A DNA vaccine to prevent transmission of human malaria

描述（由申请人提供）：本申请是根据编号为NOT-OD-058的通知提交的，该通知题为“使RPG能够利用NCRR中心和类似中心的计划”。RO 1AI 0470889的研究重点是开发针对人类疟疾的疫苗。针对疟疾的传播阻断疫苗（TBV）旨在诱导针对感染蚊子的寄生虫阶段的免疫力，从而减少或停止疟疾传播。靶抗原包括在配子母细胞中合成的蛋白质（受精前抗原，在恶性疟原虫中：Pfs 230和Pfs 48/45）和在受精卵-动合子中合成的蛋白质（受精后抗原，在恶性疟原虫中：Pfs 25和Pfs 28），并且由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性构象。在母基金中提出的研究旨在（1）鉴定受精前抗原中的免疫学相关结构域，（2）通过阳离子脂质中的疫苗制剂和通过体内电穿孔的疫苗递送来优化受精前和受精后抗原的组合，（3）在非人灵长类动物中通过体内电穿孔评估候选DNA疫苗（Macaca mulatta），并使用用于恶性疟原虫感染的Aotus模型，测试针对受精前抗原的免疫可以通过在自然感染期间加强来维持的概念。此外，Pfs 25转基因伯氏疟原虫的开发将提供基于Pfs 25的人疟疾TBV的体内评价方法，与标准的体外膜喂养测定相比。由于大多数疫苗在非人灵长类动物中进行免疫原性和功能评价（在生物学可行的情况下），因此现在建议修改母基金的范围，以开发表达Pfs 25的转基因非人疟原虫，这将有助于优化和评价基于Pfs 25的TBV。 公共卫生相关性：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，本申请中提出的研究将导致开发一种非人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.