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Enhanced Potency of Plasmid DNA Microparticle Human Immunodeficiency Virus Vaccines in Rhesus Macaques by Using a Priming-Boosting Regimen with Recombinant Proteins

Gillis R. Otten,^1* Mary Schaefer,¹ Barbara Doe,¹ Hong Liu,¹ Indresh Srivastava,¹ Jan zur Megede,¹ Jina Kazzaz,¹ Ying Lian,¹ Manmohan Singh,¹ Mildred Ugozzoli,¹ David Montefiori,² Mark Lewis,^3, David A. Driver,^1, Thomas Dubensky,^1, John M. Polo,¹ John Donnelly,¹ Derek T. O'Hagan,¹ Susan Barnett,¹ and Jeffrey B. Ulmer¹

Chiron Corporation, Emeryville, California,¹ Duke University Medical Center, Durham, North Carolina,² Southern Research Institute, Frederick, Maryland³

Received 11 November 2004/ Accepted 17 March 2005

DNA vaccines have been used widely in experimental primate models of human immunodeficiency virus (HIV), but their effectiveness has been limited. In this study, we evaluated three technologies for increasing the potency of DNA vaccines in rhesus macaques. These included DNA encoding Sindbis virus RNA replicons (pSINCP), cationic poly(lactide-co-glycolide) (PLG) microparticles for DNA delivery, and recombinant protein boosting. The DNA-based pSINCP replicon vaccines encoding HIV Gag and Env were approximately equal in potency to human cytomegalovirus (CMV) promoter-driven conventional DNA vaccines (pCMV). The PLG microparticle DNA delivery system was particularly effective at enhancing antibody responses induced by both pCMV and pSINCP vaccines and had less effect on T cells. Recombinant Gag and Env protein boosting elicited rapid and strong recall responses, in some cases to levels exceeding those seen after DNA or DNA/PLG priming. Of note, Env protein boosting induced serum-neutralizing antibodies and increased frequencies of gamma interferon-producing CD4 T cells severalfold. Thus, PLG microparticles are an effective means of delivering DNA vaccines in nonhuman primates, as demonstrated for two different types of DNA vaccines encoding two different antigens, and are compatible for use with DNA prime-protein boost regimens.

Present address: BioQual, Rockville, MD 20850.

Present address: BioMedica Inc., San Diego, CA 92121.

Present address: Cerus Corporation, Concord, CA 94520.

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