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(申请人提供)：疟疾作为全球三大传染病杀手之一的地位，加上最近抗药性恶性疟原虫的迅速传播，使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显示了大量潜在的候选疫苗，这使得只有当单个抗原满足特定的通过/不通过标准时才沿着疟疾疫苗开发流程向下移动是至关重要的。这项应用将把这样严格的标准应用于两个杰出的血液期候选疫苗抗原，密切相关的裂殖子表面蛋白PfMSP3和PfMSP6。这项提议的长期目标是了解在疟疾流行社区中PfMSP3和PfMSP6序列是如何随时间变化的，并生成这两个候选抗原的所有亚域的保护数据的关键关联。这项工作之所以成为可能，是因为我们能够获得独特的样本，这些样本是在秘鲁亚马逊地区正在进行的纵向队列研究的一部分收集的，这项研究的设置使我们能够追踪个体从他们第一次感染恶性疟原虫开始，通过几年的多次随访访问，从诊断时起就可以获得血清和恶性疟原虫DNA样本。在具体目标1中，我们将通过跟踪PfMSP3和PfMSP6基因在种群水平、传播季节之间和个体水平上的等位基因间和等位基因内多样性，以及同一个体的后续感染之间的差异，来建立这两个基因遗传多样性的时间动态。特定目标2将使用在特定目标1中进行了基因分型的个体感染的血清，以调查特定的PfMSP3和PfMSP6亚域对发展功能性抗疟疾免疫的相对贡献。为了实现这一点，我们将跟踪针对PfMSP3和PfMSP6每个亚区的抗体水平，并使用侵袭抑制和抗体依赖的细胞抑制试验来确定这些抗体在抑制恶性疟原虫生长方面的功能。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感染追踪个体，并建立每个感染的基因和对该感染的抗体反应。因此，结合来自两个特定目的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具有交叉保护作用，以及确定哪些亚域与保护最密切相关。其基本原理是，通过了解PfMSP3/PfMSP6疫苗必须在其中运行的多样性限制以及每个亚域对抗疟疾功能免疫的相对贡献，我们将能够应用合理的Go/no-go标准来规则疫苗开发过程中或之外的特定亚域。因此，对疟疾疫苗设计的总体影响将是重大的，这是一个紧迫的公共卫生重要问题。恶性疟原虫每年导致100多万人死亡，最近抗药性寄生虫的快速传播使恶性疟原虫疫苗的开发成为公共卫生的当务之急。这项建议侧重于两个杰出的疫苗候选抗原，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一项独特的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亚域对发展功能性抗疟疾免疫的相对贡献。这些数据将通过允许我们在正在进行的疟疾疫苗开发过程中或正在进行的疟疾疫苗开发过程中对特定的子域进行规则来直接影响疫苗设计。