study HPV-008 conducted in Australia, Brazil, Canada, Finland, Mexico, Thailand, and the USA (NCT00122681); females aged 26–45 y from Study HPV-014 conducted in Europe (NCT00196937). Note that published global data are not available for smaller age strata.

Figure 5. Solicited local symptoms reported during the 7-d period following any vaccine dose. Data are shown for the total vaccinated cohort. Bars represent the percentage of doses followed by the specified symptom at least once in the 7-d period after any vaccine dose with exact 95% confidence interval. Ctrl, control; HPV, HPV vaccine. The control was Al(OH)3 for females aged 9–17 y and hepatitis B vaccine for females aged 26–45 y. Grade 3 redness or swelling defined as surface area ≥50 mm in diameter. Grade 3 pain defined as preventing normal activity. Data for females aged 9–17 y are from Study HPV-058. Data for females aged 26–45 y are from HPV-069.

Figure 6. Solicited general symptoms reported during the 7-d period following any vaccine dose. Data are shown for the total vaccinated cohort. Bars represent the percentage of doses followed by the specified symptom at least once in the 7-d period after any vaccine dose with exact 95% confidence interval. Ctrl, control; HPV, HPV vaccine; GI, gastrointestinal. The control was Al(OH)3 for females aged 9–17 y and hepatitis B vaccine for females aged 26–45 y. Fever defined as oral/axillary temperature >37.0 °C; grade 3 fever defined as oral/axillary temperature >39.0 °C. For all other symptoms, grade 3 defined as symptom that prevents normal activity. Data for females aged 9–17 y are from Study HPV-058. Data for females aged 26–45 y are from Study HPV-069.