Collaborative Development of a Vaccine against Cutaneous and Visceral Leishmanias

描述（由申请人提供）：利什曼原虫是原生动物寄生虫，可导致亚热带和热带地区的严重和衰弱性疾病。没有有效的疫苗可用，化疗是有问题的，因为药物毒性，耐药性的发展，获得医疗保健的机会少，费用高。利什曼病疫苗开发面临的挑战包括鉴定针对不同物种和临床形式的利什曼病交叉保护的抗原，以及鉴定诱导免疫保护的疫苗的最佳途径和制剂。该应用程序代表了三个实验室之间的合作努力，致力于抗利什曼病疫苗开发的统一主题。剑桥大学的Jenefer Blackwell博士的实验室已经在小鼠中使用DNA疫苗接种来筛选100个独特的利什曼原虫基因，作为针对高剂量毒性利什曼原虫的候选疫苗。严重感染鉴定了14种新的和可重复的保护性抗原。威尔逊博士在爱荷华州大学的实验室通过免疫血清和T细胞的cDNA文库筛选发现了六种新的抗原。麦克马洪-普拉特博士在耶鲁大学的实验室已经鉴定出四种抗原，并鉴定了它们对L。amazonensis和/或L.婴儿感染这产生了总共24种潜在的保护性新抗原，其可以有助于亚单位疫苗。在将抗原用于犬和/或人体试验之前，仍有几个问题有待解决，并已制定为本项目的三个具体目标：（1）使用符合GMP标准的DNA疫苗，在标准化条件下对来自三个合作实验室的24种候选疫苗进行保护/交叉保护再筛选，并将前6-10种疫苗测试为高达6价的DNA疫苗;（2）使用两种良好表征的抗原（TryP和LACK），以进一步评估在标准化条件下添加佐剂与DNA引发是否改善针对不同物种/临床形式的利什曼病的DNA/MVA引发-加强疫苗接种;（3）选择抗原和递送系统的最佳组合，用于可用于犬、灵长类动物和人临床试验的多价交叉保护性异源初免-加强疫苗。通过三个实验室的协调方法，我们将系统地对几种利什曼原虫进行临床前试验，目标是开发泛利什曼原虫保护性疫苗。

DESCRIPTION (provided by applicant): Leishmania are protozoan parasites that can lead to severe and debilitating disease in sub-tropical and tropical regions. There are no effective vaccines available, and chemotherapy is problematic because of drug toxicity, the development of resistance, poor access to medical care, and expense. Challenges facing Leishmania vaccine development include identification of antigens that cross-protect against the different species and clinical forms of leishmaniasis, and identification of the optimal route and formulation of vaccines to induce immune protection. This application represents a collaborative effort between three laboratories working on the unified theme of vaccine development against leishmaniasis. Dr. Jenefer Blackwell's lab at the University of Cambridge has used DNA vaccination in mice to screen 100 unique Leishmania genes as vaccine candidates against high dose virulent L. major infection. Fourteen novel and reproducibly protective antigens were identified. Dr. Wilson's lab at the University of Iowa has discovered six novel antigens through cDNA library screening with immune serum and T cells. Dr. McMahon-Pratt's lab at Yale University has identified four antigens and characterized them for protection against L. amazonensis and/or L. infantum infection. This yields a total of 24 potentially protective novel antigens that can contribute to a subunit vaccine. Before antigens can be taken forward into canine and/or human trials, several issues remain to be addressed, and have been formulated into the three specific aims of this project: (1) To re-screen the 24 candidate vaccines from the three collaborating laboratories for protection/ cross-protection under standardized conditions using DNA vaccines made to GMP standards, and to test the top 6-10 vaccines as up to 6-valent DNA vaccines; (2) To use two well characterized antigens (TryP and LACK) to further evaluate whether the addition of adjuvants with DNA priming improves DNA/MVA prime-boost vaccination against different species/clinical forms of leishmaniasis under standardized conditions; and (3) To choose the best combination of antigens and delivery system for a multi-valent cross-protective heterologous prime- boost vaccine that can be taken forward into canine, primate and human clinical trials. Through a coordinated approach in the three laboratories, we will systematically perform pre-clinical testing against several Leishmania species, with the goal of developing a pan-leishmania protective vaccine.