title: Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only.
abstract: An effective virus-like particle (VLP) based prophylactic vaccine designed to protect against persistent infection with human papillomavirus (HPV) types 16 and 18 and subsequent lesion development will need to induce a strong humoral and cellular immune response capable of providing long-term protection. Our objective was to evaluate the ability of an HPV16/18 L1 VLP vaccine formulated with the AS04 adjuvant system (3-O-desacyl-4'-monophosphoryl lipid A (MPL) and aluminium salt) to induce an immune response of higher magnitude and persistence compared to a vaccine formulated with aluminium salt only. We demonstrated that MPL adsorbed onto aluminium salt retains its capacity to activate an innate immune response as assessed by the production of TNFalpha by human monocytes (U937). In addition, vaccination of mice, monkeys or human subjects with AS04 formulations induced higher total anti-L1 VLP16 and L1 VLP18 antibody responses (1.6-8.5-fold) than the aluminium salt only formulations. The enhanced antibody response induced by the AS04 vaccine formulation (1.6-4.1-fold) in monkeys and humans was shown to be targeted to functional neutralising L1 VLP16 and L1 VLP18 epitopes as assessed by V5/J4 specific ELISAs or HPV16 and HPV18 pseudo-neutralization assays. The enhanced immune profile observed with the AS04 formulation in terms of both total, V5/J4 specific and neutralizing antibodies was shown to persist for at least 3.5-year post-vaccination in human subjects. Finally, using the newly developed B cell ELISPOT assay we also demonstrated that the AS04 formulation elicited an increased frequency (2.2-5.2-fold) of HPV L1 VLP specific memory B cells when compared with the aluminium salt only formulations. These data strongly support the role of the AS04 adjuvant, which includes the immunostimulant MPL, in triggering a persistent vaccine-induced immune response of high quality.
authors.affiliation: Research & Development, GlaxoSmithKline Biologicals, Rue de l'Institut 89, 1330 Rixensart, Belgium. sandra.giannini@gskbio.com
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Giannini
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hanon
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Marcelle
authors.initials: M
authors.lastname: Van Mechelen
authors.forename: Sandra
authors.initials: S
authors.lastname: Morel
authors.forename: Francis
authors.initials: F
authors.lastname: Dessy
authors.forename: Marc A
authors.initials: MA
authors.lastname: Fourneau
authors.forename: Brigitte
authors.initials: B
authors.lastname: Colau
authors.forename: Joann
authors.initials: J
authors.lastname: Suzich
authors.forename: Genevieve
authors.initials: G
authors.lastname: Losonksy
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Martin
authors.forename: Gary
authors.initials: G
authors.lastname: Dubin
authors.forename: Martine A
authors.initials: MA
authors.lastname: Wettendorff
mesh_terms: D000276:Adjuvants, Immunologic; D000293:Adolescent; D000328:Adult; D017607:Aluminum Compounds / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology; D009500:Neutralization Tests; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014764:Viral Proteins; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D017607:Aluminum Compounds; D000914:Antibodies, Viral; D036022:Capsid Proteins; D008050:Lipid A; D009856:Oncogene Proteins, Viral; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D014765:Viral Vaccines; C063317:L1 protein, Human papillomavirus type 16; C480565:L1 protein, Human papillomavirus type 18