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Journal of Virology, October 2001, p. 9037-9043, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9037-9043.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Induction of Potent Immune Responses by Cationic Microparticles with Adsorbed Human Immunodeficiency Virus DNA Vaccines

Derek O'Hagan,1,* Manmohan Singh,1 Mildred Ugozzoli,1 Carl Wild,2 Susan Barnett,1 Minchao Chen,1 Mary Schaefer,1 Barbara Doe,1 Gillis R. Otten,1 and Jeffrey B. Ulmer1

Vaccines Research, Chiron Corporation, Emeryville, California 94608,1 and Panacos Pharmaceuticals, Gaithersburg, Maryland 208772

Received 24 April 2001/Accepted 29 June 2001

The effectiveness of cationic microparticles with adsorbed DNA at inducing immune responses was investigated in mice, guinea pigs, and rhesus macaques. Plasmid DNA vaccines encoding human immunodeficiency virus (HIV) Gag and Env adsorbed onto the surface of cationic poly(lactide-coglycolide) (PLG) microparticles were shown to be substantially more potent than corresponding naked DNA vaccines. In mice immunized with HIV gag DNA, adsorption onto PLG increased CD8+ T-cell and antibody responses by ~100- and ~1,000-fold, respectively. In guinea pigs immunized with HIV env DNA adsorbed onto PLG, antibody responses showed a more rapid onset and achieved markedly higher enzyme-linked immunosorbent assay and neutralizing titers than in animals immunized with naked DNA. Further enhancement of antibody responses was observed in animals vaccinated with PLG/DNA microparticles formulated with aluminum phosphate. The magnitude of anti-Env antibody responses induced by PLG/DNA particles was equivalent to that induced by recombinant gp120 protein formulated with a strong adjuvant, MF-59. In guinea pigs immunized with a combination vaccine containing HIV env and HIV gag DNA plasmids on PLG microparticles, substantially superior antibody responses were induced against both components, as measured by onset, duration, and titer. Furthermore, PLG formulation overcame an apparent hyporesponsiveness of the env DNA component in the combination vaccine. Finally, preliminary data in rhesus macaques demonstrated a substantial enhancement of immune responses afforded by PLG/DNA. Therefore, formulation of DNA vaccines by adsorption onto PLG microparticles is a powerful means of increasing vaccine potency.

* Corresponding author. Mailing address: Derek O'Hagan, Chiron Corporation, 4560 Horton St., Mail Stop 4.3, Emeryville, CA 94608-2916. Phone: (510) 923-7662. Fax: (510) 658-0329. E-mail: derek_o'hagan{at}chiron.com.

Journal of Virology, October 2001, p. 9037-9043, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9037-9043.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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