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: 7313494
• 负责人: Julian Charles Rayner
• 金额: $ 21.75万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313494
• 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（申请人提供）：疟疾作为全球三大传染病杀手之一，加上近期耐药性恶性疟原虫寄生虫的迅速传播，使得开发有效的恶性疟原虫疫苗成为当务之急。然而，恶性疟原虫生命周期的复杂性及其基因组的大小提供了大量潜在的候选疫苗，因此只有当单个抗原满足特定的通过/不通过标准时，才将其转移到疟疾疫苗开发流程中至关重要。该应用将如此严格的标准应用于两种出色的血液阶段候选疫苗抗原，即密切相关的裂殖子表面蛋白 PfMSP3 和 PfMSP6。该提案的长期目标是了解 PfMSP3 和 PfMSP6 序列在疟疾流行社区中如何随时间变化，并为两种候选抗原的所有子域生成保护数据的关键相关性。这项工作之所以成为可能，是因为我们获得了秘鲁亚马逊正在进行的纵向队列研究的一部分所收集的独特样本，该研究的设置使我们能够追踪个体首次感染恶性疟原虫的情况，从诊断时到数年的多次随访，可以获得血清和恶性疟原虫 DNA 样本。在具体目标 1 中，我们将通过在群体水平、传播季节之间和个体水平、同一个体的后续感染之间跟踪这两个基因的等位基因间和等位基因内多样性，建立 PfMSP3 和 PfMSP6 遗传多样性的时间动态。具体目标 2 将使用已在具体目标 1 中进行基因分型的个体感染者血清来研究特定 PfMSP3 和 PfMSP6 子结构域对功能性抗疟疾免疫发展的相对贡献。为了实现这一目标，我们将跟踪针对 PfMSP3 和 PfMSP6 每个子结构域的抗体水平，并使用入侵抑制和抗体依赖性细胞抑制测定来确定这些抗体在抑制恶性疟原虫生长中的功能。由于低流行研究地点和纵向队列设计的独特组合，我们将能够通过几轮单一分离株感染来跟踪个体，并确定每次感染的基因型和对该感染的抗体反应。因此，结合来自两个特定目标的基因分型和抗体数据将使我们能够确定针对一个 PfMSP3 或 PfMSP6 等位基因产生的抗体是否在功能上对另一个等位基因具有交叉保护作用，以及确定哪些子结构域与保护最密切相关。其基本原理是，通过了解 PfMSP3/PfMSP6 疫苗必须发挥作用的多样性限制以及每个子域对功能性抗疟疾免疫的相对贡献，我们将能够应用合理的通过/不通过标准来将特定子域纳入或排除在疫苗开发过程中。因此，疟疾疫苗设计的总体影响将是一个具有紧迫公共卫生重要性的问题。恶性疟原虫寄生虫每年导致超过 100 万人死亡，最近耐药寄生虫的迅速传播使得恶性疟原虫疫苗的开发成为一项紧迫的公共卫生优先事项。该提案重点关注两种出色的疫苗候选抗原：恶性疟原虫裂殖子表面蛋白 3 和 6，并将使用从秘鲁伊基托斯正在进行的独特疟疾队列研究中收集的 DNA 和血清样本，以确定这些抗原的不同子结构域对功能性抗疟疾免疫力发展的相对贡献。这些数据将直接影响疫苗设计，让我们能够在正在进行的疟疾疫苗开发过程中或排除特定的子领域。