Immunodominance of poxviral-specific CTL in a human trial of recombinant-modified vaccinia Ankara.
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.
Smith
Caroline L
CL
Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom.
Mirza
Fareed
F
Pasquetto
Valerie
V
Tscharke
David C
DC
Palmowski
Michael J
MJ
Dunbar
P Rod
PR
Sette
Alessandro
A
Harris
Adrian L
AL
Cerundolo
Vincenzo
V
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*
D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D014614:Vaccines, Synthetic