Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study

Abstract

The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 μg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 μg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9-14, 15-19, 20-25 y) were randomized to receive 2 doses of 20/20F at Months (M) 0,6 (n=240), 40/40F at M0,6 (n=241) or 40/40F at M0,2 (n=240), or 3 doses of 20/20F at M0,1,6 (licensed schedule/formulation, n=239). One month after the last dose, the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 (lower limit of 95% CI geometric mean antibody titer (GMT) ratio [2D/3D] < 0.5). For both HPV-16 and HPV-18, the 2D schedules in girls 9-14 y were immunologically non-inferior to the 3D schedule in women 15-25 y (the age group in which efficacy has been demonstrated) (upper limit of 95% CI for GMT ratio [3D/2D] < 2) one month after the last dose. At Month 24, non-inferiority was maintained for the 2D M0,6 schedules in girls 9-14 y versus the 3D schedule in women 15-25 y. All formulations had acceptable reactogenicity and safety profiles. These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9-14 y and that the 2D schedule is likely adequate for younger females.

Figures

Figure 1

Participant disposition. ATP, according to protocol.

Figure 2

Kinetics of antibody responses against HPV-16 and HPV-18 (according to protocol immunogenicity cohort, initially seronegative subjects). CI, confidence interval; EU, ELISA unit; GMT, geometric mean titer. Natural infection, GMT in subjects who had cleared a natural infection (i.e., 29.8 [28.5 to 31.1] EU/mL for HPV-16 and 22.7 [21.7 to 23.7] EU/mL for HPV-18). Plateau, GMT at the plateau level (Month 45–50) in a study in which sustained protection with the HPV-16/18 AS 04-adjuvanted vaccine was shown up to 6.4 y after first vaccination (i.e., 397.8 [344.7 to 459.1] EU/mL for HPV-16 and 297.3 [258.2 to 342.2] EU/mL for HPV-18).

Figure 3

Incidence of solicited local symptoms reported during the 7-d post-vaccination period following any dose, overall per dose (total vaccinated cohort). CI, confidence interval; Grade 3, pain that prevented normal activity or diameter of redness or swelling >50 mm.

Figure 4

Incidence of solicited general symptoms reported during the 7-d post-vaccination period following any dose, overall per dose (total vaccinated cohort). CI, confidence interval; GI, gastrointestinal; Grade 3, symptom that prevented normal activity or fever >39°C.