title: Immunodominance of poxviral-specific CTL in a human trial of recombinant-modified vaccinia Ankara.
abstract: Many recombinant poxviral vaccines are currently in clinical trials for cancer and infectious diseases. However, these agents have failed to generate T cell responses specific for recombinant gene products at levels comparable with T cell responses associated with natural viral infections. The recent identification of vaccinia-encoded CTL epitopes, including a new epitope described in this study, allows the simultaneous comparison of CTL responses specific for poxviral and recombinant epitopes. We performed detailed kinetic analyses of CTL responses in HLA-A*0201 patients receiving repeated injections of recombinant modified vaccinia Ankara encoding a string of melanoma tumor Ag epitopes. The vaccine-driven CTL hierarchy was dominated by modified vaccinia Ankara epitope-specific responses, even in patients who had not received previous smallpox vaccination. The only recombinant epitope that was able to impact on the CTL hierarchy was the melan-A26-35 analog epitope, whereas responses specific for the weaker affinity epitope NY-ESO-1(157-165) failed to be expanded above the level detected in prevaccination samples. Our results demonstrate that immunodominant vaccinia-specific CTL responses limit the effectiveness of poxviruses in recombinant vaccination strategies and that more powerful priming strategies are required to overcome immunodominance of poxvirus-specific T cell responses.
authors.affiliation: Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Smith
authors.forename: Fareed
authors.initials: F
authors.lastname: Mirza
authors.forename: Valerie
authors.initials: V
authors.lastname: Pasquetto
authors.forename: David C
authors.initials: DC
authors.lastname: Tscharke
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palmowski
authors.forename: P Rod
authors.initials: PR
authors.lastname: Dunbar
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D006801:Humans; D016056:Immunodominant Epitopes; D007700:Kinetics; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D011212:Poxviridae / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology* / Q000592:standards / Q000627:therapeutic use; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D014614:Vaccines, Synthetic