Discovery & validation of novel P. vivax antigens for identification and monitori

描述（由申请人提供）：随着国家疟疾控制计划的加强和向消灭目标迈进，主要重点已从病例管理转移到阻断传播。这将需要有效和准确地查明可专门针对消除的残余传播病灶。最佳监测系统应持续收集信息，以便对变化进行几乎实时的评估，同时可与其他方案信息相结合，以协助规划、实施和修改/调整疟疾控制活动，从而提高方案绩效。鉴于目前的工具不是特别适合于这一目的，血清学测量，抗体流行的基础上，已被提议作为一种替代方法。虽然这在稳定、低水平传播的地区效果很好，但所评价的疫苗抗原跟踪传播变化非常缓慢，因此在需要及时和可采取行动的信息的快速变化的环境中使用有限。因此，迫切需要鉴定一种具有相对短的半衰期（6-8周）和有限记忆的新型抗原，用于监测活动。这种需要对于间日疟原虫是特别迫切的，因为严重缺乏良好表征的间日疟原虫候选抗原。本研究旨在鉴定间日疟原虫蛋白质，这些蛋白质可用作筛选短半衰期免疫应答的抗原，从而为寄生虫感染的近期历史提供信息。在一项队列流行病学研究中，使用多重珠粒分析，将针对在不同时间间隔从疟疾流行区临床发作期间和风险人群中的间日疟原虫感染受试者中收集的人血浆筛选无细胞系统产生的1，000多种间日疟原虫蛋白，该研究具有明确的新发感染和治疗后寄生虫清除持续时间。将通过分析所有时间点的抗体滴度来确定针对100种选定抗原的抗体的完整动力学曲线，以确定抗体半衰期。将选择具有最佳动力学特征的20种抗原（治疗后抗体产生有限，抗体半衰期为6-8周，个体变异有限），作为监测候选抗原进行进一步验证，以确定传播热点，使用来自疟疾流行和非流行地区学龄儿童的血浆。本研究将导致开发一种新的血清学检测方法，以确定间日疟原虫传播及其在人群中检测（残留）传播“热点”和近期感染的实用性。

DESCRIPTION (provided by applicant): As national malaria-control programs are intensifying and moving towards the goal of elimination, the primary focus has shifted from case management to the interruption of transmission. This will require the efficient and accurate identification of residual transmission foci that can be specifically targeted for elimination. Optimal surveillance systems should collect information on an ongoing basis to allow for a virtually real-time assessment of changes, while at the same time can be combined with other programmatic information to assist in planning, implementation, and modification/adjustment of malaria control activities to improve program performance. Whereas the current tools are not particularly suitable for this purpose, serological measurement, based on antibody prevalence, has been proposed as an alternative approach. Although this works well in areas of stable, low-level transmission, the vaccine antigens evaluated track changes in transmission very slowly and are thus of limited use in a rapidly changing environment where timely and actionable information is required. Thus there is an urgent need to identify a novel category of antigens with relatively short half-lives (6-8 weeks), and limited memory, for use in surveillance activitie. This need is particularly urgent for P. vivax, because well- characterized P. vivax candidate antigens are severely lacking. This study proposes to identify P. vivax proteins that can be used as antigens to screen for short half-life immune response, informing the recent history of parasite infection. Using multiplex bead assays, over 1,000 P. vivax proteins, produced by cell-free systems, will be screened against human plasma collected at different time intervals from P. vivax-infected subjects during clinical episodes and populations at risk in malaria endemic areas under a cohort epidemiological study with well-defined duration of new infection and post-treatment parasite clearance. The full kinetics profiles for antibodies to 100 selected antigens will be determined though analyzing the antibody titers at all time-points, to determine antibody half-lives. The 20 antigens with the best kinetic profiles (limited post-treatment antibody production, antibody half-life of 6-8 weeks, limited individual variation) will be selected for furher validation for use as surveillance candidate antigen to identify transmission hot-spots, using plasma from school-aged children in malaria-endemic and non-endemic areas. This study will result in the development of a novel serological assay to identify P. vivax transmission and its utility for detecting (residual) transmission 'hot-spots' among populations, and recent infections.