Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a two-dose schedule in adolescent girls: Five-year clinical data and modeling predictions from a randomized study

Abstract

In this randomized, partially-blind study ( clinicaltrials.gov ; NCT00541970), the licensed formulation of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (20 μg each of HPV-16/18 antigens) was found highly immunogenic up to 4 y after first vaccination, whether administered as a 2-dose (2D) schedule in girls 9-14 y or 3-dose (3D) schedule in women 15-25 y. This end-of-study analysis extends immunogenicity and safety data until Month (M) 60, and presents antibody persistence predictions estimated by piecewise and modified power law models. Healthy females (age stratified: 9-14, 15-19, 20-25 y) were randomized to receive 2D at M0,6 (N = 240 ) or 3D at M0,1,6 (N = 239). Here, results are reported for girls 9-14 y (2D) and women 15-25 y (3D). Seropositivity rates, geometric mean titers (by enzyme-linked immunosorbent assay) and geometric mean titer ratios (GMRs; 3D/2D; post-hoc exploratory analysis) were calculated. All subjects seronegative pre-vaccination in the according-to-protocol immunogenicity cohort were seropositive for anti-HPV-16 and -18 at M60. Antibody responses elicited by the 2D and 3D schedules were comparable at M60, with GMRs close to 1 (anti-HPV-16: 1.13 [95% confidence interval: 0.82-1.54]; anti-HPV-18: 1.06 [0.74-1.51]). Statistical modeling predicted that in 95% of subjects, antibodies induced by 2D and 3D schedules could persist above natural infection levels for ≥ 21 y post-vaccination. The vaccine had a clinically acceptable safety profile in both groups. In conclusion, a 2D M0,6 schedule of the HPV-16/18 AS04-adjuvanted vaccine was immunogenic for up to 5 y in 9-14 y-old girls. Statistical modeling predicted that 2D-induced antibodies could persist for longer than 20 y.

Keywords: administration schedule; female adolescents; human papillomavirus vaccine; immunogenicity; randomized controlled trial; safety; women.

Figure 1.

Flow of participants through the trial. 2D, 2-dose schedule; 3D, 3-dose schedule; 20/20, licensed HPV-16/18 AS04-adjuvanted vaccine formulation containing 20 μg each of HPV-16 and −18 L1 virus-like particles and adjuvanted with AS04; 40/40, alternative HPV-16/18 AS04-adjuvanted vaccine formulation containing 40 μg each of HPV-16 and −18 L1 virus-like particles and adjuvanted with AS04; ATP-I, according-to-protocol immunogenicity cohort; M, month; y, years. *Excluding one subject who attended the Month 60 visit but did not sign the informed consent form for this visit. This article focuses on subjects randomized to receive the HPV-16/18 AS04-adjuvanted licensed vaccine formulation (3D 20/20 M0,1,6 and 2D 20/20 M0,6 groups; shaded boxes). Disposition data are also shown for subjects randomized to receive the alternative HPV-16/18 AS04-adjuvanted vaccine formulation (2D 40/40 M0,6 and 2D 40/40 M0,2 groups) for completeness.

Figure 2.

Observed HPV-16 and −18 geometric mean antibody titers (GMT) and corresponding 95% confidence intervals (CI) by enzyme-linked immunosorbent assay (ELISA) at each time point for subjects in the Month 60 according-to-protocol immunogenicity cohort (ATP-I) who were seronegative at baseline for the corresponding antigen. 2D, 2-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 3D, 3-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation. M, month; N, number of evaluable seronegative subjects in the Month 60 ATP-I; Plateau, GMTs at the plateau level (Month 45-50 time point) in women aged 15-25 y administered 3 doses of the HPV-16/18 AS04-adjuvanted vaccine at months 0, 1 and 6 in a previous trial (NCT00120848) were 397.8 and 297.3 ELISA unit (EU)/mL for HPV-16 and −18 antibodies, repectively. Natural infection, GMTs in women aged 15-25 y who had cleared a natural infection in a previous trial (NCT00122681) were 29.8 and 22.7 EU/mL for HPV-16 and −18 antibodies, repectively.

Figure 3.

Predicted HPV-16 and −18 geometric antibody mean antibody titers (GMTs) over 20 y, as predicted by the piecewise model (panels A and B) and modified power law model (panels C and D). Blue solid line, predicted GMTs for girls aged 9-14 y administered 2 doses of the licensed HPV-16/18 AS04-adjuvanted vaccine at months 0 and 6, modeled on the basis of 5 y of follow-up data from the current study. Red dashed line, predicted GMTs for women aged 15-25 y administered 3 doses of the licensed HPV-16/18 AS04-adjuvanted vaccine at months 0, 1 and 6, modeled on the basis of 5 y of follow-up data from the current study. Green dotted line, predicted GMTs for women aged 15-25 y administered 3 doses of the licensed HPV-16/18 AS04-adjuvanted vaccine at months 0, 1 and 6, modeled on the basis of 6.4 y of follow-up data from a previous efficacy study (NCT00120848). Black dashed line, GMTs in women who had cleared a natural infection in a previous trial (NCT00122681) (29.8 and 22.7 ELISA unit (EU)/mL for anti-HPV-16 and −18, respectively). ELISA, enzyme-linked immunosorbent assay.