Validation of a new VL vaccine candidate in dogs that significantly protects mice

描述（由申请方提供）：本研究项目的长期目标是在犬中验证抗内脏利什曼病（VL）的候选疫苗，以便在未来的临床评价中进行评价。我们最近描述了一种强大而可靠的抗原发现策略，以直接识别人体分泌物中的微生物疫苗候选抗原。我们结合RP-HPLC和质谱法，并分类三种不同的婴儿利什曼原虫蛋白质，推测产生于寄生虫感染的器官（肝/脾/骨髓），并在VL患者的尿液中排泄。这些研究的基本假设是在宿主体液中发现的微生物抗原是潜在有效的疫苗 候选分子，因为它们代表了体内大量产生的微生物分子，可以直接与宿主防御相关。编码这些L.已克隆了在患者尿液中发现的婴儿蛋白，并获得了纯化的重组分子。用这些蛋白质与佐剂MPLA-SE混合免疫的小鼠产生了强烈的Th 1应答。重要的是，这些蛋白质中的一种在这些动物中用强毒L.婴儿这些发现的临床转化的下一个务实挑战是扩展这些初步开发研究，并表明这种新型分子在犬中诱导保护性免疫，这是测试人类和犬VL候选疫苗的最终动物模型。 公共卫生相关性：内脏利什曼病（VL）仍然是全球人类和犬发病和死亡的主要传染性原因。这种疾病的发病率仍然很高，而且在世界许多地区还在增加。没有有效的疫苗来预防VL，并且这种疾病的治疗是困难的，并且药物是有毒的。本项目建议在犬疾病模型中验证一种新型且有前途的候选疫苗，用于在未来针对人和犬VL的临床评价中进行评估。

DESCRIPTION (provided by applicant): The long-term goal of this research program is to validate in dogs a candidate vaccine against visceral leishmaniasis (VL) for evaluation in future clinical evaluations. We have recently described a powerful and reliable antigen discovery strategy to directly identify microbial vaccine candidate antigens in human bodily secretions. We combined RP-HPLC and mass spectrometry and categorized three distinct Leishmania infantum proteins presumably produced in parasite infected organs (liver/spleen/bone marrow) and excreted in the urine of patients with VL. The hypothesis underlying these studies was that microbial antigens found in vivo in the bodily fluids of the host are potentially effective vaccine candidate molecules because they represent microbial molecules abundantly produced in vivo that can be directly associated with the host defenses. The genes coding for these L. infantum proteins found in the patients' urine have been cloned, and the purified recombinant molecules have been obtained. Mice immunized with these proteins mixed with the adjuvant MPLA-SE developed robust Th1 response. Importantly one of these proteins induced strong protection in these animals after challenged with virulent L. infantum. The next and pragmatic challenge in the clinical translation of these findings is to expand these initial developmental studies and show that this novel molecule induces protective immunity in dogs, which are the ultimate animal model to test vaccine candidates for both human and canine VL. PUBLIC HEALTH RELEVANCE: Visceral Leishmaniasis (VL) remains a major infectious cause of morbidity and mortality worldwide in both humans and dogs. The incidence of the disease remains high and is increasing in many parts of the world. There is no efficacious vaccine to prevent VL and treatment of this disease is difficult and the drugs are toxic. The present project proposes to validate in the dog model of the disease a novel and promising vaccine candidate for assessment in future clinical evaluations against both human and canine VL.