Development of a lipopeptide-based therapeutic vaccine to treat chronic HBV infection. I. Induction of a primary cytotoxic T lymphocyte response in humans.
Our goal is to use peptide epitopes that are recognized by cytotoxic T lymphocytes (CTL) as immunogens for the development of prophylactic and therapeutic vaccines with chronic hepatitis B virus (HBV) infection being our first therapeutic target. Because most CTL peptide epitopes are poor immunogens, we specifically modified them by covalently attaching two additional components: a T helper peptide epitope and two lipid molecules. Using the murine influenza virus CTL epitope NP 147-155 as a model system, we found this construct to be highly immunogenic, and a single injection resulted in memory CTL induction that persisted for > 1 yr. Based on the animal studies, a vaccine was designed and tested for both safety and its ability to induce a primary CTL response in normal subjects. The three vaccine components included HBV core antigen peptide 18-27 as the CTL epitope, tetanus toxoid peptide 830-843 as the T helper peptide, and two palmitic acid molecules as the lipids. A dose escalation trial (5, 50, and 500 micrograms) carried out in 26 normal subjects showed that the vaccine was safe and able to induce a primary HBV-specific CTL response. A dose-response curve was observed and five out of five subjects responded to the 500-micrograms dose.
Vitiello
A
A
Department of Immunology, Cytel Corporation, San Diego, California 92001.
Ishioka
G
G
Grey
H M
HM
Rose
R
R
Farness
P
P
LaFond
R
R
Yuan
L
L
Chisari
F V
FV
Furze
J
J
Bartholomeuz
R
R
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002908:Chronic Disease; D003602:Cytotoxicity, Immunologic; D015195:Drug Design; D006509:Hepatitis B / Q000628:therapy*; D006512:Hepatitis B Core Antigens / Q000627:therapeutic use; D006801:Humans; D007114:Immunization; D055666:Lipopeptides; D008074:Lipoproteins / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000627:therapeutic use; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000627:therapeutic use
D006512:Hepatitis B Core Antigens; D055666:Lipopeptides; D008074:Lipoproteins; D010169:Palmitic Acids; D010446:Peptide Fragments; D013745:Tetanus Toxoid; C091434:Theradigm-HBV; D019308:Palmitic Acid