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.

项目概要/摘要尽管最近取得了进展，但恶性疟原虫 (Pf) 在撒哈拉以南非洲地区造成的疟疾负担仍然存在高得令人无法接受。疫苗提供了针对疟疾提供持续保护的最大潜力，但是唯一获得许可的疟疾疫苗的寿命很短，而且效果有限。经过数十年的研究无法生产出接近自然获得性免疫（NAI）功效的可行疫苗，它为许多流行地区的成年人提供了几乎完全的针对症状性疾病的保护。 NAI 疟疾十分复杂，发展缓慢。抗体是 NAI 的关键效应物，并最终克服高 Pf 抗原进化出的遗传多样性程度在宿主-寄生虫相互作用中很重要。这种多样性可能这是 NAI 发展缓慢和当前疫苗相对无效的原因。虽然它被粗略地理解增加对 Pf 的累积接触会导致更强的免疫力，但基本问题仍然存在无人回答。该项目的目的是（1）确定数量、时间和遗传的影响儿童期 NAI 血期 Pf 感染的构成； (2) 确定数字的影响，儿童时期接触 Pf 的时间和遗传组成对抗体库的影响，以及抗体如何产生反应与免疫力有关。我们处于独特的地位，可以通过利用广泛的资源来实现这些目标一组现有样本和数据，来自乌干达多个密切跟踪的幼儿群体拥有一支经验丰富的合作者团队，他们在疟疾流行病学、统计学、基因组学和免疫学。在目标 1 中，我们首先将对我们的 Pf 感染子集进行全基因组测序。队列在潜在选择下系统地识别抗原变异。这些抗原以及其他抗原从现有数据中识别出的，将使用高度多重深度测序从所有感染时间点进行深度测序测序。我们将利用详细的临床数据量化抗寄生虫和抗疾病免疫力，并结合这些数据用于检验有关暴露与免疫力之间关系的 3 个基本假设。在目标 2，我们将使用超高通量长期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，包括所有已识别的抗原变体。我们将确定来自这些实验和目标 1 的关键抗原序列，并进一步评估抗体反应使用定制蛋白质阵列并通过功能测定进行实验验证。使用这些数据，我们将测试另外 3 个假设。在该项目结束时，我们将确定驱动因素 NAI 的发展，包括菌株特异性与超验免疫的作用以及抗原变异体与免疫力最相关，因此最适合包含在疟疾疫苗中。