Recent advances in basic immunology have led to an increased understanding of the factors influencing the host immune response to infectious pathogens. The application of this knowledge to the design of disease specific vaccines holds the promise of significantly impacting on our ability to successfully immunize people against numerous pathogens. T cells occupy a central position in the regulation of the immune response to antigen, influencing antibody production, macrophage and granulocyte function, and natural killer cell activity. In addition, T cells may function directly as effector cells, providing anti microbial activity through the lysis of infected host cells or through the elaboration of cytokines capable of interfering with the propagation of the invading organism. The broad objective of this study is to augment the immune response to specific antigens using strategies aimed at enhancing the T cell response. Studies in vitro indicate that T cell responses vary quantitatively and qualitatively depending on 1) the density of peptide-MHC complexes on the surface of antigen presenting cells, and 2) the nature of co-stimulatory signals delivered to the T cell in conjunction with T cell receptor engagement. We have developed strategies to alter both parameters in vivo in the context of recombinant vaccines. By modifying antigen to contain lysosomal targeting sequences, antigen processing may be altered, leading to increased association with MHC class II for presentation to CD4+T cells. By expressing antigen along with co-stimulatory molecules or cytokines, the nature of the T cell response may be favorably influenced. Using influenza A and human papillomavirus (HPV) as model pathogens, recombinant vaccinia virus constructs will be created enabling these strategies to be tested for disease specific antigens (influenza hemagglutinin and HPV-16 E7), focusing on the nature of the ensuing response and the magnitude of protection generated against an in vivo challenge. These strategies may be directly compared to other routes of antigen delivery and trafficking being investigated in the proposals of Drs. Ahearn and Siliciano.
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