title: Enhanced multiepitope-based vaccines elicit CD8+ cytotoxic T cells against both immunodominant and cryptic epitopes.
abstract: A frequent issue in vaccinology is to elicit balanced T cell responses against both immunodominant and cryptic T cell epitopes, from one or several antigens presented at the same time to the immune system. Using HLA-A2.1.1 restricted epitopes from the Melan A/MART-1 or gp 100 melanoma-associated antigens as a model, we engineered a series of constructs in the ALVAC canarypox vector system: T cell epitopes were expressed either as linear polyepitopes (with or without spacers), or as minigenes encoding a single epitope. The latter were found to allow the best processing and presentation of most T cell epitopes, following infection by ALVAC recombinants of the HLA A2+ bladder carcinoma cell line and stimulation of epitope-specific human TIL lines. These various constructs were also used to immunize HLA-A2.1.1 HHD transgenic mice to compare their capacity to elicit T cells responses. Polyepitopes but also minigenes encoding wild-type epitopes could not elicit in a reliable manner balanced CTL responses against all target epitopes from gp100. We could rescue T cells responses against poorly immunogenic epitopes after introducing appropriate point mutations to enhance their interaction with MHC Class I molecules. Epitope enhancement within either polyepitope, multiepitopes (i.e. minigenes expressed under the control of separate promoters) or full length immunogens should be systematically considered when designing vaccines containing both cryptic and immunodominant target epitopes.
authors.affiliation: Virogenetics Corporation, 465 Jordan Road, Troy, NY 12180, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Tine
authors.forename: Huseyin
authors.initials: H
authors.lastname: Firat
authors.forename: Anne
authors.initials: A
authors.lastname: Payne
authors.forename: Guy
authors.initials: G
authors.lastname: Russo
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Davis
authors.forename: Jim
authors.initials: J
authors.lastname: Tartaglia
authors.forename: François A
authors.initials: FA
authors.lastname: Lemonnier
authors.forename: Pierre Langlade
authors.initials: PL
authors.lastname: Demoyen
authors.forename: Philippe
authors.initials: P
authors.lastname: Moingeon
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D058965:MART-1 Antigen; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D014614:Vaccines, Synthetic