VACCINATION OF DOGS TO REDUCE TRANSMISSION OF LEISHMANIA

内脏利什曼病(VL)是由查加西利什曼原虫(Leishmania Chagasi)在新大陆引起的一种人畜共患疾病，其主要宿主为家犬。沙蝇Lutzmyia long gipalpis是主要媒介。这项建议的重点是为犬内脏利什曼病接种疫苗，目的是减少水库对沙蝇媒介的传染性，从而阻断这种寄生虫向人类的传播。我们推测，即使对狗的部分保护也会显著影响这种宿主感染沙蝇媒介和维持查加西乳杆菌的传播的能力。这些拟议的研究是我们以前工作的延伸，其中i)定义了查加西钩端螺旋体在流行区内的地方性传播率，ii)表征了查加西钩端螺旋体感染犬的临床和寄生虫学状态与它们对沙蝇的感染性之间的关系，iii)鉴定了一种在VL小鼠模型中诱导保护性免疫反应的多组分DNA疫苗，以及iv)开发了用作疫苗佐剂的犬类细胞因子DNA结构。我们将确定DNA疫苗的最佳接种途径，以及联合传递细胞因子DNA是否能在犬疫苗模型中起到佐剂作用。多组分疫苗的保护效果将通过以下方式进行平行测试：i)对接种了鲁氏杆菌的狗和对照狗进行实验挑战。2)通过暴露于自然感染的Lu而进行的自然攻击。地方病流行地区的长触角线虫。主要的疗效终点将是减少接种疫苗的狗对实验室饲养的沙蝇的传染性。疫苗效力的次要终点将是与未接种疫苗的狗相比，接种疫苗的狗的临床疾病和寄生虫负担减少。在地方性疾病中成功接种疫苗可以减少地方性传播(在犬类宿主中)和人畜共患病(从犬类宿主向人类)传播。

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.