A DNA vaccine to prevent transmission of human malaria

描述(由申请人提供)：本申请是响应编号为NOT-OD-058的通知提交的，标题为“使RPG能够利用NCRR中心和类似中心的计划”。家长资助RO1AI0470889的研究重点是开发一种针对人类疟疾的疫苗。针对疟疾的传播阻断疫苗(TBV)旨在诱导对感染蚊子的寄生虫阶段的免疫力，从而减少或阻止疟疾的传播。靶抗原包括在配子体(受精前抗原，恶性疟原虫：Pfs230和Pfs48/45)和受精卵-卵子(受精后抗原，恶性疟原虫：Pfs25和Pfs28)中合成的蛋白质，传递阻断抗体识别的表位本质上是富含半胱氨酸的还原敏感构象。父母资助的研究旨在(1)确定受精前抗原中的免疫相关区域，(2)通过阳离子脂类疫苗配方和体内电穿孔疫苗递送来优化受精前后抗原的组合，(3)通过体内电穿孔在非人灵长类动物(猕猴)体内评价候选DNA疫苗，并使用恶性疟原虫感染的Aotus模型测试自然感染期间通过增强对受精前抗原的免疫力这一概念。此外，Pfs25转基因伯氏疟原虫的建立将为基于Pfs25的人疟疾TBV的体内评估提供一种方法，与标准的体外膜喂养试验相比。由于大多数疫苗都要在非人类灵长类动物身上进行免疫原性和功能评估(只要在生物学上可行)，现在建议修改父母拨款的范围，以开发表达Pfs25的转基因非人类疟疾寄生虫，这将促进基于Pfs25的TBV的优化和评估。 与公共卫生相关：疟疾在全世界造成3亿多人感染。我们的长期目标是开发一种疫苗来阻止疟疾的传播。特别是在这项申请中提出的研究将导致开发一种非人类灵长类动物模型来测试这种人类疟疾传播阻断疫苗。

DESCRIPTION (provided by applicant): The current application is submitted in response to the notice number NOT-OD-058 entitled "Enabling RPGs to Leverage NCRR Center and Centers-like Programs". The research focus of the parent grant RO1AI0470889 is to develop a vaccine targeting human malaria. Transmission blocking vaccines (TBVs) against malaria are intended to induce immunity against the stages of the parasite that infect mosquitoes so that malaria transmission is reduced or halted. The target antigens include proteins synthesized in the gametocytes (pre-fertilization antigens, in P. falciparum: Pfs230 and Pfs48/45) and in the zygotes-ookinetes (post-fertilization antigens, in P. falciparum: Pfs25 and Pfs28) and the epitopes recognized by transmission blocking antibodies are cysteine-rich reduction-sensitive conformational in nature. Studies proposed in the parent grant were aimed at (1) identifying immunologically relevant domains in the pre- fertilization antigens, (2) optimizing the combination of pre- and post-fertilization antigens by vaccine formulation in cationic lipids and vaccine delivery by in vivo electroporation, (3) evaluating a candidate DNA vaccine by in vivo electroporation in nonhuman primates (Macaca mulatta) and testing the concept that immunity against pre-fertilization antigens can be maintained by boosting during natural infection using an Aotus model for P. falciparum infection. Moreover, the development of Pfs25 transgenic P. berghei will provide an approach for in vivo evaluation of human malaria TBV based on Pfs25, as compared to a standard in vitro membrane feeding assay. Since most vaccines go through immunogenicity and functional evaluation (wherever biologically feasible) in nonhuman primates, it is now proposed to revise the scope of the parent grant to develop transgenic nonhuman malaria parasite expressing Pfs25 which would then facilitate optimization and evaluation of Pfs25-based TBV. PUBLIC HEALTH RELEVANCE: Malaria causes more than 300 million infections worldwide. Our long term goal is to develop a vaccine to stop transmission of malaria. Research proposed in this application, in particular, will result in the development of a nonhuman primate model to test such human malaria transmission blocking vaccines.