Comparative humoral and cellular immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: follow-up through Month 48 in a Phase III randomized study

Abstract

We previously reported higher anti-HPV-16 and -18 immune responses induced by HPV-16/18 vaccine compared with HPV-6/11/16/18 vaccine at Month 7 (one month after completion of full vaccination series) in women aged 18-45 y in an observer-blind study NCT00423046; the differences of immune response magnitudes were maintained up to Month 24. Here we report follow-up data through Month 48. At Month 48, in according-to-protocol cohort for immunogenicity (seronegative and DNA-negative for HPV type analyzed at baseline), geometric mean titers of serum neutralizing antibodies were 2.0- to 5.2-fold higher (HPV-16) and 8.6- to 12.8-fold higher (HPV-18) in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. The majority of women in both vaccine groups remained seropositive for HPV-16. The same trend was observed for HPV-18 in HPV-16/18 vaccine group; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably, particularly in the older age groups. In the total vaccinated cohort (regardless of baseline serological and HPV-DNA status), anti-HPV-16 and -18 neutralizing antibody levels induced by HPV-16/18 vaccine were higher than those induced by HPV-6/11/16/18 vaccine. CD4+ T-cell response for HPV-16 and HPV-18 was higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Memory B-cell responses appeared similar between vaccine groups. Both vaccines were generally well tolerated. Overall, the higher immune response observed with the HPV-16/18 vaccine was maintained up to Month 48. A head-to-head study incorporating clinical endpoints would be required to confirm whether the observed differences in immune response between the vaccines influence the duration of protection they provided.

Keywords: 50 μg) adsorbed on aluminum salt (500 μg Al(OH)3); ANOVA, analysis of variance; AS04, Adjuvant System containing 3-O-desacyl-4’-monophosphoryl lipid A (MPL; ATP, according-to-protocol; CI, confidence interval; CMI, cell-mediated immune; CVS, cervicovaginal secretion; Cervarix®; ED50, effective dose producing 50% response; ELISA, enzyme-linked immunosorbent assay; GM, geometric mean; GMR, geometric mean (titer) ratio; GMT, geometric mean titer; Gardasil®; HPA, Health Protection Agency; HPV, human papillomavirus; IgG, immunoglobulin G; MSC, medically significant condition; NOAD, new onset autoimmune disease; NOCD, new onset chronic disease; PBMC, peripheral blood mononuclear cells; PBNA, pseudovirion-based neutralization assay; SAE, serious adverse event; TVC, total vaccinated cohort; VLP, virus-like particle; human papillomavirus; immunogenicity; nAb(s), neutralizing antibody(ies); safety.

Figure 1.

Subject disposition ATP, according-to-protocol. The ATP cohort for immunogenicity included all evaluable subjects who received 3 vaccine doses (i.e., those meeting all eligibility criteria and complying with the procedures defined in the protocol) for whom data concerning immunogenicity endpoint measures were available. This included subjects for whom assay results were available for antibodies against at least one study vaccine antigen (HPV-16 or HPV-18) at the time point under analysis.

Figure 2.

GMTs for serum anti-HPV-16 and anti-HPV-18 type-specific neutralizing antibodies at Months 6, 7, 12, 18, 24, 36 and 48 (PBNA, ATP kinetic cohort; seronegative and DNA-negative for the HPV type analyzed prior to vaccination) Black lines, Human Papillomavirus Types 16 and 18 Vaccine (Recombinant, AS04-adjuvanted, adsorbed) (Cervarix®); gray lines, Human Papillomavirus Types 6, 11, 16 and 18 Vaccine, Recombinant (Gardasil®). Error bars denote 95% confidence intervals of geometric mean titers (GMTs). Dashed line, neutralizing antibody GMTs measured by pseudovirion-based neutralization assay (PBNA) in women in the total vaccinated cohort of the HPV-010 study who had cleared natural infection prior to vaccination (i.e., those who were seropositive and DNA-negative at Month 0): 180.1 ED₅₀ for HPV-16 and 137.3 ED₅₀ for HPV-18. Solid line, PBNA limit of detection (40 ED₅₀). ED₅₀, effective dose producing 50% response. The according-to-protocol (ATP) kinetic cohort is a sub-cohort of the ATP cohort for immunogenicity (seronegative and DNA-negative at baseline) that included all subjects without any elimination codes and with valid results available for the HPV type(s) and the assay considered in the analysis for each time point.