Drexel University College of Medicine, in collaboration with University of Pennsylvania School of Medicine, Cheyney University of Pennsylvania, and Inovio Biomedical Corporation, received a grant funded for $2.8 million over four years from the Commonwealth Universal Research Enhancement (CURE) competitive grant program funded through Pennsylvania’s share of the 2009-2010 national tobacco settlement (RFA 08-07-07). The title of the grant is “Development of a DNA Vaccine Strategy for Hepatitis C Virus” (SAP 4100051718). Working with Dr. Jeffrey Jacobson and Dr. Michele Kutzler from the Division of Infectious Diseases & HIV Medicine are Seth Welles, Ph.D., of Drexel University’s School of Public Health, David Weiner, Ph.D. of University of Pennsylvania School of Medicine, Sakkar Eva, Ph.D. and Abdel Bior, Ph.D., of Cheyney University, and Niranjan Y. Sardesai, Ph.D., of Inovio Pharmaceuticals, Inc.
Members of the collaborative group are conducting research to develop effective vaccines that target Hepatitis C Virus (HCV). Persons with chronic HCV infection face an increased risk of developing hepatocellular cancer, a difficult-to-treat cancer with a poor prognosis. Therefore, researchers expect that developing a vaccine to better treat HCV will ultimately lead to a reduction in hepatocellular cancer. Funds will be used to conduct pre-clinical studies to test the safety and immunogenicity of an IL-28 molecular adjuvanted-DNA based vaccine that is designed as both a preventative vaccine in high-risk individuals or as a therapeutic approach to treat persons who are chronically infected with the HCV. In addition, the funding will support basic research that aims to further understand the mechanisms by which long-lasting protective immunity against HCV is acquired, as well as the development of next generation DNA antigenic design (SynCon® technology), use of molecular adjuvants and novel delivery methods (electroporation using CELLECTRA® device) all of which boost immunogenicity and efficacy.
In the past decade and a half, the DNA vaccine concept has been tested and applied against various pathogens and tumor antigens. In theory, this conceptually safe, non-live vaccine approach represents a unique and technically simple means to induce immune responses. Importantly, DNA vaccines drive not only humoral immunity but also the holy grail of live infection, cellular immunity — in particular, the elusive induction of killer cytotoxic T cells (CTL). A novel SynCon® antigenic engineering method was used for the Hepatitis C antigens NS3/4A, NS4B, NS5A and NSB5 to be used in the proposed DNA vaccine strategy. As shown in the figure, the vaccine antigens are delivered to the inoculation site followed by an in vivo electroporation (using CELLECTRA® device) pulse through the skin, subcutaneum into the muscle resulting in the introduction of temporary openings in the cellular membranes at the inoculation site. Using host cellular machinery, the plasmid enters the nucleus of transfected myocytes and resident antigen presenting cells (APCs); here the plasmid components initiate gene transcription, protein production in the cytoplasm, followed by formation of foreign antigens as proteins. The cell provides natural post-translational modifications to the antigen so that native protein conformations are maintained and customize the antigens as well as process them for antigen presentation to the immune system in a similar manner to that induced by live infection. The intracellular expression (a), processing (b), and presentation by host antigen presenting cells (c) of these host-synthesized antigens then lead to the induction of cellular and humoral immune responses (d). These processes coordinately elicit specific immunity against plasmid-encoded HCV antigens by activating both T and B cells which, now “armed”, can traffic through efferent lymphatic system and provide a surveillance system. Together, the two arms of the immune system induced specifically following DNA vaccination can create a powerful defense against HCV infection and subsequent therapy.