Drivers of strain-specific and strain-transcendent antimalarial immunity in childhood

儿童时期菌株特异性和菌株超越性抗疟免疫的驱动因素

基本信息

批准号：
10630290
负责人：
Bryan R Greenhouse
金额：
$ 80.64万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630290
关键词：
Address Adult Africa South of the Sahara Age Antibodies Antibody Repertoire Antibody Response Antibody titer measurement Antigens Antimalarials Area Automobile Driving Biological Assay Birth Blood Chemoprevention Child Childhood Clinical Clinical Data Cohort Studies Complex Custom Data Development Disease Drug resistance Epidemiology Erythrocytes Evaluation Exposure to Falciparum Malaria Fever Genetic Genetic Variation Genomics Immune response Immunity Immunology Individual Infection Insecticide Resistance Insecticides Intervention Investments Licensing Life Longitudinal Studies Malaria Malaria Vaccines Measurement Methods Molecular Natural Immunity Outcome Parasites Peptides Pharmacotherapy Plasmodium falciparum Positioning Attribute Protein Array Recording of previous events Research Residual state Resistance Role Sampling Testing Time Uganda Vaccines Validation Variant acquired immunity cohort deep sequencing early childhood experience experimental study genome sequencing improved response statistics tool whole genome

项目摘要

Project Summary/Abstract Despite recent gains, the burden of malaria caused by P. falciparum (Pf) in sub-Saharan Africa remains unacceptably high. Vaccines offer the greatest potential to produce sustained protection against malaria, but the only licensed vaccine for malaria is short lived and only modestly effective. Decades of research have been unable to produce a feasible vaccine which approaches the efficacy of naturally acquired immunity (NAI), which provides nearly complete protection against symptomatic disease in adults in many endemic areas. NAI to malaria is complex slow to develop. Antibodies are key effectors of NAI, and eventually overcome the high degree of genetic diversity evolved by Pf antigens important in host-parasite interactions. This diversity may underlie the slow development of NAI and relative inefficacy of current vaccines. While it is loosely understood that increasing cumulative exposure to Pf leads to greater immunity, fundamental questions remain unanswered. The aims of this project are (1) to determine the effect of the number, timing, and genetic composition of blood stage Pf infections on NAI in childhood; and (2) to determine the effect of the number, timing, and genetic composition of exposure to Pf in childhood on the antibody repertoire, and how antibody responses relate to immunity. We are in a unique position to achieve these aims by leveraging an extensive set of existing samples and data from multiple intensively followed early childhood cohorts in Uganda along with a team of experienced collaborators with expertise in malaria epidemiology, statistics, genomics, and immunology. In Aim 1, we will initially perform whole genome sequencing on a subset of Pf infections in our cohorts to systematically identify antigenic variants under potential selection. These antigens, along with others identified from existing data, will be deep sequenced from all infected time points using highly multiplexed deep sequencing. We will quantify anti-parasite and anti-disease immunity using detailed clinical data, and combine these data to test 3 fundamental hypotheses regarding the relationship between exposure and immunity. In Aim 2, we will longitudinally evaluate antibody responses to Pf in our cohorts using ultra-high throughput long peptide arrays, targeting the entire genome including all identified antigenic variants. We will identify sequences of key antigens from these experiments and from Aim 1, and further evaluate antibody responses using custom protein arrays with experimental validation using functional assays. Using these data, we will test an additional 3 hypotheses. At the conclusion of this project, we will have identified fundamental factors driving the development of NAI, including the role of strain-specific vs. transcendent immunity and the identification of antigenic variants most associated with immunity and thus most appropriate for inclusion in a malaria vaccine.

项目摘要/摘要尽管最近收益，但撒哈拉以南非洲的恶性疟原虫（PF）造成的疟疾负担仍然存在高度高。疫苗为持续保护疟疾提供了最大的潜力，但唯一的疟疾持牌疫苗是短暂的，只有适度的有效。数十年的研究已经无法生产可行的疫苗，该疫苗接近自然获得免疫（NAI）的功效，在许多地方性地区的成年人中，几乎可以完全保护有症状疾病。奈疟疾的发展缓慢。抗体是NAI的关键效应器，最终克服了高 PF抗原在宿主 - 寄生虫相互作用中重要的遗传多样性程度。这种多样性可能 NAI的缓慢发展和当前疫苗的相对效率低下。虽然它被松散地理解累积暴露于PF会导致更大的免疫力，基本问题仍然存在未得到答复。该项目的目的是（1）确定数量，时机和遗传的影响童年时代NAI的血液阶段感染的组成；（2）确定数字的效果，抗体库中儿童期暴露于PF的时间和遗传组成，以及抗体如何反应与免疫有关。我们处于独特的位置，可以通过利用广泛的一组现有的样本和来自多个强烈遵循乌干达的幼儿同伙的数据和数据沿着与经验丰富的合作者团队具有疟疾流行病学，统计学，基因组学和免疫学。在AIM 1中，我们最初将对我们的PF感染子集进行整个基因组测序在潜在选择下系统地识别系统识别抗原变异的同类。这些抗原以及其他从现有数据中确定，将使用高度多重的深度从所有感染的时间点进行深入测序测序。我们将使用详细的临床数据量化抗寄生虫和抗疾病免疫力，并结合这些数据以测试有关暴露与免疫之间关系的3个基本假设。在 AIM 2，我们将使用超高的吞吐量长时间纵向评估我们队列中对PF的抗体反应肽阵列，针对整个基因组，包括所有已鉴定出的抗原变体。我们将确定来自这些实验和AIM 1的关键抗原序列，并进一步评估抗体反应使用使用功能测定的自定义蛋白质阵列进行实验验证。使用这些数据，我们将测试另外3个假设。该项目结束时，我们将确定驱动的基本因素 NAI的发展，包括菌株特异性与超然免疫的作用以及鉴定抗原变异与免疫最相关，因此最适合纳入疟疾疫苗。