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的候选抗原 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，从而大大减少人类疟疾(寄生虫)的发病率 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。 传统上，阻断传播的疫苗主要集中在阻断配子受精和卵母细胞。 蚊子媒介的入侵事件。然而，另一个目标是存在的，即配子细胞的减少 (疟疾的可传播形式)在人类宿主中。支持开发反病毒药物可行性的证据 配子体与反配子TBV相比，来自纵向田间研究的弹簧 记录了儿童和成人对受配子细胞感染的红细胞的抗体的获得，以及 关键的是，这些抗体与配子体密度降低有关。蚊子感染流行情况 也被发现在低配子体密度时减少，这表明疫苗诱导的 人类配子细胞症可能通过减少蚊子感染而有助于阻断传播。 在这个方案中，我们将应用我们的整个蛋白质组差异筛选平台来询问配子体 已采集的肯尼亚青少年/成人血浆的蛋白质组，具有和不具有抗药性 外周微小配子细胞症(以及来自肯尼亚儿童的第二个队列，我们将在其中 能够量化亚显微配子细胞症)以识别唯一编码蛋白质的寄生虫基因 被抗但不易患配子细胞症的个体的血浆所识别。我们假设 这些抗原的一个子集可以激发调节配子体密度的抗体。在初步数据中 我们已经确定了一种独特的配子体抗原，它的抗体 (在高发季节开始时测量)预测配子细胞症在18- 肯尼亚青少年-成人队列中的每周传播季节(P=0.021)(日本国际开发署，2018年)。 为了完成我们的抗配子体疫苗抗原发现和验证过程，我们提出了以下建议 具体目标：1)利用我们的差异鉴定新的抗配子体TBV候选抗原 全配子体蛋白质组筛选平台及其相关抗原特异性免疫球蛋白反应的研究 在两个独立的肯尼亚队列中发现配子细胞症，在2)中，我们将验证SA1中鉴定的抗原是否为 基于细胞位置、表面表达和诱导配子体能力的合适的TBV候选者 控制体外检测中的免疫反应。 这一应用程序的交付内容将包括识别配子体特异性抗原，这些抗原是 以控制配子细胞症的抗体为靶标。这些抗原的发现和验证，将代表着 在开发抗配子体TBV的道路上取得了里程碑式的成就。

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.