Vaccines are the most effective means to prevent infectious diseases, especially for viral infection. The key to an excellent antiviral vaccine is the ability to induce long-term protective immunity against a specific virus. Bacterial vaccine vectors have been used to impart protection against self, as well as heterologous antigens. One significant benefit of using live bacterial vaccine vectors is their ability to invade and colonize deep effector lymphoid tissues after mucosal delivery. The bacterium Salmonella is considered the best at this deep colonization. This is critically essential for inducing protective immunity. This chapter describes the methodology for developing genetically modified self-destructing Salmonella (GMS) vaccine delivery systems targeting influenza infection. Specifically, the methods covered include the procedures for the development of GMSs for protective antigen delivery to induce cellular immune responses and DNA vaccine delivery to induce systemic immunity against the influenza virus. These self-destructing GMS could be modified to provide effective biological containment for genetically engineered bacteria used for a diversity of purposes in addition to vaccines.