title: Hepatitis C VLPs delivered to dendritic cells by a TLR2 targeting lipopeptide results in enhanced antibody and cell-mediated responses.
abstract: Although many studies provide strong evidence supporting the development of HCV virus-like particle (VLP)-based vaccines, the fact that heterologous viral vectors and/or multiple dosing regimes are required to induce protective immunity indicates that it is necessary to improve their immunogenicity. In this study, we have evaluated the use of an anionic self-adjuvanting lipopeptide containing the TLR2 agonist Pam(2)Cys (E(8)Pam(2)Cys) to enhance the immunogenicity of VLPs containing the HCV structural proteins (core, E1 and E2) of genotype 1a. While co-formulation of this lipopeptide with VLPs only resulted in marginal improvements in dendritic cell (DC) uptake, its ability to concomitantly induce DC maturation at very small doses is a feature not observed using VLPs alone or in the presence of an aluminium hydroxide-based adjuvant (Alum). Dramatically improved VLP and E2-specific antibody responses were observed in VLP+E(8)Pam(2)Cys vaccinated mice where up to 3 doses of non-adjuvanted or traditionally alum-adjuvanted VLPs was required to match the antibody titres obtained with a single dose of VLPs formulated with this lipopeptide. This result also correlated with significantly higher numbers of specific antibody secreting cells that was detected in the spleens of VLP+E(8)Pam(2)Cys vaccinated mice and greater ability of sera from these mice to neutralise the binding and uptake of VLPs by Huh7 cells. Moreover, vaccination of HLA-A2 transgenic mice with this formulation also induced better VLP-specific IFN-γ-mediated responses compared to non-adjuvanted VLPs but comparable levels to that achieved when coadministered with complete freund's adjuvant. These results suggest overall that the immunogenicity of HCV VLPs can be significantly improved by the addition of this novel adjuvant by targeting their delivery to DCs and could therefore constitute a viable vaccine strategy for the treatment of HCV.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Brendon Y
authors.initials: BY
authors.lastname: Chua
authors.forename: Douglas
authors.initials: D
authors.lastname: Johnson
authors.forename: Amabel
authors.initials: A
authors.lastname: Tan
authors.forename: Linda
authors.initials: L
authors.lastname: Earnest-Silveira
authors.forename: Toshiki
authors.initials: T
authors.lastname: Sekiya
authors.forename: Ruth
authors.initials: R
authors.lastname: Chin
authors.forename: Joseph
authors.initials: J
authors.lastname: Torresi
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D055666:Lipopeptides / Q000276:immunology*; D051379:Mice; D051195:Toll-Like Receptor 2 / Q000737:chemistry*; D058425:Vaccines, Virus-Like Particle / Q000235:genetics / Q000276:immunology*; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D018937:Hepatitis C Antibodies; D055666:Lipopeptides; D051195:Toll-Like Receptor 2; D058425:Vaccines, Virus-Like Particle