Comparison of long-term 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: end-of-study analysis of a Phase III randomized trial

Mark H Einstein, Peter Takacs, Archana Chatterjee, Rhoda S Sperling, Nahida Chakhtoura, Mark M Blatter, Jacob Lalezari, Marie-Pierre David, Lan Lin, Frank Struyf, Gary Dubin, HPV-010 Study Group, Mark H Einstein, Peter Takacs, Archana Chatterjee, Rhoda S Sperling, Nahida Chakhtoura, Mark M Blatter, Jacob Lalezari, Marie-Pierre David, Lan Lin, Frank Struyf, Gary Dubin, HPV-010 Study Group

Abstract

The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immunogenicity and safety of HPV-16/18 and HPV-6/11/16/18 vaccines in healthy women aged 18-45 y was completed. Five y after vaccination, in subjects from the Month 60 according-to-protocol cohort (seronegative and DNA negative for HPV type analyzed at baseline), serum neutralizing antibody (nAb) responses induced by HPV-16/18 vaccine remained 7.8-fold (18-26-y stratum), 5.6-fold (27-35-y stratum) and 2.3-fold (36-45-y stratum) higher than those induced by HPV-6/11/16/18 vaccine for HPV-16. For HPV-18, the fold differences were 12.1, 13.0 and 7.8, respectively. At Month 60, all (100%) subjects in HPV-16/18 vaccine group and the majority (95.7%-97.5%) in HPV-6/11/16/18 vaccine group were seropositive for HPV-16. For HPV-18, the majority (98.1%-100%) of subjects in HPV-16/18 vaccine group were seropositive; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably (61.1%-76.9%) across the 3 age strata. In the total vaccinated cohort (received ≥1 dose regardless of baseline HPV serostatus and DNA status), geometric mean titers for anti-HPV-16 and anti-HPV-18 nAb were higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Based on the 5-y data, piece-wise and modified power-law models predicted a longer durability of nAb response for HPV-16/18 vaccine compared to HPV-6/11/16/18 vaccine. Beyond the differences apparent between the vaccines in terms of immunogenicity and modeled persistence of antibody responses, comparative studies including clinical endpoints would be needed to determine whether differences exist in duration of vaccine-induced protection.

Keywords: 50 μg) adsorbed on aluminum salt (500 μg Al3+); AAHS, amorphous aluminum hydroxyphosphate sulfate; ANOVA, analysis of variance; AS04, Adjuvant System containing 3-O-desacyl-4’-monophosphoryl lipid A (MPL; ATP, according-to-protocol; CI, confidence interval; Cervarix®; ED50, effective dose producing 50% response; ELISA, enzyme-linked immunosorbent assay; GMT, geometric mean titer; Gardasil®; HPV, human papillomavirus; MSC, medically significant condition; NOAD, new onset autoimmune disease; NOCD, new onset chronic disease; PBNA, pseudovirion-based neutralization assay; SAE, serious adverse event; SP, seropositivity; TVC, total vaccinated cohort; antibodies; human papillomavirus; immunogenicity; models; nAb, neutralizing antibodies; neutralizing; safety; statistical.

