P. falciparum vaccine: Evaluating candidacy of PfMSP3/PfMSP6 in an endemic settin

恶性疟原虫疫苗：评估地方性流行病中 PfMSP3/PfMSP6 的候选资格

• 批准号: 7496944
• 负责人: Julian Charles Rayner
• 金额: $ 17.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496944
• 关键词: Alleles; Antibodies; Antibody Formation; Antigens; Antimalarials; Biological Assay; Blood; C-terminal; Cellular Immunity; Cessation of life; Classification; Cohort Studies; Communicable Diseases; Communities; Coupled; DNA; Data; Data Protection; Development; Diagnosis; Drug resistance; Funding; Genes; Genetic Variation; Genome; Genotype; Goals; Growth; Health Priorities; Immune response; Immunity; Individual; Infection; Life Cycle Stages; Malaria; Malaria Vaccines; Measures; Molecular; Molecular Epidemiology; Molecular and Cellular Biology; Numbers; Outcome; Parasites; Pattern; Peru; Plasmodium; Plasmodium falciparum; Plasmodium vaccine; Population; Positioning Attribute; Prevalence; Prevention; Process; Proteins; Public Health; Publishing; Relative (related person); Research; Resources; Sampling; Seasons; Serum; Site; Staging; Targeted Research; Testing; Time; Vaccine Antigen; Vaccine Design; Vaccines; Visit; Work; cohort; cross reactivity; design; experience; follow-up; killings; knowledge base; merozoite surface protein; novel; programs; response; size; transmission process; vaccine development

DESCRIPTION (provided by applicant): The status of malaria as one of the top three global infectious disease killers, coupled with the recent rapid spread of drug-resistant Plasmodium falciparum parasites, have made the development of an effective P. falciparum vaccine an urgent priority. However the complexity of the P. falciparum life cycle and the size of its genome present a large number of potential vaccine candidates, making it critical that individual antigens are moved down the malaria vaccine development pipeline only when they meet specific go/no-go criteria. This application will apply such rigorous criteria to two outstanding blood stage candidate vaccine antigens, the closely related merozoite surface proteins PfMSP3 and PfMSP6. The long-term objectives of this proposal are to understand how PfMSP3 and PfMSP6 sequences change over time in a malaria-endemic community and to generate critical correlation of protection data for all sub-domains of both candidate antigens. This work is made possible by our access to unique samples that are collected as part of an ongoing longitudinal cohort study in the Peruvian Amazon, the set-up of which allows us to track individuals from their first P. falciparum infection, with sera and P. falciparum DNA samples available from the time of diagnosis through multiple follow-up visits over the course of several years. In Specific Aim 1 we will establish the temporal dynamics of PfMSP3 and PfMSP6 genetic diversity by following inter- and intra-allelic diversity in these two genes both at a population level, between transmission seasons, and at an individual level, between subsequent infections in the same individual. Specific Aim 2 will use sera from individual infections that have been genotyped in Specific Aim 1 to investigate the relative contribution of specific PfMSP3 and PfMSP6 sub-domains to the development of functional anti-malaria immunity. To achieve this we will both follow antibody levels against each sub-domain of PfMSP3 and PfMSP6, and also use inhibition of invasion and antibody dependent cellular inhibition assays to establish the function of these antibodies in inhibiting P. falciparum parasite growth. Because of the unique combination of a hypoendemic study site and a longitudinal cohort design we will be able to track individuals through several rounds of single isolate infections, and establish both the genotype of each infection and the antibody response to that infection. Combining genotyping and antibody data from the two specific aims will therefore allow us to establish whether antibodies generated against one PfMSP3 or PfMSP6 allele are functionally cross-protective against the other, as well as to establish which sub-domains most closely correlate with protection. The rationale is that by understanding the diversity constraints within which a PfMSP3/PfMSP6 vaccine must operate and the relative contribution of each sub-domain to functional anti-malaria immunity, we will be able to apply rational go/no-go criteria to rule specific sub-domains in or out of the vaccine development process. The overall impact on malaria vaccine design, a question of urgent public health importance, will therefore be significant. Plasmodium falciparum parasites kill more than 1 million people each year and the recent rapid spread of drug resistant parasites have made the development of a P. falciparum vaccine an urgent public health priority. This proposal focuses on two outstanding vaccine candidate antigens, P. falciparum Merozoite Surface Proteins 3 and 6, and will use DNA and sera samples collected from a unique ongoing malaria cohort study in Iquitos, Peru, to establish the relative contribution of distinct sub-domains of these antigens to the development of functional anti-malaria immunity. This data will directly impact vaccine design by allowing us to rule specific sub-domains in or out of the ongoing malaria vaccine development process.

