Impact of P. falciparum diversity on transmission reducing immunity

项目摘要 这个修改后的K23申请是由医学博士劳伦·柯希提交的，儿科传染病专家 在马里兰州医学院疟疾研究部。柯西博士的长期目标 是成为一个独立的调查员，专注于通过设计和 评估减少恶性疟原虫传播的干预措施。为了实现这个目标，她提出了一个职业生涯 发展计划，提供蚊子喂养分析、基因组学和微阵列方面的指导培训 分析. 减少恶性疟原虫传播的干预措施对实现疟疾目标至关重要 根除一个有希望的方法是开发阻断传播的疫苗。这些疫苗旨在 诱导抗体，限制蚊子体内寄生虫的发育，防止传播给下一个人。 主持人目前的疫苗候选抗原是基于天然获得性免疫应答鉴定的 这些抗原导致传播减少。然而，目前尚不清楚是否是自然获得的， 疫苗诱导的传播减少免疫应答（TRI）是菌株特异性的。菌株特异性，含义 基于单一菌株的免疫应答不能提供对其他菌株的保护， 靶向寄生虫的无性致病阶段的现有疟疾疫苗的效力。了解 天然获得的和疫苗诱导的TRI的菌株特异性对潜在的 传播阻断疫苗的成功以及TRI流行病学研究。的上下文中 在马拉维疟疾传播动力学的更大研究中，Cohee博士将评估 自然获得和疫苗诱导的传播降低免疫力。具体来说，她会用蚊子 喂养试验，以测量针对多种寄生虫菌株的TRI，包括常见的实验室菌株， 马拉维田间分离株，使用来自马拉维研究参与者的血清和单克隆抗体， 传播阻断疫苗候选抗原（Aim 1）。然后她将确定这些抗体的相关性， 反应使用一种新的多样性为基础的肽微阵列（目标2）。从完成任务中获得的知识 这些目标将1）为传播阻断疫苗的合理开发提供信息，2）确定抗体 相关性，可用于大规模研究TRI的发展和流行病学，以促进我们的 了解恶性疟原虫传播的动力学。 在完成这一指导研究和培训期间，博士。 对于R01，评估传播降低免疫力的发展，并确定 传播减少了对疟疾控制干预措施的免疫力。

PROJECT SUMMARY This revised K23 application is submitted by Lauren Cohee, M.D., a pediatric infectious disease specialist in the Division of Malaria Research at the University of Maryland School of Medicine. Dr. Cohee's long-term goal is to become an independent investigator focused on advancing the elimination of malaria by designing and evaluating interventions to decrease P. falciparum transmission. Towards this goal, she proposes a career development plan which provides mentored training in mosquito feeding assays, genomics, and microarray analysis. Interventions to decrease P. falciparum transmission are critical to achieving the goal of malaria eradication. One promising approach is the development of transmission blocking vaccines. These vaccines aim to induce antibodies that limit parasite development in the mosquito and prevent transmission to the next human host. Current vaccine candidate antigens have been identified based on naturally-acquired immune responses to these antigens resulting in decreased transmission. However, it is not known if either naturally-acquired or vaccine-induced transmission reducing immune responses (TRI) are strain-specific. Strain specificity, meaning failure of immune responses based on a single strain to provide protection from other strains, has led to limited efficacy of prior malaria vaccines targeting the asexual disease-causing stage of the parasite. Understanding the strain-specificity of naturally-acquired and vaccine-induced TRI has significant implications for the potential success of transmission blocking vaccines as well as studies of the epidemiology of TRI. In the context of a larger study of the dynamics of malaria transmission in Malawi, Dr. Cohee will evaluate the strain-specificity of naturally-acquired and vaccine-induced transmission reducing immunity. Specifically, she will use mosquito feeding assays to measure TRI against multiple parasite strains, including common laboratory strains and Malawian field isolates, using serum from Malawian study participants and monoclonal antibodies to transmission blocking vaccine candidate antigens (Aim 1). She will then identify antibody correlates of these responses using a novel diversity-based peptide microarray (Aim 2). The knowledge gained from accomplishing these aims will 1) inform the rational development of transmission blocking vaccines and 2) identify antibody correlates that can be used on a large scale to study the development and epidemiology of TRI to advance our understanding of the dynamics of P. falciparum transmission. Upon completion of this mentored research and training period, Dr. Cohee will be well-positioned to apply for an R01 to evaluate the development of transmission reducing immunity and determine the dynamics of transmission reducing immunity in response to malaria control interventions.