title: Competition between CTL narrows the immune response induced by prime-boost vaccination protocols.
abstract: Recombinant vaccines encoding strings of virus- or tumor-derived peptides and/or proteins are currently being designed for use against both cancer and infectious diseases. These vaccines aim to induce cytotoxic immune responses against several Ags simultaneously. We developed a novel tetramer-based technique, based on chimeric HLA A2/H-2K(b) H chains, to directly monitor the CTL response to such vaccines in HLA-A2 transgenic mice. We found that priming and boosting with the same polyepitope construct induced immune responses that were dominated by CTL of a single specificity. When a mixture of viruses encoding single proteins was used to boost the polyepitope primed response, CTL of multiple specificities were simultaneously expanded to highly effective levels in vivo. In addition, we show that a preexisting response to one of the epitopes encoded within a polyepitope construct significantly impaired the ability of the vaccine to expand CTL of other specificities. Our findings define a novel vaccination strategy optimized for the induction of an effective polyvalent cytotoxic response.
authors.affiliation: Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palmowski
authors.forename: Ed Man-Lik
authors.initials: EM
authors.lastname: Choi
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hermans
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Gilbert
authors.forename: Ji-Li
authors.initials: JL
authors.lastname: Chen
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: Aline
authors.initials: A
authors.lastname: Van Pel
authors.forename: Stephen
authors.initials: S
authors.lastname: Man
authors.forename: Eivor
authors.initials: E
authors.lastname: Bonin
authors.forename: Peter
authors.initials: P
authors.lastname: Liljestrom
authors.forename: P Rod
authors.initials: PR
authors.lastname: Dunbar
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015789:HLA-A2 Antigen; D064532:Histocompatibility Antigen H-2D; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA