Efficient protection against diseases caused by infectious agents often requires the action of both humoral and cellular immune mechanisms. Therefore, an ideal antigen delivery system should be capable of stimulating all branches of the immune system, in particular if such a delivery vector is to be used to construct polyvalent vaccines. We and others have made use of avirulent strains of Salmonella typhimurium endowed with the ability to express cloned genes from other pathogens to stimulate immune responses against the recombinant virulence antigens. Following oral inoculation, these organisms are known to invade and proliferate in the gut associated lymphoid tissue (GALT) therefore most researchers have focused on the use of avirulent Salmonella vectors to stimulate mucosal immune responses to heterologous antigens. Even though humoral (in particular mucosal) immune responses are an important part of the protective mechanisms against pathogens, it is clear that for efficient protection, cell mediated immunity is often essential. This is particularly so when the pathogen in question is a virus or an intracellular bacterium. In these cases, Class I restricted immune responses are thought to be crucial for protection. During its entire intracellular life cycle in the host, S. typhimurium remains enclosed in an endocytic vesicle. As a consequence of this characteristic, Class I restricted immune responses against heterologous antigens carried by these organisms are generally poor. It is the objective of our proposed research project to construct novel avirulent strains of S. typhimurium capable of stimulating vigorous Class I restricted immune responses in the vaccinated host by altering their intracellular traffic. The effectiveness of this approach will be assessed by testing the ability of the engineered strains to induce Class I restricted immune responses against peptides derived from the Influenza virus Nucleoprotein. The availability of avirulent S. typhimurium strains better suited to stimulate Class I restricted immune responses will significantly aid the development of polyvalent vaccines against viral as well as a variety of very important bacterial pathogens.
