Safety and immunogenicity of human papillomavirus-16/18 AS04-adjuvanted vaccine: a randomized trial in 10-25-year-old HIV-Seronegative African girls and young women

Abstract

Background: Cervical cancer is a major public health problem for women in sub-Saharan Africa. Availability of a human papillomavirus (HPV) vaccine could have an important public health impact.

Methods: In this phase IIIb, double-blind, randomized, placebo-controlled, multicenter trial (NCT00481767), healthy African girls and young women seronegative for human immunodeficiency virus (HIV) were stratified by age (10-14 or 15-25 years) and randomized (2:1) to receive either HPV-16/18 AS04-adjuvanted vaccine (n = 450) or placebo (n = 226) at 0, 1, and 6 months. The primary objective was to evaluate HPV-16/18 antibody responses at month 7. Seropositivity rates and corresponding geometric mean titers (GMTs) were measured by enzyme-linked immunosorbent assay.

Results: In the according-to-protocol analysis at month 7, 100% of initially seronegative participants in the vaccine group were seropositive for both anti-HPV-16 and anti-HPV-18 antibodies (n = 130 and n = 128 for 10-14-year-olds, respectively; n = 190 and n = 212 for 15-25-year-olds). GMTs for HPV-16 and HPV-18 were higher in 10-14-year-olds (18 423 [95% confidence interval, 16 185-20 970] and 6487 [5590-7529] enzyme-linked immunosorbent assay units (EU)/mL, respectively) than in 15-25-year-olds (10 683 [9567-11 930] and 3743 [3400-4120] EU/mL, respectively). Seropositivity was maintained at month 12. No participant withdrew owing to adverse events. No vaccine-related serious adverse events were reported.

Conclusions: The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic and had a clinically acceptable safety profile when administered to healthy HIV-seronegative African girls and young women.

Figure 1.

Flow of participants through the trial. Excluded participants may have had more than one reason for elimination from the according-to-protocol (ATP) immunogenicity cohort; therefore, the sum of reasons for elimination is more than the total number of participants excluded.

Figure 2.

Kinetics of anti–human papillomavirus (HPV) 16 and anti–HPV-18 antibody responses in initially seronegative participants in the vaccine group of the according-to-protocol (ATP) immunogenicity month 7 cohort. The ATP immunogenicity cohort at month 7 was used for the months 0, 2, and 7 time points; the ATP immunogenicity cohort at month 12, for the month 12 time point. Natural infection indicates GMT in women who had cleared a natural infection [16]; plateau, GMT at plateau level (months 45–50) from a previous study in women aged 15–25 years, in which sustained protection with the HPV-16/18 AS04-adjuvanted vaccine was shown up to 6.4 years after first vaccination [18]. Abbreviations: CI, confidence interval; EU, enzyme-linked immunosorbent assay units.

Figure 3.

Geometric mean titers (GMTs) for anti–human papillomavirus (HPV)-16 and anti–HPV-18 at month 7 in initially seronegative participants in the vaccine group of the according-to-protocol ATP immunogenicity month 7 cohort. Values above bars show GMTs by stratum; percentages below bars, seroconversion rates; n, number of evaluable participants at month 7. Abbreviations: CI, confidence interval; EU, enzyme-linked immunosorbent assay units. Data for Europe are from Pedersen et al [13].

Figure 4.

Incidence of solicited symptoms during the 7-day period after any dose (total vaccinated cohort). Abbreviations: CI, exact 95% confidence interval; n, total number of documented doses.