Visceral leishmaniaisis (VL), caused by Leishmania chagasi in the New World, is a zoonotic disease in which the domestic dog is the principal reservoir host in the peridomestic setting. The sand fly Lutzomyia longipalpis is the principal vector. This proposal is focused on vaccination against canine visceral leishmaniasis with the goal of decreasing the reservoir's infectivity to the sand fly vector, and thus interrupting transmission of this parasite to humans. We hypothesize that even partial protection of dogs will significantly impact the ability of this host to infect the sand fly vector and maintain the transmission of L. chagasi. These proposed studies are an extension of previous work in which we have i) defined the rate of enzootic transmission of L. chagasi within an endemic area, ii) characterized the relationship between the clinical and parasitological status of L. chagasi infected dogs and their infectivity to sand flies, iii) identified a multi-component DNA vaccine that induces a protective immune response in a murine model of VL, and iv) developed canine cytokine DNA constructs for use as vaccine adjuvants. We will determine the optimal route of vaccine delivery of the DNA vaccine and if co-delivery of cytokine DNA can have an adjuvant effect in the canine vaccine model. The protective efficacy of the multi- component vaccine will be tested in parallel by: i) experimental challenge of immunized and control dogs with Lu. longipalpis-derived metacyclic promastigotes, and ii) natural challenge by exposure to naturally infected Lu. longipalpis in an endemic area. The primary efficacy endpoint will be a reduction in the infectivity of the vaccinated dogs to laboratory-reared sand flies. The secondary endpoints for vaccine efficacy will be a reduction in clinical disease and parasite burden in the vaccinated compared to unvaccinated dogs. Successful vaccination of dogs in an endemic could reduce both enzootic (among the canine reservoir) and zoonotic (from the canine reservoir to humans) transmission.
