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

描述(申请人提供)：随着国家疟疾控制方案的加强和向消灭目标迈进，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确定可专门针对消除的残余传播焦点。最佳监测系统应持续收集信息，以实现对变化的几乎实时评估，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，以提高方案绩效。虽然目前的工具并不特别适合于此目的，但已提出以抗体流行率为基础的血清学测量作为替代方法。虽然这在稳定、低水平传播的地区效果很好，但评估的疫苗抗原跟踪传播变化的速度非常慢，因此在需要及时和可行信息的快速变化的环境中使用有限。因此，迫切需要确定一种半衰期相对较短(6-8周)、记忆力有限的新型抗原，用于监测活动。这一需求对间日疟原虫尤其迫切，因为特征良好的间日疟原虫候选抗原严重缺乏。这项研究建议鉴定可用作抗原的间日疟原虫蛋白，以筛选短半衰期免疫反应，告知寄生虫感染的近期历史。利用多重珠粒分析，将根据一项具有明确新感染持续时间和治疗后寄生虫清除时间的队列流行病学研究，对由无细胞系统产生的1,000多种间日疟原虫蛋白进行筛选，以对抗在疟疾流行地区临床发作期间和高危人群中以不同时间间隔从间日疟原虫感染者那里收集的人血浆。将通过分析所有时间点的抗体滴度来确定针对100个选定抗原的抗体的完整动力学曲线，以确定抗体的半衰期。将选择动力学特征最好的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)进行进一步验证，以使用疟疾流行和非流行地区学龄儿童的血浆作为监测候选抗原来识别传播热点。这项研究将导致开发一种新的血清学方法来识别间日疟原虫的传播及其在人群和最近感染中检测(残留)传播“热点”的有效性。

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.