Cationic microparticles are a potent delivery system for a HCV DNA vaccine.
We initially evaluated in mice the ability of naked DNA encoding intracellular forms of the E1E2 envelope proteins from HCV to induce antibody responses and compared the responses induced with the same plasmid adsorbed onto cationic poly (lactide co-glycolide) (PLG) microparticles. Although naked DNA was only able to induce detectable responses at the 100 microg dose level, making this approach impractical for evaluation in larger animals, PLG/DNA induced detectable responses at 10 microg. In addition, the PLG/DNA microparticles induced significantly enhanced responses to naked DNA when compared at the same dose level. Remarkably, PLG/DNA induced comparable responses to recombinant E1E2 protein adjuvanted with the emulsion MF59. Furthermore, PLG/DNA effectively primed for a booster response with protein immunization, while naked DNA did not. Therefore, PLG/DNA was selected for further evaluation in a non-human primate model. In a study in rhesus macaques, PLG/DNA induced seroconversion in 3/3 animals following three immunizations. Although the antibody responses appeared lower than those induced with recombinant protein adjuvanted with MF59, following a fourth dose, PLG/DNA and protein induced comparable responses. However, a single booster dose of recombinant protein administered to the animals previously immunized with PLG/DNA induced much higher responses. In addition, one of three animals immunized with PLG/DNA showed a cytotoxic T lymphocyte response in peripheral blood lymphocytes. In conclusion, cationic PLG microparticles with adsorbed HCV DNA generates potent immune responses.
O'Hagan
Derek T
DT
Vaccines Research, Chiron Corporation, 4560 Horton St., M/S 4.3, Emeryville, CA 94608 USA. derek_ohagan@chiron.com
Singh
Manmohan
M
Dong
Christine
C
Ugozzoli
Mildred
M
Berger
Kim
K
Glazer
Edward
E
Selby
Mark
M
Wininger
Mark
M
Ng
Philip
P
Crawford
Kevin
K
Paliard
Xavier
X
Coates
Steven
S
Houghton
Michael
M
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002412:Cations; D003601:Cytotoxicity Tests, Immunologic; D004279:DNA, Viral; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006526:Hepatitis C / Q000517:prevention & control*; D018937:Hepatitis C Antibodies / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D008253:Macaca mulatta; D051379:Mice; D008863:Microspheres; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry; D011136:Polysorbates / Q000008:administration & dosage / Q000494:pharmacology; D013185:Squalene / Q000008:administration & dosage / Q000494:pharmacology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage* / Q000276:immunology
D000276:Adjuvants, Immunologic; D002412:Cations; D004279:DNA, Viral; D004337:Drug Carriers; C087035:E1 protein, Hepatitis C virus; D018937:Hepatitis C Antibodies; D007074:Immunoglobulin G; C089950:MF59 oil emulsion; D011108:Polymers; D011136:Polysorbates; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D014761:Viral Hepatitis Vaccines; C091015:glycoprotein E2, Hepatitis C virus; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D013185:Squalene