The hepatitis B virus-specific CTL responses induced in humans by lipopeptide vaccination are comparable to those elicited by acute viral infection.
We have previously described the development of a lipopeptide-based vaccine, Theradigm-HBV, capable of inducing CTL responses in humans. This vaccine incorporates the HLA-A2.1-restricted CTL epitope hepatitis B core Ag 18-27, linked to the universal helper T lymphocyte (HTL) epitope tetanus toxoid (TT) 830-843. Herein, we report the results of a phase I trial designed to examine the effects of Theradigm-HBV dose and regimen on the magnitude and duration of the memory CTL response. A total of four injections of up to 5 mg/dose were found to be a safe and effective means of generating substantial memory CTL responses. Precursor frequency analysis demonstrated CTL responses of similar magnitude to those previously observed in patients who successfully cleared hepatitis B virus infection and to influenza-specific memory CTL responses induced by natural exposure to influenza virus. Theradigm-HBV induced CTL responses that persisted for more than 9 months after the last injection. HTL responses were associated with significant CTL responses, and sustained HTL activity was necessary for development of persistent memory CTL activity. These results represent the first demonstration of the importance of HTL activity for development of long-lived memory CTL responses in humans. In conclusion, our results show that lipopeptides safely induce specific CTL activity in humans of such magnitude and persistence as to be of potential therapeutic significance.
Livingston
B D
BD
Cytel Corp., San Diego, CA 92121, USA. brian_livingston@cytelcorp.com
Crimi
C
C
Grey
H
H
Ishioka
G
G
Chisari
F V
FV
Fikes
J
J
Grey
H
H
Chesnut
R W
RW
Sette
A
A
D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006509:Hepatitis B / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology; D055666:Lipopeptides; D008074:Lipoproteins / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D013234:Stem Cells / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology*
D000939:Epitopes; D015789:HLA-A2 Antigen; D017325:Hepatitis B Vaccines; D055666:Lipopeptides; D008074:Lipoproteins; D010446:Peptide Fragments; C091434:Theradigm-HBV; D014614:Vaccines, Synthetic