In the early 1990s, vaccine researchers were surprised to discover that simply injecting DNA sequences encoding protein antigens could induce substantial immune responses in mice. For a time there was a great deal of excitement about the potential of these "naked DNA" vaccines, particularly because they are extremely cheap and easy to produce. However, as studies escalated into larger animals and humans, it quickly became apparent that the immunogenicity of the vaccines declined dramatically in these settings. Several candidates abjectly failed to induce detectable immune reponses in humans. Nevertheless, researchers have continued to work on improving DNA vaccine immunogenicity and recent phase I trial results from NIH's Vaccine Research Center suggest that HIV DNA vaccines delivered by a needle-free device called a Biojector can be a viable component of a prime-boost vaccine regimen. In parallel, researchers at Wyeth Vaccines have also been exploring ways to soup up their DNA vaccine candidates. Inclusion of "molecular adjuvants" (such as genes encoding potentially immune-boosting cytokines like IL-12 and IL-15) is one strategy Wyeth has explored, with some incremental improvements seen when IL-12 DNA is delivered along with an HIV DNA vaccine.
Now, in J. Virology, Wyeth researchers report far more dramatic results obtained using a technique called electroporation. This technique involves delivering a short burst of electrical stimulation to the area where the DNA vaccine is injected using a special wand. The electricity opens transient pores in local cell membranes, allowing the DNA vaccine easier access to the nucleus where it can then produce vaccine-encoded antigens. Furthermore, electroporation also attracts inflammatory cells - including antigen-presenting dendritic cells - to the site of immunization. The new study reports that electroporation massively enhanced the T cell response to an SIV DNA vaccine in macaques. Specifically, although animals receiving electroporation were given 1/5 the DNA vaccine dose, SIV-specific T cell responses were 10-40 fold higher than those seen in macaques immunized with DNA vaccines alone. The study authors note that while electroporation seemed safe in macaques, the question of safety and tolerability in humans will need to be comprehensively addressed in phase I trials. The manufacturers of the technology used in this study, Inovio, issued an accompanying press release which states that they are also collaborating with other partners and several human trials of DNA vaccines and immunotherapies combined with their electroporation device are ongoing. Results from these trials should reveal whether electroporation can safely give DNA vaccines the zap they need.
JVI Accepts, published online ahead of print on 28 February 2007
J. Virol. doi:10.1128/JVI.00055-07
Amara Luckay, Maninder K. Sidhu, Rune Kjeken, Shakuntala Megati, Siew-Yen Chong, Vidia Roopchand, Dorys Garcia-Hand, Rashed Abdullah, Ralph Braun, David C. Montefiori, Margherita Rosati, Barbara K. Felber, George N. Pavlakis, Iacob Mathiesen, Zimra R. Israel, John H. Eldridge, and Michael A. Egan*
Wyeth Vaccines Research, Pearl River, New York 10965; Inovio AS, Forskningsveien 2a, 0373, Oslo, Norway, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA, Human Retrovirus Section, Basic Research Laboratory, National Cancer Institute-Frederick, Frederick, Maryland 21702-1201
Abstract
Since HIV-specific cell-mediated immune (CMI) response are critical in the early control and resolution of HIV infection and correlate with post challenge outcome 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-1 derived antigens for further development. Previously a number of 2-, 3- and 4-vector pDNA vaccine designs were identified as capable of eliciting HIV-1 antigen-specific CMI responses in mice (Egan MA et al, Vaccine 24:4510, 2006). We then sought to further characterize the relative immunogenicity of these 2-, 3- and 4-vector pDNA vaccine designs in non-human primates and to determine the extent to which in vivo electroporation (EP) could improve the resulting immune responses. The results indicate that a 2-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 10-40-fold increase in HIV-specific ELISpot responses compared to macaques receiving a 5-fold higher dose of vaccine without in vivo EP. This increase in CMI responses translates to an apparent 50-200-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 indicate 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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