title: Effect of plasmid DNA vaccine design and in vivo electroporation on the resulting vaccine-specific immune responses in rhesus macaques.
abstract: 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-log(10) 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.
authors.affiliation: Wyeth Vaccines Research, 401 N. Middletown Rd., Bldg. 180/216-10, Pearl River, NY 10965, USA.
authors.forename: Amara
authors.initials: A
authors.lastname: Luckay
authors.forename: Maninder K
authors.initials: MK
authors.lastname: Sidhu
authors.forename: Rune
authors.initials: R
authors.lastname: Kjeken
authors.forename: Shakuntala
authors.initials: S
authors.lastname: Megati
authors.forename: Siew-Yen
authors.initials: SY
authors.lastname: Chong
authors.forename: Vidia
authors.initials: V
authors.lastname: Roopchand
authors.forename: Dorys
authors.initials: D
authors.lastname: Garcia-Hand
authors.forename: Rashed
authors.initials: R
authors.lastname: Abdullah
authors.forename: Ralph
authors.initials: R
authors.lastname: Braun
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Margherita
authors.initials: M
authors.lastname: Rosati
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Felber
authors.forename: George N
authors.initials: GN
authors.lastname: Pavlakis
authors.forename: Iacob
authors.initials: I
authors.lastname: Mathiesen
authors.forename: Zimra R
authors.initials: ZR
authors.lastname: Israel
authors.forename: John H
authors.initials: JH
authors.lastname: Eldridge
authors.forename: Michael A
authors.initials: MA
authors.lastname: Egan
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018274:Electroporation; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D015483:HIV Antibodies / Q000097:blood*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D023421:Models, Animal; D009500:Neutralization Tests; D010957:Plasmids; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D019444:Vaccines, DNA; D007371:Interferon-gamma