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

本申请的总体目标是鉴定和描述抗配子体的新候选抗原 人恶性疟疾传播阻断疫苗（TBV）。疟疾疫苗的开发， 减少寄生虫的传播，从而大大降低人类疟疾（寄生虫）的发病率 人们普遍认为，感染是今后疟疾控制工作取得成功的关键决定因素。 阻断传播的疫苗传统上集中在阻断配子受精和动合子 蚊子的入侵事件。然而，另一个目标存在，即减少配子体 (the疟疾的传播形式）。支持开发抗- 与抗配子TBV相比，配子体TBV来自纵向实地研究， 记录了儿童和成人获得配子体感染红细胞的抗体， 关键是这些抗体与配子体密度降低相关。苔藓感染率 也发现在低配子体密度时减少，这表明疫苗诱导的 人类配子体血症可能通过减少蚊子感染而有助于阻断传播。 在本研究中，我们将应用我们的全蛋白质组差异筛选平台来研究配子体 蛋白质组与已收集的肯尼亚青少年/成人血浆，有和没有抵抗， 外周显微镜下配子体血症（以及第二组肯尼亚儿童，我们将在其中 能够量化亚显微镜下的配子体血症），以鉴定编码蛋白质的寄生虫基因 由对配子体血症具有抗性但不敏感的个体的血浆识别。我们假设 这些抗原的一个子集，引发调节配子体密度的抗体。初步数据显示 我们已经确定了一种独特的配子母细胞抗原， （在高传播季节开始时测量）预测在18- 19岁期间， 在我们的肯尼亚青少年-成年人队列中，传播季节为1周（P = 0.021）（JID，2018）。 为了完成我们的抗配子细胞疫苗抗原发现和验证过程，我们提出以下建议 具体目的：1）使用我们的差异表达技术鉴定另外的新的抗配子体TBV候选抗原。 全配子体蛋白质组筛选平台和相关的抗原特异性IgG应答以抵抗 在两个独立的肯尼亚队列中，我们将验证SA 1中鉴定的抗原， 基于细胞位置、表面表达和引发配子体的能力的合适的TBV候选物 在体外测定中控制免疫应答。 本申请的可交付成果将包括配子体特异性抗原的鉴定， 靶向控制配子体血症的抗体。这些抗原的发现和验证，将代表一个 这是在开发抗配子体TBV的道路上取得的里程碑式成就。

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.