Targeted Vaccine Development for Pediatric Falciparum Malaria

描述(由申请人提供)：这项提案的总体目标是确定和评估儿童恶性疟疾疫苗的新候选抗原。儿童罹患疟疾的发病率和死亡率最高--然而，疫苗开发的鉴定阶段并没有针对这一年龄段。流行区的人类居民在他们生命的头1-3年内产生保护性免疫，以限制寄生虫血症和疾病，这种自然获得的人类免疫为疫苗开发提供了一个有吸引力的模式。在这项应用中，我们建议利用我们在先前研究的儿童队列中收集的血浆、寄生虫学和流行病学数据，并使用这些材料来确定儿童恶性疟原虫的新候选疫苗。在以前的研究中，我们已经开发了一种差异筛选方法来识别由抗体识别的寄生虫蛋白，这些抗体是由抗性但不敏感的成年人唯一表达的。我们现在建议利用这种方法来识别2岁儿童耐药但不敏感的寄生虫蛋白。这些筛查实验也将在具有抵抗力和敏感性的3岁儿童中进行。我们之前在坦桑尼亚的Muheza进行了一项关于儿童早期疟疾感染的纵向研究。我们将利用这个队列中已有的血浆和寄生虫学数据来确定儿童疟疾的新候选疫苗。利用这些材料，我们建议用来自最具抵抗力的个体的血浆池进行恶性疟原虫cdna表达文库的差异筛选，并使用来自最敏感儿童的血浆池来对比这些结果。这些初步实验将确定其蛋白产物优先被恶性疟原虫感染自然获得性高水平儿童血清中的抗体识别的基因。这些基因产品代表了合理确定的候选疫苗。随后的实验将证实这些候选人的体液免疫识别与抵抗再感染之间的关系，目前有1000名儿童参加了盖茨基金会资助的一个项目，该项目设在德克萨斯州莫罗戈罗。公共卫生意义：恶性疟原虫疟疾是发展中国家发病率和死亡率的主要原因，每年在撒哈拉以南非洲感染数亿人并导致100多万儿童死亡。这项提议的总体目标是确定儿童恶性疟疾的新候选疫苗。在这项应用中，我们将使用我们在先前研究的儿童队列中收集的血清、寄生虫学和流行病学数据，并使用这些材料来确定儿童恶性疟原虫新的候选疫苗。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to identify and evaluate novel candidate antigens for a vaccine against pediatric falciparum malaria. Children suffer the greatest morbidity and mortality from malaria- yet this age group has not been targeted at the identification stage of vaccine development. Human residents of endemic areas develop protective immunity that limits parasitemia and disease during their first 1-3 years of life, and this naturally acquired human immunity provides an attractive model for vaccine development. In this application, we propose to capitalize on the plasma, and parasitologic, and epidemiologic data which we collected on a previously studied cohort of children and use these materials to identify new vaccine candidates for pediatric P. falciparum. In previous studies, we have developed a differential screening method to identify parasite proteins recognized by antibodies that are uniquely expressed by resistant but not susceptible adults. We now propose to utilize this method to identify parasite proteins that are recognized by resistant, but not susceptible, 2 yr old children. These screening experiments will also be performed in resistant and susceptible 3 yr old children. We have previously performed a longitudinal study of malaria infection during early childhood in Muheza, Tanzania. We will capitalize on plasma and parasitology data already available from this cohort to identify new vaccine candidates for pediatric malaria. Using these materials, we propose to perform differential screening of P. falciparum cDNA expression libraries with plasma pooled from the most resistant individuals and contrasting these results using plasma pooled from the most susceptible children. These initial experiments will identify genes whose protein products are preferentially recognized by antibodies in the sera of children with a high level of naturally acquired resistance to P. falciparum infection. These gene products represent rationally identified vaccine candidates. Subsequent experiments will confirm the relationship between humoral immune recognition of these candidates and resistance to reinfection in a cohort of 1000 children currently being enrolled in a Gates Foundation funded project based in Morogoro, TZN. PUBLIC HEALTH RELEVANCE: P. falciparum malaria is a leading cause of morbidity and mortality in developing countries, infecting hundreds of millions of individuals and killing over one million children in sub-Saharan Africa each year. The overall objective of this proposal is to identify novel vaccine candidates for pediatric falciparum malaria. In this application, we will use sera, parasitologic, and epidemiologic data which we collected on a previously studied cohort of children and use these materials to identify new vaccine candidates for pediatric P. falciparum.