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In a recently developed vaccination strategy, plasmid DNA encoding antigenic proteins is injected directly into the muscle of the recipient. Muscle cells take up the DNA and the encoded protein antigen is expressed, leading to both a humoral antibody response and a cell-mediated response. What is most surprising about this finding is that the injected DNA is taken up and expressed by the muscle cells with much greater efficiency than in tissue culture. The DNA appears either to integrate into the chromosomal DNA or to be maintained for long periods in an episomal form. The viral antigen is expressed not only by the muscle cells but also by dendritic cells in the area that take up the plasmid DNA and express the viral antigen. The fact that muscle cells express low levels of class I MHC molecules and do not express co-stimulatory molecules suggests that local dendritic cells may be crucial to the development of antigenic responses to DNA vaccines (Figure 18-6).

DNA vaccines offer advantages over many of the existing vaccines. For example, the encoded protein is expressed in the host in its natural form—there is no denaturation or modification. The immune response is therefore directed to the antigen exactly as it is expressed by the pathogen. DNA vaccines also induce both humoral and cell-mediated immunity; to stimulate both arms of the immune response with non-DNA vaccines normally requires immunization with a live attenuated preparation, which introduces additional elements of risk. Finally, DNA vaccines cause prolonged expression of the antigen, which generates significant immunological memory.

The practical aspects of DNA vaccines are also very promising (Table 18-5). Refrigeration is not required for the handling and storage of the plasmid DNA, a feature that greatly lowers the cost and complexity of delivery. The same plasmid vector can be custom tailored to make a variety of proteins, so that the same manufacturing techniques can be used for different DNA vaccines, each encoding an antigen from a different pathogen. An improved method for administering these vaccines entails coating microscopic gold beads with the plasmid DNA and then delivering the coated particles through the skin into the underlying muscle with an air gun (called a gene gun). This will allow rapid delivery of a

Gene for antigenic_

protein

Gene for antigenic_

protein

Gene Gun Application

Memory B cell

Memory T cell

FIGURE 18-6

Memory T cell

Memory B cell

FIGURE 18-6

Use of DNA vaccines raises both humoral and cellular immunity. The injected gene is expressed in the injected muscle cell and in nearby APCs. The peptides from the protein encoded by the DNA are expressed on the surface of both cell types after processing as an endogenous antigen by the MHC class I pathway. Cells that present the antigen in the context of class I MHC molecules stimulate development of cytotoxic T cells. The protein encoded by the injected DNA is also expressed as a soluble, secreted protein, which is taken up, processed, and presented in the context of class II MHC molecules. This pathway stimulates B-cell immunity and generates antibodies and B-cell memory against the protein. [Adapted from D. B. Werner and R. C. Kennedy, 1999, Sci. Am. 281:50.]

vaccine to large populations without the requirement for huge supplies of needles and syringes.

Tests of DNA vaccines in animal models have shown that these vaccines are able to induce protective immunity against a number of pathogens, including the influenza virus. It has been further shown that the inclusion of certain DNA sequences in the vector leads to enhanced immune response. At present, there are human trials underway with several different DNA vaccines, including those for malaria, AIDS, influenza, and herpesvirus. Future experimental trials of DNA vaccines will mix genes for antigenic proteins with those for cytokines or chemokines that direct the immune response to the optimum pathway. For example, the IL-12 gene may be included in a DNA vaccine; expression of IL-12 at the site of immunization will stimulate TH1-type immunity induced by the vaccine.

DNA vaccines will likely be used for human immunization within the next few years. However, they are not a universal solution to the problems of vaccination; for example, only protein antigens can be encoded—certain vaccines, such as those for pneumococcal and meningococcal infections, use protective polysaccharide antigens.

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