title: Lipid-containing mimetics of natural triggers of innate immunity as CTL-inducing influenza vaccines.
abstract: Anti-viral CD8(+) T cell responses can be induced using synthetic lipopeptides and a range of different lipid moieties have been examined in a variety of model systems and in man for this purpose. Nevertheless, only limited data exist on comparative efficacy of different lipopeptides in a single model of protection so that the optimal composition for vaccination purposes remains unknown. In this study, we examined different lipid structures from bacterial or non-bacterial sources coupled to peptides representing influenza viral epitopes recognized by CD8(+) and CD4(+) T cells. These were assessed in the context of intra-nasal (i.n.) immunization in the absence of added adjuvant. The strongest immunogens were those containing bacterially derived lipids that induced dendritic cell (DC) maturation via Toll-like receptor 2 (TLR2) binding. The number of DCs induced to mature in vitro was directly associated with the strength of the CD8(+) T cell-mediated viral clearing responses in primed mice. Mice immunized with the TLR2-binding lipopeptides showed greatly enhanced numbers of specific IFN-gamma-secreting CD8(+) T cells at the site of infection after i.n. exposure to virus, which resulted in enhanced protection of the pneumonic lung. Importantly, lipopeptide-pulsed DCs were able to induce the appropriate T cells, indicating that the self-adjuvanting effects could occur in the absence of free lipopeptide interacting with additional TLR2-bearing cells in vivo. This study defines a hierarchy of lipopeptide constructs that can program DC to prime memory CD8(+) T cells that on recall function to clear influenza virus from the infected lung.
authors.affiliation: Cooperative Research Centre for Vaccine Technology, Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.
authors.forename: Yuk Fai
authors.initials: YF
authors.lastname: Lau
authors.forename: Georgia
authors.initials: G
authors.lastname: Deliyannis
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zeng
authors.forename: Ashley
authors.initials: A
authors.lastname: Mansell
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
authors.forename: Lorena E
authors.initials: LE
authors.lastname: Brown
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D032701:Biomimetics; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007114:Immunization; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity; D053122:Influenza A Virus, H3N2 Subtype / Q000235:genetics / Q000472:pathogenicity; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008074:Lipoproteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D016865:Reassortant Viruses / Q000235:genetics / Q000472:pathogenicity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D007252:Influenza Vaccines; D008074:Lipoproteins; D010455:Peptides