Priming with plasmid DNAs expressing interleukin-12 and simian immunodeficiency virus gag enhances the immunogenicity and efficacy of an experimental AIDS vaccine based on recombinant vesicular stomatitis virus.
Of the various approaches being developed as prophylactic HIV vaccines, those based on a heterologous plasmid DNA prime, live vector boost vaccination regimen appear especially promising in the nonhuman primate/simian-human immunodeficiency virus (SHIV) challenge model. In this study, we sought to determine whether a series of intramuscular priming immunizations with a plasmid DNA vaccine expressing SIVgag p39, in combination with plasmid expressed rhesus IL-12, could effectively enhance the immunogenicity and postchallenge efficacy of two intranasal doses of recombinant vesicular stomatitis virus (rVSV)-based vectors expressing HIV-1 env 89.6P gp160 and SIVmac239 gag p55 in rhesus macaques. In macaques receiving the combination plasmid DNA prime, rVSV boost vaccination regimen we observed significantly increased SIVgag- specific cell-mediated and humoral immune responses and significantly lower viral loads postintravenous SHIV89.6P challenge relative to macaques receiving only the rVSV vectored immunizations. In addition, the plasmid DNA prime, rVSV boost vaccination regimen also tended to increase the preservation of peripheral blood CD4+ cells and reduce the morbidity and mortality associated with SHIV89.6P infection. An analysis of immune correlates of protection after SHIV89.6P challenge revealed that the prechallenge SHIV-specific IFN-gamma ELISpot response elicited by vaccination and the ability of the host to mount a virus-specific neutralizing antibody response postchallenge correlated with postchallenge clinical outcome. The correlation between vaccine-elicited cell-mediated immune responses and an improved clinical outcome after SHIV challenge provides strong justification for the continued development of a cytokine-enhanced plasmid DNA prime, rVSV vector boost immunization regimen for the prevention of HIV infection.
Egan
Michael A
MA
Wyeth Vaccines Research, Pearl River, New York 10965, USA. eganm@wyeth.com
Chong
Siew Yen
SY
Megati
Shakuntala
S
Montefiori
David C
DC
Rose
Nina F
NF
Boyer
Jean D
JD
Sidhu
Maninder K
MK
Quiroz
Jorge
J
Rosati
Margherita
M
Schadeck
Eva B
EB
Pavlakis
George N
GN
Weiner
David B
DB
Rose
John K
JK
Israel
Zimra R
ZR
Udem
Stephen A
SA
Eldridge
John H
JH
D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D015683:Gene Products, gag / Q000235:genetics*; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000235:genetics*; D008253:Macaca mulatta; D009500:Neutralization Tests; D010957:Plasmids; D011995:Recombination, Genetic; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics*; D019562:Viral Load
D016915:AIDS Vaccines; D017931:DNA Primers; D015683:Gene Products, gag; D018664:Interleukin-12; D004247:DNA