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As an alternate method of immunization against influenza virus (e.g., use of a plasmid), DNA vaccines have become promising approaches for the protection of mucosal surfaces. Like recombinant vectors, the transfected DNA results in the presentation of antigenic epitopes in association with the class I MHC. In addition, the significant advantages of using gene transfer technology for mucosal immunization against a pathogen such as the influenza virus are that (1) no infectious agents are being used, (2) combined vaccines are easily and rapidly made, and (3) DNA stability is not affected by high temperatures and therefore is more suitable as a vaccine in less developed countries.

The feasibility of polynucleotide vaccines was first shown in studies in which plasmid DNA was directly injected into the quadriceps of mice. Many recent studies have shown that protection against mucosal pathogens may be achieved by DNA immunization. Most DNA immunization protocols performed so far have used inoculation of the DNA into muscle cells or particle bombardment into dermal or epidermal cells. However, in nature, most foreign antigens are first confronted by the mucosa. Thus, gene administration to the mucosal surfaces would mimic exposure to most pathogens and may more efficiently induce a protective immune response. In this regard, it has been shown in mice that intranasal inoculation of a plasmid expression system for influenza virus hemagglutinin induces resistance to lethal challenge with live influenza viruses.

This technology has more recently been extended to other viruses including antigen components of human immunodeficiency virus, simian immunodeficiency virus, and rabies virus, among others. Thus far, most preclinical results have been promising, and phase I trials with DNA vaccines are now under way.

Recent Advances in Development of Novel Adjuvants

Most vaccine antigens yield only weak immune responses when given by themselves either parenterally or orally. Thus, the generation of an effective immune response usually requires the addition of an adjuvant, which is a substance that enhances the immune response. Adjuvants have been shown to affect virtually every measurable aspect of antibody responses, including the kinetics, duration, quantity, isotype, avidity, and generation of neutralizing or protective antibodies.

Certain adjuvants can enhance T-cell-mediated immunity, including both delayed-type hypersensitivity mediated by CD4+ cells and CTL responses mediated by CD8+ cells. However, fewer adjuvants tend to stimulate cell-mediated immune responses than to stimulate antibody formation.

Although adjuvants have been used empirically for many years, the mechanisms by which they act are not well understood, partly because the adjuvants themselves have been very complex, making such evaluations difficult (Waksman, 1979). The best-understood adjuvants have a multiplicity of effects



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