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Journal of Virology, May 2007, p. 5257-5269, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.00055-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effect of Plasmid DNA Vaccine Design and In Vivo Electroporation on the Resulting Vaccine-Specific Immune Responses in Rhesus Macaques{triangledown}

Amara Luckay,1 Maninder K. Sidhu,1 Rune Kjeken,2 Shakuntala Megati,1 Siew-Yen Chong,1 Vidia Roopchand,1 Dorys Garcia-Hand,1 Rashed Abdullah,1 Ralph Braun,1 David C. Montefiori,3 Margherita Rosati,4 Barbara K. Felber,5 George N. Pavlakis,4 Iacob Mathiesen,2 Zimra R. Israel,1 John H. Eldridge,1 and Michael A. Egan1*

Wyeth Vaccines Research, Pearl River, New York 10965,1 Inovio AS, Forskningsveien 2a, 0373, Oslo, Norway,2 Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710,3 Human Retrovirus Section,4 Human Retrovirus Pathogenesis Section, National Cancer Institute-Frederick, Frederick, Maryland 21702-12015

Received 9 January 2007/ Accepted 20 February 2007

Since human immunodeficiency virus (HIV)-specific cell-mediated immune (CMI) responses are critical in the early control and resolution of HIV infection and correlate with postchallenge outcomes in rhesus macaque challenge experiments, we sought to identify a plasmid DNA (pDNA) vaccine design capable of eliciting robust and balanced CMI responses to multiple HIV type 1 (HIV-1)-derived antigens for further development. Previously, a number of two-, three-, and four-vector pDNA vaccine designs were identified as capable of eliciting HIV-1 antigen-specific CMI responses in mice (M. A. Egan et al., Vaccine 24:4510-4523, 2006). We then sought to further characterize the relative immunogenicities of these two-, three-, and four-vector pDNA vaccine designs in nonhuman primates and to determine the extent to which in vivo electroporation (EP) could improve the resulting immune responses. The results indicated that a two-vector pDNA vaccine design elicited the most robust and balanced CMI response. In addition, vaccination in combination with in vivo EP led to a more rapid onset and enhanced vaccine-specific immune responses. In macaques immunized in combination with in vivo EP, we observed a 10- to 40-fold increase in HIV-specific enzyme-linked immunospot assay responses compared to those for macaques receiving a 5-fold higher dose of vaccine without in vivo EP. This increase in CMI responses translates to an apparent 50- to 200-fold increase in pDNA vaccine potency. Importantly, in vivo EP enhanced the immune response against the less immunogenic antigens, resulting in a more balanced immune response. In addition, in vivo EP resulted in an approximate 2.5-log10 increase in antibody responses. The results further indicated that in vivo EP was associated with a significant reduction in pDNA persistence and did not result in an increase in pDNA associated with high-molecular-weight DNA relative to macaques receiving the pDNA without EP. Collectively, these results have important implications for the design and development of an efficacious vaccine for the prevention of HIV-1 infection.

* Corresponding author. Mailing address: Vaccine Discovery, Wyeth Vaccines Research, 401 N. Middletown Rd., Bldg. 180/216-10, Pearl River, NY 10965. Phone: (845) 602-3036. Fax: (845) 602-4941. E-mail: eganm{at}wyeth.com

{triangledown} Published ahead of print on 28 February 2007.

Journal of Virology, May 2007, p. 5257-5269, Vol. 81, No. 10
0022-538X/07/$08.00+0     doi:10.1128/JVI.00055-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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