title: Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9-14 years: Results to month 12 from a randomized trial.
abstract: This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9-14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49-1.91] for anti-HPV-16 and 4.52 [3.97-5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54-1.93] for anti-HPV-16 and 3.22 [2.82-3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9-14 years).
authors.affiliation: a Department of Paediatrics ; The Chinese University of Hong Kong ; Shatin , Hong Kong.
authors.forename: Ting Fan
authors.initials: TF
authors.lastname: Leung
authors.forename: Anthony Pak-Yin
authors.initials: AP
authors.lastname: Liu
authors.forename: Fong Seng
authors.initials: FS
authors.lastname: Lim
authors.forename: Franck
authors.initials: F
authors.lastname: Thollot
authors.forename: Helen May Lin
authors.initials: HM
authors.lastname: Oh
authors.forename: Bee Wah
authors.initials: BW
authors.lastname: Lee
authors.forename: Lars
authors.initials: L
authors.lastname: Rombo
authors.forename: Ngiap Chuan
authors.initials: NC
authors.lastname: Tan
authors.forename: Roman
authors.initials: R
authors.lastname: Rouzier
authors.forename: Damien
authors.initials: D
authors.lastname: Friel
authors.forename: Benoit
authors.initials: B
authors.lastname: De Muynck
authors.forename: Stéphanie
authors.initials: S
authors.lastname: De Simoni
authors.forename: Pemmaraju
authors.initials: P
authors.lastname: Suryakiran
authors.forename: Marjan
authors.initials: M
authors.lastname: Hezareh
authors.forename: Nicolas
authors.initials: N
authors.lastname: Folschweiller
authors.forename: Florence
authors.initials: F
authors.lastname: Thomas
authors.forename: Frank
authors.initials: F
authors.lastname: Struyf
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000293:Adolescent; D052685:Alphapapillomavirus / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D002648:Child; D005260:Female; D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007115:Immunization Schedule; D030361:Papillomavirus Infections / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D013997:Time Factors; D064166:Vaccine Potency
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000068857:Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18; D053918:Papillomavirus Vaccines; C510352:human papillomavirus vaccine, L1 type 16, 18
keywords: 2D, 2-dose; 3D, 3-dose; AAHS, aluminum hydroxyphosphate sulfate; ANOVA, analysis of variance; AS04, Adjuvant System containing 50 µg 3-O-desacyl-4 ′-monophosphoryl lipid A (MPL) adsorbed on aluminum salt (500 µg Al3+); ATP-I, according-to-protocol immunogenicity cohort; CI, confidence interval; CMI, cell-mediated immunity; ED50, effective dose producing 50% response; ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunosorbent spot assay; EU, ELISA unit; GMR, geometric mean titer ratio; GMT, geometric mean antibody titer; HPV, human papillomavirus; HPV-16/18(2D), 2-dose schedule of the HPV-16/18 vaccine; HPV-6/11/16/18(2D), 2-dose schedule of the HPV-6/11/16/18 vaccine; HPV-6/11/16/18(3D), 3-dose schedule of the HPV-6/11/16/18 vaccine; IFNγ, interferon; IgG, immunoglobulin G; M, month(s); PBMC, peripheral blood mononuclear cells; PBNA, pseudovirion-based neutralisation assay; SAE, serious adverse event; TVC, total vaccinated cohort; VLP, virus-like particle; administration schedule; female adolescents; human papillomavirus (HPV) vaccines; immunogenicity; pIMD, potential immune-mediated disease; safety; y, year(s)