Optimization of epitope processing enhances immunogenicity of multiepitope DNA vaccines.
Experimental DNA vaccines comprised of multiple minimal cytotoxic T lymphocytes (CTL) epitopes can effectively induce broad CTL responses; however, such constructs frequently exhibit significant variation in epitope immunogenicity. Antigenicity assays utilizing human cells transfected with one such multiepitope construct revealed that the epitopes with poor immunogenicity were inefficiently processed in transfected cells. Compilation of a database of 94 epitope/flanking region combinations, for which immunogenicity was measured experimentally, revealed that the type of residue immediately following the carboxyl-terminus of the epitope exerted a prominent effect on immunogenicity. Experiments utilizing a variety of HBV-specific vaccine constructs demonstrated epitope immunogenicity could be modulated by the insertion of a single amino acid and the effect on immunogenicity could be ascribed to modulation of processing efficiency. These findings demonstrate that multiepitope DNA vaccines can be engineered to enhance CTL immunogenicity by increasing processing efficiency.
Livingston
B D
BD
Epimmune Inc., 5820 Nancy Ridge Drive Suite 100, San Diego, CA 92121, USA. blivingston@epimmune.com
Newman
M
M
Crimi
C
C
McKinney
D
D
Chesnut
R
R
Sette
A
A
D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017951:Antigen Presentation; D002851:Chromatography, High Pressure Liquid; D016208:Databases, Factual; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006183:H-2 Antigens / Q000737:chemistry / Q000235:genetics; D006678:HIV / Q000235:genetics / Q000276:immunology*; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019169:Jurkat Cells / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D019444:Vaccines, DNA / Q000276:immunology*
D016915:AIDS Vaccines; D000939:Epitopes; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015488:HIV Antigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009838:Oligodeoxyribonucleotides; D010455:Peptides; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D007371:Interferon-gamma