Targeted Vaccine Development for Pediatric Falciparum Malaria

小儿恶性疟疾针对性疫苗开发

• 批准号: 7932170
• 负责人: Jonathan D. Kurtis
• 金额: $ 65.82万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-17 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932170
• 关键词: Achievement; Adolescent; Adult; Africa South of the Sahara; Age; Aged, 80 and over; Antibodies; Antibody Formation; Antigens; Area; Birth; Blood; Child; Childhood; Cohort Studies; Data; Developing Countries; Disease; Drops; Enrollment; Expression Library; Falciparum Malaria; Foundations; Funding; Genes; Human; IgG1; IgG2; Immune; Immune response; Immunity; Individual; Infection; Investigation; Life; Longitudinal Studies; Malaria; Measures; Mediating; Methods; Modeling; Morbidity - disease rate; Parasitemia; Parasites; Parasitology; Pathway interactions; Plasma; Plasmodium falciparum; Proteins; Proteome; Relative (related person); Resistance; Resistance to infection; Sampling; Screening procedure; Serum; Staging; Tanzania; Vaccine Antigen; Vaccines; Work; age group; base; cDNA Expression; cohort; density; early childhood; epidemiologic data; follow-up; killings; member; mortality; novel; novel vaccines; prospective; public health relevance; research study; response; rhoptry; vaccine candidate; vaccine development

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.

描述（由申请人提供）：该提案的总体目的是识别和评估针对小儿恶性疟疾的疫苗的新型候选抗原。儿童遭受疟疾的发病率和死亡率最大 - 但该年龄段并未在疫苗开发的鉴定阶段被针对。流行地区的人类居民发展了保护性免疫，在生命的头1 - 3年中限制了寄生虫和疾病，这种自然获得的人类免疫力为疫苗开发提供了有吸引力的模型。在此应用中，我们建议利用血浆，寄生虫学和流行病学数据，并在先前研究的儿童队列上收集，并使用这些材料来鉴定新的候选小儿p. falciparum候选疫苗。在先前的研究中，我们开发了一种差异筛选方法，以鉴定由抗体识别的寄生虫蛋白，这些抗体以抗性但不易感成年人为独特的抗体识别。现在，我们建议利用这种方法来识别抗药性但不易感的2岁儿童所识别的寄生虫蛋白。这些筛查实验也将在耐药和易感3岁的孩子中进行。我们以前在坦桑尼亚穆赫扎（Muheza）的幼儿期间对疟疾感染进行了纵向研究。我们将利用该队列中已经获得的血浆和寄生虫数据，以识别儿科疟疾的新疫苗候选者。使用这些材料，我们建议对恶性假单胞菌表达文库进行差异筛选，并使用来自最具耐药性的个体合并的等离子体，并使用来自最易感儿童的等离子体来对比这些结果。这些最初的实验将鉴定其蛋白产物优先识别的基因，这些基因被高水平自然获得的恶性疟原虫感染的儿童血清中的抗体识别。这些基因产物代表合理鉴定的疫苗候选物。随后的实验将确认对这些候选者的体液免疫识别与抗性之间的关系，在目前招募在TZN Morogoro的盖茨基金会资助的项目中的1000名儿童中。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100万以上儿童。该提案的总体目的是确定小儿恶性疟疾的新型候选疫苗。在此应用中，我们将使用血清，寄生虫学和流行病学数据，并在先前研究的儿童队列上收集，并使用这些材料来识别用于恶性疟原虫的新疫苗候选物。