Effect of plasmid DNA vaccine design and in vivo electroporation on the resulting vaccine-specific immune responses in rhesus macaques

被引:160
作者
Luckay, Amara
Sidhu, Maninder K.
Kjeken, Rune
Megati, Shakuntala
Chong, Siew-Yen
Roopchand, Vidia
Garcia-Hand, Dorys
Abdullah, Rashed
Braun, Ralph
Montefiori, David C.
Rosati, Margherita
Felber, Barbara K.
Pavlakis, George N.
Mathiesen, Iacob
Israel, Zimra R.
Eldridge, John H.
Egan, Michael A.
机构
[1] Wyeth Vaccines Res, Vaccine Discovery, Pearl River, NY 10965 USA
[2] Inovio AS, N-0373 Oslo, Norway
[3] Duke Univ, Ctr Med, Dept Surg, Durham, NC 27710 USA
[4] Natl Canc Inst Frederick, Human Retrovirus Sect, Ft Detrick, MD 21702 USA
[5] Natl Canc Inst Frederick, Human Retrovirus Pathogenesis Sect, Ft Detrick, MD 21702 USA
关键词
D O I
10.1128/JVI.00055-07
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
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页码:5257 / 5269
页数:13
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