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: Caroline L Smith, Fareed Mirza, Valerie Pasquetto, David C Tscharke, Michael J Palmowski, P Rod Dunbar, Alessandro Sette, Adrian L Harris, Vincenzo Cerundolo
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 175 Issue 12 Pg. 8431-7 (Dec 15 2005) ISSN: 0022-1767 [Print] United States
• PMID: 16339586 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-A Antigens
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• Immunodominant Epitopes
• Vaccines, Synthetic

Topics

• HLA-A Antigens
• HLA-A2 Antigen
• Humans
• Immunodominant Epitopes
• Kinetics
• Melanoma (immunology, therapy)
• Poxviridae (immunology)
• T-Cell Antigen Receptor Specificity
• T-Lymphocytes, Cytotoxic (immunology)
• Vaccines, Synthetic (immunology, standards, therapeutic use)
• Vaccinia virus (immunology)