Immune signatures of protection induced by whole parasite malaria vaccines

最近，经过杀虫剂处理的蚊帐的使用增加，有助于在少数地方性疾病中降低发病率和死亡率。我们正处在一个转折点，迫切需要一种有效的疟疾疫苗来实现全球消灭疟疾，以防止疟疾再次失败。对疟疾的无菌免疫只能通过接种活的减毒寄生虫来实现。在用减毒子孢子免疫的人中，寄生虫在无症状的肝期发展受阻，临床上不会发生疟疾。识别保护子孢子和肝脏寄生虫的预测相关因素将大大加快有效重组疟疾疫苗的开发和测试。一种基因减毒恶性疟原虫(PfGAP)疫苗即将进行临床试验，这种疫苗可以在肝脏中滞留。 保护免疫也可以通过暴露于受感染蚊子叮咬联合抗血液期寄生虫药物氯喹(CQ)或抗肝期寄生虫药物伯氨喹(PQ)治疗来实现。2010年将进行感染治疗疫苗接种(ITV)试验，以比较ITV-PQ和ITV-CQ诱导的保护作用。在这个项目中，我们建议分析来自用基因或化学减毒寄生虫疫苗免疫的志愿者的血浆和PBMC样本。我们将使用系统方法(多参数流动分析、血浆蛋白图谱和恶性疟原虫抗原阵列分析)来描绘复杂的调控网络，在此基础上，通过三种疫苗接种策略来制定保护性免疫反应，以确定1)预测在初次免疫后获得保护性免疫的标志，2)区分保护性免疫和非保护性免疫，以及3)预测保护持续时间。我们预计，PfGAP、PF-ITV-PQ和PF-ITV-CQ疫苗将诱导完全到高水平的保护，但诱导模式、保护程度和免疫模式有所不同。这些差异将有助于我们理解疟疾保护性免疫的相关因素。我们还将开发能够预测疫苗效力的标记物的分析，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者。

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.