Abstract
Pulse-induced permeabilization of cellular membranes, generally referred to as electroporation (EP), has been used for years as a tool to increase macromolecule uptake in tissues, including nucleic acids, for gene therapeutic applications, and this technique has been shown to result in improved immunogenicity. In this study, we assessed the utility of EP as a tool to improve the efficacy of HB-110, a novel therapeutic DNA vaccine against chronic hepatitis B, now in phase 1 of clinical study in South Korea. The potency of HB-110 in mice was shown to be improved by EP. The rapid onset of antigen expression and higher magnitude of humoral and cellular responses in electric pulse-treated mice revealed that EP may enable a substantial reduction in the dosage of DNA vaccine required to elicit a response similar in magnitude to that achievable via conventional administration. This study also showed that EP-based vaccination at 4-week-intervals elicited a cellular immune response which was about two-fold higher than the response elicited by conventional vaccination at 2-week intervals. These results may provide a rationale to reduce the clinical dose and increase the interval between the doses in the multidose vaccination schedule. Electric pulsing also elicited a more balanced immune response against four antigens expressed by HB-110: S, preS, Core, and Pol.
Highlights
Remarkable progress has been made in gene transfer technology, which confers upon “genes” the potential to substitute for classic protein vaccines as preventive or therapeutic vaccines
We evaluated the utility of electroporation as a tool to improve the efficacy of HB-110, a novel therapeutic DNA vaccine against chronic hepatitis B, currently in phase 1 of clinical study in South Korea
We observed that electroporation significantly accelerated and enhanced both the gene expression and immune responses of HB-110
Summary
Remarkable progress has been made in gene transfer technology, which confers upon “genes” the potential to substitute for classic protein vaccines as preventive or therapeutic vaccines. An ideal gene delivery system should possess well-characterized pharmaceutical properties; it should provide prolonged expression of transgenes at therapeutic levels, with the ability to be re-dosed; it should not induce auto-antibody responses; and it should be able to be manufactured at a reasonable cost. Plasmid DNA fulfills all of these requirements, but tends to be ineffective as the result of its poor cellular uptake. The application of electrical pulses (electroporation) has been demonstrated to overcome this fatal flaw of plasmid DNA by increasing its cellular permeability, which results in an increase of cellular DNA uptake, high level protein expression, and improved humoral and cellular immune responses (Hurk et al, 2004; Wang et al, 2005; Luzembourg, 2006; Tjelle et al, 2006; Penga et al, 2007). Electroporation (EP) resolves this problem via the introduction of plasmid DNA into the cells to a degree adequate for optimal immune response at
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