Article

Clinical Applications of DNA Vaccines: Current Progress

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Clinical Infectious Diseases (Impact Factor: 9.42). 08/2011; 53(3):296-302. DOI: 10.1093/cid/cir334
Source: PubMed

ABSTRACT It was discovered almost 20 years ago that plasmid DNA, when injected into the skin or muscle of mice, could induce immune responses to encoded antigens. Since that time, there has since been much progress in understanding the basic biology behind this deceptively simple vaccine platform and much technological advancement to enhance immune potency. Among these advancements are improved formulations and improved physical methods of delivery, which increase the uptake of vaccine plasmids by cells; optimization of vaccine vectors and encoded antigens; and the development of novel formulations and adjuvants to augment and direct the host immune response. The ability of the current, or second-generation, DNA vaccines to induce more-potent cellular and humoral responses opens up this platform to be examined in both preventative and therapeutic arenas. This review focuses on these advances and discusses both preventive and immunotherapeutic clinical applications.

Full-text

Available from: Bernadette Ferraro, Jun 05, 2015
0 Followers
 · 
131 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA vaccines are simple to produce and can generate strong cellular and humoral immune response, making them attractive vaccine candidates. However, a major shortcoming of DNA vaccines is their poor immunogenicity when administered intramuscularly. Transcutaneous immunization (TCI) via microneedles is a promising alternative delivery route to enhance the vaccination efficacy. A novel dissolving microneedle array (DMA)-based TCI system loaded with cationic liposomes encapsulated with hepatitis B DNA vaccine and adjuvant CpG ODN was developed and characterized. The pGFP expression in mouse skin using DMA was imaged over time. In vivo immunity tests in mice were performed to observe the capability of DMA to induce immune response after delivery of DNA. The results showed that pGFP could be delivered into skin by DMA and expressed in skin. Further, the amount of expressed GFP was likely to peak at day 4. The immunity tests showed that the DMA-based DNA vaccination could induce effective immune response. CpG ODN significantly improved the immune response. The cationic liposomes could further improve the immunogenicity of DNA vaccine. In conclusion, the novel DMA-based TCI system can effectively deliver hepatitis B DNA vaccine into skin, and induce effective immune response.
    Procedia in Vaccinology 12/2015; 9. DOI:10.1016/j.provac.2015.05.004
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The leishmaniases are a complex of vector-borne diseases caused by protozoan parasites of the genus Leishmania. LEISHDNAVAX is a multi-antigen, T cell epitope enriched DNA vaccine candidate against human leishmaniasis. The vaccine candidate has been proven immunogenic and showed prophylactic efficacy in preclinical studies. Here, we describe the safety testing of LEISHDNAVAX in naïve mice and rats, complemented by demonstration of tolerability in Leishmania infected mice. Biodistribution and persistence were examined following single and repeated intradermal administration to rats. DNA vectors were distributed systemically but did not accumulate upon repeated injections. While vector DNA was cleared from most other tissues within 60 days after the last injection, it persisted in skin at the site of injection and in draining lymph nodes. Evaluation of single-dose and repeated-dose toxicity of the vaccine candidate after intradermal administration to naïve, non-infected mice did not reveal any safety concerns. LEISHDNAVAX was also well tolerated in Leishmania infected mice. Taken together, our results substantiate a favorable safety profile of LEISHDNAVAX in both naïve and infected animals and thus, support the initiation of clinical trials for both preventive and therapeutic applications of the vaccine.Gene Therapy accepted article preview online, 14 April 2015. doi:10.1038/gt.2015.35.
    Gene therapy 04/2015; DOI:10.1038/gt.2015.35 · 4.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Signaling through the Fas/Apo-1/CD95 death receptor is known to affect virus-specific cell-mediated immune (CMI) responses. We tested whether modulating the Fas-apoptotic pathway can enhance immune responses to DNA vaccination or lymphocytic choriomeningitis virus (LCMV) infection. Mice were electroporated with plasmids expressing a variety of pro- or anti-apoptotic molecules related to Fas signaling and then either LCMV-infected or injected with plasmid DNA expressing SIV or HIV antigens. Whereas Fas or FasL knockout mice had improved CMI, down-regulation of Fas or FasL by shRNA or antibody failed to improve CMI and was accompanied by increases in regulatory T cells (Treg). Two "adjuvant" plasmids were discovered that significantly enhanced plasmid immunizations. The adjuvant effects of Fas-associated death domain (FADD) and of cellular FLICE-inhibitory protein (cFLIP) were consistently accompanied by increased effector memory T lymphocytes and increased T cell proliferation. This adjuvant effect was also observed when comparing murine infections with LCMV-Armstrong and its persisting variant LCMV-Clone 13. LCMV-Armstrong was cleared in 100% of mice nine days after infection, while LCMV-Clone 13 persisted in all mice. However, half of the mice pre-electroporated with FADD or cFLIP plasmids were able to clear LCMV-Clone 13 by day nine, and, in the case of cFLIP, increased viral clearance was accompanied by higher CMI. Our studies imply that molecules in the Fas pathway are likely to affect a number of events in addition to the apoptosis of cells involved in immunity.
    Viruses 03/2015; 7(3):1429-53. DOI:10.3390/v7031429 · 3.28 Impact Factor