Targeted Vaccine Development for Pediatric Falciparum Malaria

描述（由申请方提供）：本提案的总体目标是鉴定和评价用于抗小儿恶性疟疾疫苗的新型候选抗原。儿童是疟疾发病率和死亡率最高的群体-然而，在疫苗研制的鉴定阶段，这一年龄组尚未成为目标。流行地区的人类居民在其生命的前1-3年内产生限制寄生虫血症和疾病的保护性免疫，并且这种天然获得的人类免疫为疫苗开发提供了有吸引力的模型。在本申请中，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，并使用这些材料来鉴定儿科恶性疟原虫的新疫苗候选物。在以前的研究中，我们已经开发了一种差异筛选方法，以确定由抗体识别的寄生虫蛋白质，这些蛋白质由抗性但不敏感的成虫独特表达。我们现在建议利用这种方法来识别寄生虫蛋白，抵抗，但不敏感，2岁的儿童。这些筛选实验也将在3岁的抵抗和易感儿童中进行。我们以前在坦桑尼亚的Muheza进行了一项儿童早期疟疾感染的纵向研究。我们将利用这一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。使用这些材料，我们建议进行差异筛选恶性疟原虫的cDNA表达文库与血浆汇集从最耐药的个人和对比这些结果使用血浆汇集从最易感的儿童。这些初步的实验将确定其蛋白产物优先被抗体识别的基因，这些抗体存在于对恶性疟原虫感染具有高度自然获得性抗性的儿童血清中。这些基因产物代表了合理鉴定的候选疫苗。随后的实验将证实这些候选人的体液免疫识别与目前正在参加盖茨基金会资助的项目的1000名儿童队列中对再感染的抵抗力之间的关系。公共卫生相关性：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杀死100多万儿童。这项提案的总体目标是确定新的儿童恶性疟疾候选疫苗。在本申请中，我们将使用我们从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，并使用这些材料来鉴定儿科恶性疟原虫的新候选疫苗。

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.