Identification & Evaluation of Novel Malaria Anti-Gametocyte Transmission Blocking Vaccine Candidate Antigens

鉴别

• 批准号: 10665613
• 负责人: Christian Parcher Nixon
• 金额: $ 52.44万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-29 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10665613
• 关键词: Achievement; Adolescent; Adult; African; Age; Antibodies; Antigen Targeting; Antigens; Area; Biological Assay; Bite; Cessation of life; Child; Communicable Diseases; Complement; Culicidae; Data; Development; Disease; Electron Microscopy; Enrollment; Erythrocytes; Evaluation; Event; Expression Library; Falciparum Malaria; Fertilization; Future; Genes; Germ Cells; Goals; Grant; Hemoglobin; Human; Immune Sera; Immune response; Immunofluorescence Immunologic; Immunoglobulin G; In Vitro; Incidence; Individual; Infection; Interruption; Intervention; Invaded; Kenya; Legal patent; Libraries; Link; Location; Malaria; Malaria Vaccines; Measures; Mediating; Methods; Microscopic; Modeling; Molecular; Morbidity - disease rate; Parasites; Participant; Peripheral; Phage Display; Phagocytosis; Pharmacotherapy; Phenotype; Plasma; Plasmodium falciparum; Predisposition; Prevalence; Process; Proteins; Proteome; Resistance; Seasons; Surface; Surface Antigens; Time; Vaccine Antigen; Vaccines; Validation; age related; asexual; cDNA Expression; cohort; density; exposed human population; field study; follow-up; in vitro Assay; in vivo; malaria transmission; member; mortality; novel; programs; response; sample fixation; screening; success; transmission blocking; transmission process; transmission-blocking vaccine; vaccine candidate; vector mosquito

The overall goal of this application is to identify and describe novel candidate antigens for an anti-gametocyte transmission blocking vaccine (TBV) for human falciparum malaria. The development of malaria vaccines that reduce transmission of the parasite and thereby substantially reduce the incidence of human malaria (parasite) infection has been widely recognized as a pivotal determinant of the success of future malaria control efforts. Vaccines to interrupt transmission have classically focused on interrupting gamete fertilization and ookinete invasion events in the mosquito vector. However, an alternative target exists, ie, the reduction of gametocytes (the transmissible form of malaria) in the human host. Evidence to support the feasibility of developing an anti- gametocyte as compared to an anti-gamete TBV springs from longitudinal field studies that have documented the acquisition of antibodies to gametocyte-infected erythrocytes in children and adults, and critically these antibodies were correlated with decreased gametocyte densities. Mosquito infection prevalence has also been found to decrease at low gametocyte densities, suggesting that vaccine-induced decreases in human gametocytemia may contribute to transmission blocking efforts by decreasing mosquito infection. In this proposal, we will apply our whole proteome differential screening platform to interrogate the gametocyte proteome with already collected plasma from Kenyan adolescents/adults with and without resistance to peripheral microscopic gametocytemia (as well as from a second cohort of Kenyan children in which we will be able to quantify sub-microscopic gametocytemia) to identify parasite genes that encode proteins uniquely recognized by the plasma of individuals resistant but not susceptible to gametocytemia. We hypothesize that a subset of these antigens, elicit antibodies that regulate gametocyte density. In preliminary data generated for this grant, we have already identified a unique gametocyte antigen, antibodies to which (measured at the start of the high transmission season) predict significantly lower gametocytemia over the 18- week transmission season (P = 0.021) in our Adolescent-Adult Kenyan cohort (JID, 2018). To complete our anti-gametocyte vaccine antigen discovery and validation process, we propose the following specific aims; 1) To identify additional novel anti-gametocyte TBV candidate antigens using our differential whole gametocyte proteome screening platform and relate antigen specific IgG responses to resistance to gametocytemia in two independent Kenyan cohorts, and in 2) we will validate antigens identified in SA1 as suitable TBV candidates based on cellular location, surface expression and ability to elicit gametocyte controlling immune responses in in vitro assays. The deliverables of this application will include the identification of gametocyte specific antigens which are the targets antibodies that control gametocytemia. The discovery and validation of these antigens, will represent a landmark achievement on the path towards the development of an anti-gametocyte TBV.

该应用的总体目的是识别和描述抗gametocyte的新型候选抗原 人性恶性疟疾的传播阻断疫苗（TBV）。疟疾疫苗的开发 减少寄生虫的传播，从而大大减少人类疟疾的发生率（寄生虫） 感染已被广泛认为是未来疟疾控制工作成功的关键决定因素。 中断传播的疫苗通常集中于中断配子的施肥和Ookinete 蚊子载体中的入侵事件。但是，存在一个替代目标，即减少配子细胞 （疟疾的可传染形式）在人类宿主中。证据支持开发反 - 的可行性 与具有纵向野外研究的抗Gamete TBV弹簧相比 记录了对儿童和成人感染的gometocyte感染红细胞的抗体的收购， 至关重要的是，这些抗体与配子细胞密度降低相关。蚊子感染患病率 还发现在低配子细胞密度下降低，表明疫苗诱导的降低 人配子细胞血症可能通过减少蚊子感染而导致传播阻塞的努力。 在此提案中，我们将应用整个蛋白质组差分筛选平台来询问配子细胞 蛋白质组和肯尼亚青少年/成年人已经收集的血浆 外围微观配子细胞血症（以及第二个肯尼亚儿童队列 能够量化亚显微镜的子配子细胞血症），以识别独特地编码蛋白质的寄生虫基因 被耐药性的血浆认可，但不容易受到配子细胞血症的影响。我们假设这一点 这些抗原的子集，会引起调节配子细胞密度的抗体。在初步数据中 为这笔赠款生成，我们已经确定了一种独特的配子细胞抗原，抗体 （在高传输季节开始时测量）预测在18-- 我们的青少年肯尼亚人队列（Jid，2018年）在我们的青少年成年后的周期传输季节（p = 0.021）。 为了完成我们的抗摄影细胞疫苗抗原发现和验证过程，我们提出以下 具体目的； 1）使用我们的差异来识别其他新型的抗激细胞TBV候选抗原 整个配子细胞蛋白质组筛选平台，并将抗原特异性IgG响应与抗性 在两个独立肯尼亚人群中的配子细胞血症，在2）我们将在SA1中验证抗原为 基于蜂窝位置，表面表达和引起配子体的能力，合适的TBV候选者 控制体外测定中的免疫反应。 本应用程序的可交付成果将包括识别gogatocyte特定抗原，这是 靶向控制子宫毒细胞血症的抗体。这些抗原的发现和验证将代表 在开发抗gametocyte TBV的道路上的地标成就。