描述（由申请人提供）：疟疾作为全球三大传染病杀手之一，再加上最近耐药性恶性疟原虫疟原虫的迅速传播，使有效的恶性疟原虫疫苗的发展成为了紧迫的优先事项。但是，恶性疟原虫生命周期的复杂性及其基因组的大小呈现出大量潜在的候选疫苗，这使得仅在符合特定的GO/NO-NO-GO标准时，就必须将单个抗原移动到疟疾疫苗发育管道。该应用将对两种杰出的血液阶段候选疫苗抗原，密切相关的蛋白石表面蛋白PFMSP3和PFMSP6应用于严格的标准。该提案的长期目标是了解PFMSP3和PFMSP6序列在疟疾流行界如何随着时间的流逝而变化，并为两种候选抗原的所有子域的保护数据产生关键相关性。我们可以使用秘鲁亚马逊正在进行的纵向队列研究的一部分收集的独特样本来实现这项工作，该样品的设置使我们能够从他们的第一个恶性疟原虫感染中跟踪个人，并通过多次诊断期间的多次随访。在特定目标1中，我们将通过遵循这两个基因的间距和平行性多样性，在人群水平，传输季节和个体水平之间，在同一个人的后续感染之间遵循这两个基因的间隔和平行性多样性，以建立PFMSP3和PFMSP6遗传多样性的时间动力学。特定目标2将使用特定目标1中基因分型的个体感染中的血清来研究特定的PFMSP3和PFMSP6亚域对功能性抗马里菌免疫发展的相对贡献。为了实现这一目标，我们既将遵循针对PFMSP3和PFMSP6的每个亚域的抗体水平，并且还使用抑制浸润和抗体依赖性细胞抑制测定法，以确定这些抗体在抑制恶性疟原虫生长的抑制。由于弱势研究部位和纵向队列设计的独特组合，我们将能够通过几轮单分离株感染来跟踪个体，并建立每个感染的基因型和对该感染的抗体反应。因此，将两个特定目的的基因分型和抗体数据结合起来将使我们能够确定针对一种PFMSP3或PFMSP6等位基因产生的抗体是否在功能上是针对另一个PFMSP3或PFMSP6等位基因的，并且可以确定哪种亚域与保护最紧密相关。理由是，通过了解PFMSP3/PFMSP6疫苗必须运行的多样性约束，并且每个子域对功能性抗马拉里亚免疫的相对贡献，我们将能够应用合理的GO/NO-GO/NO-GO标准来统治疫苗开发过程中的特定亚domoin。因此，对疟疾疫苗设计的总体影响是紧急公共健康重要性的问题，因此将是重大的。恶性疟原虫每年杀死100万以上的人，最近耐药寄生虫的迅速传播使恶性疟原虫疫苗的发展成为了紧急的公共卫生优先事项。该提议的重点是两种出色的疫苗候选抗原，恶性疟原虫蛋白表面蛋白3和6，并将使用秘鲁伊基托斯的独特疟疾队列研究中收集的DNA和血清样品，以建立这些抗原对功能性抗元素免疫性的开发的相对分类的相对贡献。这些数据将通过允许我们在正在进行的疟疾疫苗发育过程中或外出来统治特定的子域，直接影响疫苗设计。