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

描述（由申请人提供）：随着国家疟疾控制规划不断加强并朝着消除疟疾的目标迈进，主要重点已从病例管理转向阻断传播。这将需要有效和准确地识别残留的传播焦点，可以专门针对消除。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，同时可与其他规划信息相结合，协助规划、实施和修改/调整疟疾控制活动，以改善规划绩效。鉴于目前的工具并不特别适合这一目的，基于抗体流行率的血清学测量已被提议作为一种替代方法。虽然这种方法在稳定的低水平传播地区效果良好，但评估的疫苗抗原追踪传播变化的速度非常缓慢，因此在需要及时和可操作信息的快速变化环境中用途有限。因此，迫切需要鉴定一种半衰期相对较短（6-8周）且记忆有限的新型抗原，用于监测活动。这一需求对间日疟原虫尤其迫切，因为特性明确的间日疟原虫候选抗原严重缺乏。本研究拟鉴定间日疟原虫蛋白，这些蛋白可作为抗原筛选短半衰期免疫反应，为寄生虫感染的近代史提供信息。在一项队列流行病学研究中，使用多重头测定法，将筛选由无细胞系统产生的1000多种间日疟原虫蛋白，这些血浆是在不同时间间隔从间日疟原虫感染受试者和疟疾流行地区高危人群中收集的，该研究具有明确的新感染持续时间和治疗后寄生虫清除时间。通过在所有时间点分析抗体滴度来确定抗体对100种选定抗原的完整动力学谱，以确定抗体的半衰期。将选择20种具有最佳动力学特征（治疗后抗体产生有限，抗体半衰期为6-8周，个体差异有限）的抗原进行进一步验证，使用疟疾流行地区和非流行地区学龄儿童的血浆作为监测候选抗原，以确定传播热点。这项研究将导致开发一种新的血清学检测方法，以确定间日疟原虫的传播，并将其用于检测人群中（残留的）传播“热点”和最近的感染。

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.