Immune signatures of protection induced by whole parasite malaria vaccines

最近，越来越多地使用经杀虫剂处理的蚊帐，使少数几个流行国家的发病率和死亡率有所下降。我们正处于一个临界点，迫切需要一种有效的疟疾疫苗，以实现全球消灭疟疾，防止疟疾卷土重来。针对疟疾的无菌免疫只能通过用减毒活寄生虫进行免疫来产生。在减毒子孢子免疫的人类中，寄生虫发育在无症状肝脏阶段停止，并且临床疟疾不发生。鉴定出与子孢子和肝寄生虫的保护作用相关的预测因子将大大加速有效的重组疟疾疫苗的开发和测试。一种在肝脏中停止的基因减毒恶性疟原虫（PfGAP）疫苗的临床试验即将进行。 保护性免疫也可以通过暴露于受感染蚊子的叮咬结合抗血液期寄生虫药物氯喹（CQ）或抗肝脏期寄生虫药物伯氨喹（PQ）治疗来实现。2010年将进行一项感染治疗疫苗接种（ITV）试验，以比较ITV-PQ和ITV-CQ诱导的保护作用。我们建议在这个项目中，分析血浆和PBMC样品免疫与基因或化学减毒寄生虫疫苗的志愿者。我们将采用系统方法（多参数Flow分析、血浆蛋白谱和恶性疟原虫抗原阵列分析）来描绘通过三种疫苗接种策略产生保护性免疫应答的复杂调控网络，以鉴定1）预测初次免疫后获得保护性免疫，2）区分保护性和非保护性免疫，（3）预测保护期。我们预期PfGAP、Pf-ITV-PQ和Pf-ITV-CQ疫苗将诱导完全至高水平的保护，但在诱导模式、保护程度和免疫特征方面存在差异。这些差异将为我们了解疟疾保护性免疫的相关性提供信息。我们还将开发用于预测疫苗效力的标记物的测定方法，以促进未来的试验并确定亚单位疟疾疫苗开发的有效候选物。

Recently, increased use of insecticide-treated bednets has contributed to a drop in morbidity and mortality in few endemic contries. we are at the tipping point that an efficacious malaria vaccine is urgently needed to accomplish global elimination of malaria, to prevent roll-back malaria fail again. Sterile immunity against malaria can only be developed by immunization with live attenuated parasites. In humans immunized by attenuated sporozoites, parasite development arrests during the asymptomatic liver stage and clinical malaria does not occur. Identification of predictive correlates of protection against sporozoites and liver parasites would greatly accelerate development and testing of an effective recombinant malaria vaccine. A clinical trial is imminent for a genetically-attenuated P. falciparum (PfGAP) vaccine that arrests in the liver. Protective im-munity can also be achieved by exposure to bites from infected mosquitoes combined with anti-blood stage parasite drug chloroquine (CQ) or the anti-liver stage parasite drug primaquine (PQ) treatment. An infection-treatment vaccination (ITV) trial will occur in 2010 to compare the protection induced by ITV-PQ and ITV-CQ. We propose in this project to analyze plasma and PBMC samples from volunteers immunized with gen-etically or chemically attenuated parasite vaccines. We will employ systems approaches (multi-parametric Flow analysis, plasma protein profile, and P. falciparum antigen array analsysis) to delineate the complex regulatory networks upon which protective immune responses are developed by three vaccination strategies, to identify signatures that 1) predict the acquisition of protective immunity after primary immune-ization, 2) discriminate between protective and non-protective immunizations, and 3) predict the duration of protection. We anticipate that the PfGAP, Pf-ITV-PQ, and Pf-ITV-CQ vaccines will induce complete to high levels of pro-tection, but with differences in the pattern of induction, extent of protection, and immune profiles. These dif-ferences will inform our understanding of the correlates of protective immunity against malaria. We will also develop assays for markers that allow prediction of vaccine efficacy to facilitate future trials and identify effective candidates for subunit malaria vaccine development.