Immuno-epidemiological epitope mapping of a blood stage malaria vaccine antigen

血期疟疾疫苗抗原的免疫流行病学表位作图

基本信息

批准号：
8416955
负责人：
CHRISTOPHER V. PLOWE
金额：
$ 54.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-02 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416955
关键词：
Affect Africa Africa South of the Sahara Alleles Amino Acids Animal Experiments Animals Antibodies Antibody Formation Antigenic Diversity Antigenic Variation Antigens Area Blood Cessation of life Child Clinical Clinical Research Development Disease Epidemiology Epitope Mapping Epitopes Exposure to Falciparum Malaria Genetic Genetic Polymorphism Genotype Goals Haplotypes Health Benefit Hot Spot Human Immune Immune response Immune system Immunity Individual Infant Infection Laboratory Study Lead Longitudinal Studies Malaria Malaria Vaccines Malaria prevention Mali Maps Measures Molecular Molecular Epidemiology Morbidity - disease rate Mutate Natural Immunity Nature Oryctolagus cuniculus Outcome Parasites Patients Peptides Phase II Clinical Trials Plasma Research Research Project Grants Risk Sampling Seroepidemiologic Studies Serological Serum Staging Subgroup System Testing Translational Research Vaccine Antigen Vaccines Variant acquired immunity apical membrane base biological systems clinical risk clinically relevant cohort design epidemiology study experience genetic variant global health immunogenicity mortality novel prospective protein expression response vaccine candidate vaccinology

项目摘要

DESCRIPTION (provided by applicant): An effective blood stage Plasmodium falciparum malaria vaccine would be of immense global health benefit, particularly for infants and young children who suffer the greatest burden of malaria morbidity and mortality. We propose to use novel molecular epidemiological and structural vaccinology approaches to understand the human immune response to and the resulting antigenic diversity of apical membrane antigen-1 (AMA1), a leading malaria vaccine candidate antigen. AMA1 is highly polymorphic; antigenic variation is likely a parasite immune escape mechanism that allows repeated infection with different variants in the face of natural immunity. We recently completed the first Phase 2 clinical trial of a monovalent AMA1- based malaria vaccine in children in Mali, West Africa. The vaccine had limited overall efficacy but good allele-specific efficacy against clinical malaria caused by parasites with AMA1 homologous to the vaccine strain with respect to immunologically relevant polymorphisms in AMA1. Molecular epidemiological and animal studies suggest that some regions of the AMA1 molecule represent "immunogenicity hot spots," i.e. residues within these regions are critical to development of strain-specific protective immunity. The combined results of these clinical and laboratory studies suggest that the vast diversity of AMA1 alleles may be consolidated into a smaller number of subgroups, thereby reducing the number of variants that would have to be included to achieve a broadly cross-protective AMA1 vaccine. The proposed translational research project will employ novel molecular epidemiological approaches that we have developed, as well as a novel autotransporter protein expression system, to analyze patient serum samples collected in prospective longitudinal studies in a malaria endemic area, with the aim of identifying cross-reactive and cross-protective AMA1 epitopes.

描述（由申请人提供）：有效的血液阶段恶性疟疾疟疾疫苗将具有巨大的全球健康益处，特别是对于遭受疟疾发病率和死亡率最大的婴儿和幼儿而言。我们建议使用新型的分子流行病学和结构疫苗学方法来理解人类免疫反应以及顶端膜抗原-1（AMA1）的抗原多样性，这是一种领先的疟疾疫苗候选抗原。 AMA1高度多态；抗原性变异可能是一种寄生虫免疫逃生机制，可以在天然免疫力下重复感染具有不同变体的感染。我们最近完成了西非马里儿童的单价AMA1疟疾疫苗的第一阶段临床试验。该疫苗的总体疗效有限，但良好的等位基因特异性疗效对临床疟疾引起的寄生虫与AMA1中的免疫学相关多态性相对于疫苗菌株同源。分子流行病学和动物研究表明，AMA1分子的某些区域代表“免疫原性热点”，即这些区域内的残基对于菌株特异性保护性免疫的发展至关重要。这些临床和实验室研究的综合结果表明，AMA1等位基因的大量多样性可以巩固为较小数量的亚组，从而减少了必须包括的变体数量，以实现广泛的交叉保护AMA1疫苗。拟议的翻译研究项目将采用我们开发的新型分子流行病学方法以及一种新型的自动转运蛋白蛋白表达系统，以分析疟疾中流区域中的前瞻性纵向研究中收集的患者血清样品，目的是鉴定交叉反应和交叉生产AMA11相位。