Impact of P. falciparum diversity on transmission reducing immunity

项目总结 修改后的K23申请是由儿科传染病专家Lauren Cohee医学博士提交的 在马里兰大学医学院疟疾研究部。科希博士的长期目标是 是成为一名独立的调查者，专注于通过设计和开发 评估减少恶性疟传播的干预措施。为了这个目标，她提出了一项职业 开发计划，提供蚊子喂养分析、基因组学和微阵列方面的指导性培训 分析。 减少恶性疟传播的干预措施是实现疟疾目标的关键 根除。一种有希望的方法是开发传播阻断疫苗。这些疫苗的目标是 诱导抗体来限制蚊子中寄生虫的发展并防止传播给下一个人类 主持人。目前的疫苗候选抗原是基于自然获得性免疫反应而确定的 这些抗原导致传播减少。然而，目前尚不清楚是自然获得的还是 疫苗诱导的传播降低免疫反应(TRI)是毒株特有的。品系专一性，含义 基于单一菌株的免疫反应未能提供对其他菌株的保护，导致了有限的 针对寄生虫无性致病阶段的先前疟疾疫苗的效力。了解 自然获得性和疫苗诱导的TRI的菌株特异性对潜在的 传播阻断疫苗的成功以及对TRI流行病学的研究。在一个 在马拉维对疟疾传播动力学进行更大规模的研究后，Cohee博士将评估 自然获得性和疫苗诱导的传播降低了免疫力。具体来说，她将使用蚊子 测定TRI对多种寄生虫菌株的喂养试验，包括常见的实验室菌株和 马拉维现场分离株，使用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(目标1)。然后，她将确定这些抗体的相关性 使用一种新的基于多样性的多肽微阵列进行响应(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发展提供信息，2)识别抗体 可用于大规模研究TRI的发展和流行病学的相关性，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后，Cohee博士将能够很好地申请 为R01评估传播降低免疫力的发展和确定动力学 传播降低免疫力，以应对疟疾控制干预措施。

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.