The saliva of blood-sucking arthropod vectors for disease contains molecules that have either potent pharmacological or immunosuppressive effects. These molecules aid the vector in obtaining a blood meal and these molecules also inadvertently enhance the infectivity of the pathogens that these vectors transmit (arthropods probe in the skin for a blood meal and can deliver pathogens to the skin within their saliva). The saliva of the sand fly (the vector for leishmaniasis) dramatically exacerbates infection with Leishmania in mice and can determine whether Leishmania is able to successfully establish infection in the host. These observations suggested that it may be possible to vaccinate humans against vector-borne diseases by vaccinating against the molecules in vector saliva that allow the pathogen to establish infection in the host. It is now clear maxadilan (MAX) in the saliva of the sand fly Lutzomyia longipalpis has dual functions: it is a potent vasodilator and also a modulator of the immune response. It mediates these effects via interaction with the pituitary adenylate cyclase activating polypeptide (PACAP) receptor and affects various functions of macrophages. MAX substitutes for whole saliva and exacerbates infection with Leishmania to the same extent as whole saliva. We have also produced a protein-based vaccine with MAX and have shown that it can induce profound protection in mice against challenge with Leishmania plus whole saliva. This application will explore the effects of MAX on the immune system, extend and refine our vaccine formulations against MAX and produce improved sand fly-based vaccines that utilize MAX and possibly other salivary targets. In addition, the application will explore the relevance of our findings with MAX in a mouse model to human model systems to determine whether MAX affects human cells as it does mouse cells and to what extent humans mount an immune response to MAX and other salivary molecules. Arthropods transmit some of the most serious diseases in the world (malaria, dengue, Lyme, West Nile, and many many more) and new arthropod-borne diseases emerge frequently. Moreover, because of bioterrorism, we station more and more troops in areas endemic for arthropod-borne diseases. There are currently no effective ways to control these diseases. New and effective methods (especially novel vaccine approaches such as the one described here) are sorely needed.