Figures

Figure 1.
Figure 1.
Subject disposition: CONSORT diagram ATP, according-to-protocol. The Month 60 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.
Figure 2.
GMTs for (A) serum anti-HPV-16 and (B) anti-HPV-18 type-specific neutralizing antibodies at Months 6, 7, 12, 18, 24, 36, 48 and 60 (PBNA, ATP kinetic cohort; seronegative and DNA-negative for the HPV type analyzed prior to vaccination) ATP, according-to-protocol; ED50, effective dose producing 50% response; GMT, geometric mean titers; n, number of subjects with available results; PBNA, pseudovirion-based neutralization assay. Pink narrow dashed line, HPV-16/18 vaccine 18-26 y (HPV-16 n = 27, HPV-18, n = 31); pink wide dashed line with ▪, HPV-16/18 vaccine 27-35 y (HPV-16 n = 36, HPV-18 n = 47); solid pink line with ▴, HPV-16/18 vaccine 36-45 y (HPV-16 n = 37, HPV-18 n = 46); blue narrow dashed line, HPV-6/11/16/18 vaccine 18-26 y (HPV-16 n = 36, HPV-18 n = 46); blue wide dashed line with ▪, HPV-6/11/16/18 vaccine 27-35 y (HPV-16 n = 25, HPV-18 n = 30); solid blue line with ▴, HPV‑6/11/16/18 vaccine 36-45 y (HPV-16 n = 38, HPV-18 n = 43). Error bars denote 95% confidence intervals of GMTs. Dotted line, GMTs for natural infection neutralizing antibody levels as measured by 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-18.2
Figure 3.
Figure 3.
GMTs for (A) serum anti-HPV-16 and (B) anti-HPV-18 type-specific antibodies at Months 6, 7, 12, 18, 24, 36, 48 and 60 (ELISA, ATP kinetic cohort; seronegative and DNA-negative for the HPV type analyzed prior to vaccination) ATP, according-to-protocol; ELISA, enzyme-linked immunosorbent assay; GMT, geometric mean titers; n, number of subjects with available results. Pink narrow dashed line, HPV-16/18 vaccine 18-26 y (HPV-16 n = 24, HPV-18, n = 25); pink wide dashed line with ▪, HPV-16/18 vaccine 27-35 y (HPV-16 n = 23, HPV-18 n = 34); solid pink line with ▴, HPV-16/18 vaccine 36-45 y (HPV-16 n = 25, HPV-18 n = 32); blue narrow dashed line, HPV-6/11/16/18 vaccine 18-26 y (HPV-16 n = 32, HPV-18 n = 36); blue wide dashed line with ▪, HPV-6/11/16/18 vaccine 27-35 y (HPV-16 n = 17, HPV-18 n = 23); solid blue line with ▴, HPV‑6/11/16/18 vaccine 36-45 y (HPV-16 n = 25, HPV-18 n = 36). Error bars denote 95% confidence intervals of GMTs. Dotted line, GMTs for natural infection antibody levels (measured by ELISA) in the HPV-008 study: 29.8 ELISA units/mL for HPV-16 and 22.6 ELISA units/mL for HPV-18.9
Figure 4.
Figure 4.
Serum anti-HPV-16 and anti-HPV-18 type-specific neutralizing antibody responses (by PBNA analysis) over 20 y predicted by the (A) piece-wise linear model and (B) modified power-law model (total vaccinated cohort, 3 doses) ED50, effective dose producing 50% response; GMT, geometric mean titer; PBNA, pseudovirion-based neutralization assay. Pink narrow dashed line, HPV-16/18 vaccine 18-26 y; pink wide dashed line, HPV-16/18 vaccine 27-35 y; solid pink line, HPV-16/18 vaccine 36-45 y; blue narrow dashed line, HPV-6/11/16/18 vaccine 18-26 y; blue wide dashed line, HPV-6/11/16/18 vaccine 27-35 y; solid blue line, HPV‑6/11/16/18 vaccine 36-45 y; dotted line, neutralizing antibody GMTs measured by 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-18.2 *Predicted GMTs were calculated for 20 y after the first vaccine dose.
Figure 5.
Figure 5.
Serum anti-HPV-16 and anti-HPV-18 type-specific antibody responses (by ELISA analysis) over 20 y predicted by the (A) piece-wise linear model and (B) modified power-law model (total vaccinated cohort, 3 doses) ELISA, enzyme-linked immunosorbent assay; GMT, geometric mean titer. Pink narrow dashed line, HPV-16/18 vaccine 18-26 y; pink wide dashed line, HPV-16/18 vaccine 27-35 y; solid pink line, HPV-16/18 vaccine 36-45 y; blue narrow dashed line, HPV-6/11/16/18 vaccine 18-26 y; blue wide dashed line, HPV-6/11/16/18 vaccine 27-35 y; solid blue line, HPV‑6/11/16/18 vaccine 36-45 y; dotted line, GMTs for natural infection antibody levels (measured by ELISA) in the HPV-008 study: 29.8 ELISA units/mL for HPV-16 and 22.6 ELISA units/mL for HPV-189. *Predicted GMTs were calculated for 20 y after the first vaccine dose.

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Source: PubMed

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