Rational design of a plasmid DNA vaccine capable of eliciting cell-mediated immune responses to multiple HIV antigens in mice.
Given the importance of the HIV-specific cell-mediated immune response in the early control and resolution of HIV infection and the observed correlation between pre-challenge vaccine elicited CTL responses and post challenge outcome in SHIV/rhesus macaque experiments, we sought to identify several candidate plasmid DNA (pDNA) vaccine designs capable of eliciting robust and balanced cell-mediated immune responses to multiple HIV-1 derived antigens in mice for further vaccine development. To rationally construct candidate vaccines for immunogenicity testing, we determined the relative immunogenicity of the individual HIV-derived vaccine antigens (env, gag, pol, nef, tat and vif) and the relative strength of various transcriptional control elements (HCMV, SCMV, HSV Lap1) in Balb/c mice. Next, a number of 1-, 2-, 3- and 4-vector pDNA vaccine designs were tested for their ability to elicit HIV-1 antigen-specific CMI responses. For these studies, Balb/c mice were immunized with a fixed total pDNA vaccine dose of 100 mcg in combination with 25 mcg plasmid-based murine IL-12 and tested for the induction of HIV-1 antigen-specific CMI responses by IFN-gamma ELISpot analysis. The results of this study indicate that all pDNA vaccine designs were capable of eliciting CMI responses to multiple HIV-1 antigens. As a result of this iterative comparative analysis, we have identified a number of pDNA vaccine candidates capable of eliciting potent, balanced CMI responses to multiple HIV-1 derived antigens. These results have important implications for the design and development of an efficacious vaccine for the prevention of HIV-1 infection.
Egan
Michael A
MA
Vaccine Discovery, Wyeth Vaccines Research, 401 N. Middletown Rd, Bldg. 180/216-10, Pearl River, NY 10965, USA.
Megati
Shakuntala
S
Roopchand
Vidia
V
Garcia-Hand
Dorys
D
Luckay
Amara
A
Chong
Siew-Yen
SY
Rosati
Margherita
M
Sackitey
Solomon
S
Weiner
David B
DB
Felber
Barbara K
BK
Pavlakis
George N
GN
Israel
Zimra R
ZR
Eldridge
John H
JH
Sidhu
Maninder K
MK
D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D015488:HIV Antigens / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular; D051379:Mice; D010957:Plasmids; D011401:Promoter Regions, Genetic; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
D015488:HIV Antigens; D019444:Vaccines, DNA