Improvement of DNA Vaccines by Electroporation
DNA vaccines have been on the scientific horizon since 1992, yet the past decade of clinical study has been precarious, with most trials exhibiting excellent safety, yet poor immune responses in humans. Despite the initial disappointments of immunogenicit
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Improvement of DNA Vaccines by Electroporation Arielle A. Ginsberg, Xuefei Shen, Natalie A. Hutnick, and David B. Weiner
DNA vaccines have been on the scientific horizon since 1992, yet the past decade of clinical study has been precarious, with most trials exhibiting excellent safety, yet poor immune responses in humans. Despite the initial disappointments of immunogenicity observed in early clinical trials, the advantageous properties of plasmid DNA as a vaccine strategy over existing technologies continued to drive the field forward. Recently, non- human primate preclinical models as well as data generated in a few clinical trials have suggested that there are significant improvements in immunogenicity by the renewed enhanced DNA platform. This is due to a host of new technological improvements that together have improved vaccine antigen expression, delivery, and formulation resulting in improved immune potency. Improvements in plasmid delivery by modalities including the gene gun, biojector and most recently electroporation (EP) in particular, in combination with other technological developments such as species-specific codon optimization, improved RNA structural design, incorporation of novel leader sequences, novel formulations and adjuvant strategies have had a significant effect on immune outcome in relevant primate models and now humans. This new generation of DNA vaccines will likely have a more prominent role in vaccine clinical research.
Introduction In vivo gene delivery dates back to the discovery of the functions of DNA (Yin et al. 2008). Early experiments documented the ability of cells within a live animal to take up recombinant DNA and express the gene of interest (Neumann et al. 1982; D.B. Weiner (*) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA e-mail: [email protected] J. Thalhamer et al. (eds.), Gene Vaccines, DOI 10.1007/978-3-7091-0439-2_7, © Springer-Verlag/Wien, 2012
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146 Fig. 7.1 Vectors used in gene therapy clinical trials. Clinical trials of plasmid DNA account for approximately 18% of all clinical trials utilizing gene therapy vector delivery technologies. These data support the overall preclinical success, phase I safety, and continued improvement of the platform. Previous to 1998, DNA plasmid vectors constituted an average of only 4% of all gene-therapy platform trials. (This data is adapted from Gene Therapy Trials Worldwide provided by the Journal of Gene Medicine and represents clinical trials from phase I through phase III and is current as of March, 2011.)
A.A. Ginsberg et al.
Adenovirus − 24.1% Retrovirus − 20.8% Naked/Plasmid DNA − 18.7% Vaccinia virus − 8.0% Lipofection − 6.4% Poxvirus − 5.5% Adeno−associated virus − 4.8% Herpes simplex virus − 3.3% Lentivirus − 2.2% Other − 8.4%
Dubensky and Campbell 1984; Benvenisty and Reshef 1986; Okino and Mohri 1987; Wolff et al. 1990). By the fall of 1992, three independent reports presented at the annual Cold Spring Harbor (CSH) vaccine meeting described the u
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