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DNA VACCINES14

Unlike other vaccines, which deliver the antigen itself in some form, a DNA vaccine delivers only the genes that encode for the antigen of interest. In this sense, it is nonreplicating bacterial plasma in a fairly generic expression vector that is expressed by mammalian (and ultimately primate) muscle tissue. These are not yet clinical entities, since none have been approved as yet for use in humans. However, researchers have had success with bacterial and viral antigens in a number of animal experiments, and work is beginning in England on cancer antigens as well.

Research in this area began with a paper published in 1990, detailing a process for transfecting genes into cells in vitro. When reporter genes were put into expression vectors and injected intramuscularly, the tissue expressed the protein encoded in the gene. It is still not known why muscle tissue expressed protein better that other cell and tissues types. Researchers estimate that no more than 1,000 cells actually take up the DNA and express the protein. This technique did not appear promising for gene therapy, but since there was amplification of the immune system, it might be a good way to generate antigen in situ.

Researchers had been looking for a way to deliver antigens to the cytoplasm of the cell, where their epitopes would evoke class I restricted cytotoxic T-lymphocyte responses. Because every individual’s MHC molecules are different, this would allow different HLA haplotypes to select their own epitopes, instead of concocting a “cocktail” of different types to cover an entire population. Muscle cells aren’t usually thought of as antigen-presenting cells, but the DNA vaccine approach did provide a way to have the antigen produced endogenously by a host cell.

Viral DNA Vaccines. For a protection experiment based on cytotoxic T-cell response, researchers extracted the gene-encoding nucleate protein from influenza virus. This internal protein is highly conserved between different strains of the virus. Mice were immunized with the gene taken from an H1-N1 strain from 1934, and then challenged with a very different H3-NT strain called Compound 68. The results showed that there was a cell-mediated response, and that it was protective. Antibodies were generated as well, but since they were antibodies to an internal protein this response was not protective.

Researchers have since improved on both the vector and the expression of the target protein. In recent tests, 100 percent of immunized animals survive, while 90 percent of controls die. Controls receive either saline immunization or “control DNA” that does not encode for the nucleate protein. Two years after immunization, there is still cytotoxic T-lymphocyte activity that is specific for peptide target cells and influenza-infected cells. Since this is a class I restricted

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Based on a presentation by Margaret Liu, M.D.



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