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DNA VACCINES INTRODUCTION DNA vaccine is DNA sequence used as a vaccine. This DNA sequence codes for antigenic protein of pathogen. DNA inserted into cells - translated to form antigenic protein. Since this protein is foreign to cells , so immune response is raised against this protein. In this way ,DNA vaccine provide immunity against that pathogen. HISTORY In 1990, University of Wisconsin, Jon Wolff found that injection of DNA plasmids produce a protein response in mice. In 1993, Merck Research Laboratories, Dr. Margaret Liu found that intramuscular injection of DNA from influenza virus into mice produced complete immune response In 1996, trials involving T-cell lymphoma, influenza & herpes simplex virus were started DNA vaccines Vs Traditional vaccines DNA vaccines Uses only the DNA from infectious organisms. Avoids the risk of using actual infectious organism. Provide both Humoral & Cell mediated immunity Refrigeration is not required Traditional vaccines Uses weakened or killed form of infectious organism. Creates possible risk of the vaccine being fatal. Provide primarily Humoral immunity Usually requires Refrigeration. DNA VACCINE Viral gene Recombinant DNA Technology Plasmid with foreign gene Expression plasmid Transform into bacterial cell Plasmid DNA Bacterial cell Plasmid DNA Purified Ready to use Vaccine Delivery Syringe delivery Gene Gun Gold particles Mechanism BY TWO PATHWAYS ENDOGENOUS Antigenic Protein is presented by cell in which it is produced EXOGENOUS Antigenic Protein is formed in one cell but presented by different cell CD8+ CTL MHCI CD4+ MHCII Th B cell ADVANTAGES Elicit both Humoral & cell mediated immunity Focused on Antigen of interest Long term immunity Refrigeration is not required Stable for storage Plasmid with multiple genes provide immunity against many diseases in one booster DISADVANTAGES Limited to protein immunogen only Extended immunostimulation leads to chronic inflammation Some antigen require processing which sometime does not occur CURRENT CLINICAL TRIALS June 2006,DNA vaccine examined on horse Horse acquired immunity against west nile viruses August 2007,DNA vaccination against multiple Sclerosis was reported as being effective Examples of diseases for which DNA vaccines as a single agent have demonstrated immunogenicity and ⁄ or protection ⁄ therapy in preclinical models Influenza, HIV Rabies Hepatitis B,C Ebola Herpes simplex Papilloma CMV Rotavirus Measles St. Louis encephalitis West Nile virus Bacteria B. Burgdorferi C. Tetani M. Tb. S. Typhi Parasites Malaria Mycoplasma Leishmania Toxo. gondii Taenia ovis Cancer Breast (Her2 ⁄ neu) Colon Prostate Myeloma E7-induced Lymphoma Fibrosarcoma Allergy House dust mite Experimental airway hyperresponsiveness (Asthma) Peanut Autoimmune diseases Diabetes EAE (Multiple sclerosis model) Safety Issues: Genetic Toxicity Integration of DNA vaccine into host Genome Insertional mutagenesis Chromosome instability Turn ON Oncogenes Turn OFF Tumor suppressor genes Generation of Autoimmune diseases Anti DNA Antibodies (DNA, histones, Non histone proteins bound to RNA) Autoimmune diseases Autoimmune Myositis (inflammation of muscles and sometimes skin) Antibiotic Resistance Plasmid used is resistant to antibiotics used for selection Raise the resistance to same antibiotic in the host A number of strategies are under evaluation to improve the immunogenicity of DNA vaccines. The most frequently used approach is to co administer the antigen-expressing plasmid together with a plasmid encoding an immunostimulatory function, for example, the cDNA for a selected cytokine, chemokine, growth factor, or proapoptotic gene. The immunogenicity of DNA vaccines can also be augmented by coadministering plasmids encoding protein-based Toll-like receptor ligands, providing direct adjuvant activity to the site of vaccination. DNA vaccines encoding targeting moieties fused to the antigen of interest represent an additional strategy for enhancing the immune responses of DNA vaccines by targeting the antigen directly to antigen-presenting cells.