Immune response to the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose or 3-dose schedule up to 4 years after vaccination: results from a randomized study

Abstract

This randomized, partially-blind study (ClinicalTrials.gov registration number NCT00541970) evaluated the immunogenicity and safety of 2-dose (2D) schedules of the HPV-16/18 AS04-adjuvanted vaccine. Results to month (M) 24 have been reported previously and we now report data to M48 focusing on the licensed vaccine formulation (20 μg each of HPV-16 and -18 antigens) administered at M0,6 compared with the standard 3-dose (3D) schedule (M0,1,6). Healthy females (age stratified: 9-14, 15-19, 20-25 years) were randomized to receive 2D at M0,6 (n = 240) or 3D at M0,1,6 (n = 239). In the according-to-protocol immunogenicity cohort, all initially seronegative subjects seroconverted for HPV-16 and -18 antibodies and remained seropositive up to M48. For both HPV-16 and -18, geometric mean antibody titer (GMT) ratios (3D schedule in women aged 15-25 years divided by 2D schedule in girls aged 9-14 years) at M36 and M48 were close to 1, as they were at M7 when non-inferiority was demonstrated. The kinetics of HPV-16, -18, -31, and -45 antibody responses were similar for both groups and HPV-16 and -18 GMTs were substantially higher than natural infection titers. The vaccine had a clinically acceptable safety profile in both groups. In summary, antibody responses to a 2D M0,6 schedule of the licensed vaccine formulation in girls aged 9-14 years appeared comparable to the standard 3D schedule in women aged 15-25 years up to 4 years after first vaccination. A 2D schedule could facilitate implementation of HPV vaccination programs and improve vaccine coverage and series completion rates.

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, 20 μg each of HPV-16 and -18 L1 virus-like particles; 40/40, 40 μg each of HPV-16 and -18 L1 virus-like particles; ATP, according-to-protocol; M, month. This article focuses on subjects randomized to the 3D 20/20 M0,1,6 group and the 2D 20/20 M0,6 group (shaded boxes). Disposition data are also shown for subjects enrolled in other study groups (2D 40/40 M0,6 and 2D 40/40 M0,2) for completeness.

Figure 2. Kinetics of HPV-16 and HPV-18 antibody responses for girls aged 9–14 y in the 2D 20/20 M0,6 group and women aged 15–25 y in the 3D 20/20 M0,1,6 group (according-to-protocol month 48 immunogenicity cohort, subjects seronegative at baseline). 2D, 2-dose schedule; 3D, 3-dose schedule; 20/20, 20 μg each of HPV-16 and -18 L1 virus-like particles; 95% CI, exact 95% confidence interval; EU/mL, ELISA unit per milliliter; GMT, geometric mean antibody titer; M, month. Natural infection, GMT in subjects who had cleared a natural infection. Plateau, GMT at the plateau level (month 45–50) in women aged 15–25 y (total vaccinated cohort) in a study in which sustained protection with the HPV-16/18 AS04-adjuvanted vaccine has been shown (i.e., 397.8 EU/mL for HPV-16 and 297.3 EU/mL for HPV-18).

Figure 3. Kinetics of cross-reactive HPV-31 and HPV-45 antibody responses for girls aged 9–14 y in the 2D 20/20 M0,6 group and women aged 15–25 y in the 3D 20/20 M0,1,6 group (according-to-protocol month 48 immunogenicity cohort, subjects seronegative at baseline). 2D, 2-dose schedule; 3D, 3-dose schedule; 20/20, 20 μg each of HPV-16 and -18 L1 virus-like particles; 95% CI, exact 95% confidence interval; EU/mL, ELISA unit per milliliter; GMT, geometric mean antibody titer; M, month.