The optimized gene sequence of interest is delivered to the skin (intradermally), subcutaneum or to the muscle by one of several delivery methods. Using the host cellular machinery, the plasmid enters the nucleus of transfected local cells (such as myocytes or keratinocytes), including resident antigen presenting cells (APCs). Here, gene expression from plasmid is followed by generation of foreign antigens. Although the elucidation of all immunological components involved following DNA immunization has not been entirely achieved, the mode of action of plasmid DNA vaccines appears twofold. DNA plasmids, which are derived from bacteria, stimulate the innate immune system by interacting Journal of Biomedicine and Biotechnology 3 with Toll-like receptor 9 (TLR9) [24] ), a receptor found on APCs, although the differential expression of TLR9 in mice and primate immune cells makes more complex their role as adjuvants in primates. This nonspecific immune response augments the antigen-specific immune response, where the direct and indirect presentations of antigen to APCs are involved. Two overarching models have been proposed. The antigen encoded by the plasmid is produced in host cells, either in professional APCs leading to direct priming of immune responses or in nonprofessional cells from where the antigen can be transferred to APCs leading to crosspriming.