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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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