Development of a single-shot subunit vaccine for HIV-1. 5. programmable in vivo autoboost and long lasting neutralizing response.
The subunit vaccine for HIV-1, recombinant glycoprotein 120 (rgp120), was used as a model antigen to evaluate the potential for a pulsatile single immunization vaccine formulation consisting of poly(lactic-co-glycolic) acid (PLGA) microspheres. We designed rgp120 PLGA microsphere formulations that provide a pulse of rgp120 at 1 to 6 months (depending on the polymer) after administration, mimicking another immunization. In these studies, the in vitro pulse of rgp120 correlated well with the observed in vivo autoboost as measured by an increase in anti-gp120 antibodies in guinea pigs. The immune response to the rgp120 PLGA microsphere formulations was increased by adding the soluble form of the saponin-derived adjuvant, QS-21. The use of small microspheres, however, did not increase the humoral response to rgp120. A single immunization with rgp120 PLGA microspheres resuspended in soluble rgp120 and QS-21 elicited neutralizing antibody titers that were comparable to titers obtained from two immunizations of rgp120 and QS-21 at the same total dose. Administration of rgp120 PLGA microspheres in baboons resulted in high, long-lasting neutralizing antibody titers that were greater than repeated immunizations with soluble rgp120 and QS-21. These studies also indicated that a continuous release of QS-21 at the injection site may provide a greater immune response than a bolus injection. Overall, this work demonstrated that PLGA microsphere formulations may be designed to provide in vivo pulses of an antigen eliminating the need for repeated immunizations.
Cleland
J L
JL
Department of Pharmaceutical Research and Development, Genentech, Inc., South San Francisco, California 94080, USA. cleland@gene.com
Lim
A
A
Daugherty
A
A
Barron
L
L
Desjardin
N
N
Duenas
E T
ET
Eastman
D J
DJ
Vennari
J C
JC
Wrin
T
T
Berman
P
P
Murthy
K K
KK
Powell
M F
MF
D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D001672:Biocompatible Materials / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004339:Drug Compounding / Q000379:methods; D006168:Guinea Pigs; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000627:therapeutic use; D008863:Microspheres; D009500:Neutralization Tests; D010215:Papio; D011100:Polyglycolic Acid / Q000627:therapeutic use; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000276:immunology; D012503:Saponins / Q000494:pharmacology; D013997:Time Factors
D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D015699:HIV Envelope Protein gp120; D011108:Polymers; D011994:Recombinant Proteins; D012503:Saponins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C078785:saponin QA-21V1