title: A modular approach to assembly of totally synthetic self-adjuvanting lipopeptide-based vaccines allows conformational epitope building.
abstract: The technology described here allows the chemical synthesis of vaccines requiring correctly folded epitopes and that contain difficult or long peptide sequences. The final self-adjuvanting product promotes strong humoral and/or cell-mediated immunity. A module containing common components of the vaccine (T helper cell epitope and the adjuvanting lipid moiety S-[2,3-bis(palmitoyloxy)propyl]cysteine) was assembled to enable a plug and play approach to vaccine assembly. The inclusion within the module of a chemical group with chemical properties complementary and orthogonal to a chemical group present in the target epitope allowed chemoselective ligation of the two vaccine components. The heat-stable enterotoxin of enterotoxigenic Escherichia coli that requires strict conformational integrity for biological activity and the reproductive hormone luteinizing hormone-releasing hormone were used as the target epitopes for the antibody vaccines. An epitope from the acid polymerase of influenza virus was used to assemble a CD8(+) T cell vaccine. Evaluation of each vaccine candidate in animals demonstrated the feasibility of the approach and that the type of immune response required, viz. antibody or cytotoxic T lymphocyte, dictates the nature of the chemical linkage between the module and target epitope. The use of a thioether bond between the module and target epitope had little or no adverse effect on antibody responses, whereas the use of a disulfide bond between the module and target epitope almost completely abrogated the antibody response. In contrast, better cytotoxic T lymphocyte responses were obtained when a disulfide bond was used.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zeng
authors.forename: Kylie J
authors.initials: KJ
authors.lastname: Horrocks
authors.forename: Gorjana
authors.initials: G
authors.lastname: Robevska
authors.forename: Chinn Yi
authors.initials: CY
authors.lastname: Wong
authors.forename: Kristy
authors.initials: K
authors.lastname: Azzopardi
authors.forename: Marija
authors.initials: M
authors.lastname: Tauschek
authors.forename: Roy M
authors.initials: RM
authors.lastname: Robins-Browne
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054307:Enterotoxigenic Escherichia coli / Q000737:chemistry / Q000276:immunology; D004768:Enterotoxins / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000494:pharmacology; D029968:Escherichia coli Proteins; D007987:Gonadotropin-Releasing Hormone / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D055666:Lipopeptides / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009975:Orthomyxoviridae / Q000737:chemistry / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D004768:Enterotoxins; D018984:Epitopes, T-Lymphocyte; D029968:Escherichia coli Proteins; D055666:Lipopeptides; D014614:Vaccines, Synthetic; C034151:heat stable toxin (E coli); D007987:Gonadotropin-Releasing Hormone