Genetic diversity and protective immunity to malaria infection and disease

描述（由申请人提供）：恶性疟原虫的极端遗传多样性有助于疟疾寄生虫逃避宿主免疫并阻碍疟疾疫苗的开发。人们认为，疟疾的自然获得性免疫是对一系列抗原的保护性免疫反应的积累，重要的是对这些抗原的不同变体的保护性免疫反应。但是，我们在很大程度上仍然不知道哪些抗原、多少抗原以及这些抗原的哪些变体必须被哪些免疫反应识别才能提供自然或疫苗诱导的保护。这个项目主要集中在提高这种理解上。基于之前在西非马里农村开展的临床转化研究的结果，我们建议进一步阐明自然获得的和疫苗诱导的免疫反应的机制，这些免疫反应可以防止疟疾感染和疾病，并利用这些知识为开发具有广泛保护作用的疟疾疫苗提供信息。我们将利用最新的技术进步，在全基因组水平上解决以前只能一次接近一个或几个基因的问题，开发新的工具来评估针对变异抗原和表位的免疫反应。在一项针对面临疟疾感染和疾病风险的儿童的前瞻性队列研究以及疟疾疫苗的单独临床试验中，将确定自然和疫苗诱导的恶性疟原虫感染和疾病保护性免疫的分子和免疫学相关性。预计这项研究将提供信息，阐明自然获得的疟疾免疫机制，改进下一代疟疾疫苗，并增加非洲消除疟疾的前景。

DESCRIPTION (provided by applicant): Extreme genetic diversity in Plasmodium falciparum helps malaria parasites evade host immunity and impedes malaria vaccine development. Naturally acquired immunity to malaria is thought to represent the accumulation of protective immune responses to a repertoire of antigens and, importantly, to different variants of these antigens. But we remain largely ignorant of precisely which antigens and how many and which variants of these antigens must be recognized by which sorts of immune responses to afford natural or vaccine-induced protection. This project is largely focused on improving this understanding. Building on results of previous clinical translational research conducted in rural Mali, West Africa, we propose to further elucidate the mechanisms underlying both naturally acquired and vaccine-induced immune responses that protect against malaria infection and disease, and to use this knowledge to inform the development of broadly protective malaria vaccines. We will exploit recent technological advances to address at the genome-wide level questions that could previously be approached only one or a few genes at a time, developing new tools to assess immune responses against variant antigens and epitopes. In a prospective cohort study of children at risk for malaria infection and disease and in separate clinical trials of malaria vaccines, molecular and immunological correlates of natural and vaccine-induced protective immunity to P. falciparum infections and disease will be identified. This research is expected to provide information that will elucidate mechanisms underlying naturally acquired malaria immunity, improve the next generation of malaria vaccines and increase prospects for malaria elimination in Africa. RELEVANCE (See Instructions): Malaria parasites have evolved the ability to escape protective immune responses by varying the proteins that the immune system recognizes. This genetic diversity also makes it harder to develop a successful malaria vaccine. This project will study how changes in malaria genes and proteins relate to the risk of clinical malaria illness and to the ability of vaccines to prevent malaria. Study results are expected to provide information that will guide the development of effective malaria vaccines.