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

描述（由申请人提供）：有效的血期恶性疟原虫疟疾疫苗将对全球健康产生巨大益处，特别是对疟疾发病率和死亡率负担最重的婴儿和幼儿。我们建议使用新的分子流行病学和结构疫苗学方法来了解人类对一种主要的疟疾疫苗候选抗原——顶膜抗原-1 （apical membrane antigen-1, AMA1）的免疫反应和由此产生的抗原多样性。AMA1是高度多态性的；抗原变异可能是一种寄生虫免疫逃逸机制，在面对自然免疫时允许不同变异的重复感染。我们最近在西非马里的儿童中完成了单价基于AMA1的疟疾疫苗的第一期2期临床试验。从AMA1的免疫学相关多态性来看，该疫苗对具有与疫苗菌株同源的AMA1的寄生虫引起的临床疟疾具有有限的总体效力，但具有良好的等位基因特异性效力。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等位基因的巨大多样性可能被整合为较小数量的亚群，从而减少了为实现广泛交叉保护的AMA1疫苗而必须包括的变异数量。该转化研究项目将采用我们开发的新型分子流行病学方法，以及一种新的自转运蛋白表达系统，分析在疟疾流行地区的前瞻性纵向研究中收集的患者血清样本，目的是识别交叉反应和交叉保护的AMA1表位。

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. PUBLIC HEALTH RELEVANCE: One reason there is still no malaria vaccine is because malaria parasites are able to mutate and change to escape natural immunity. This project seeks to understand how the human immune system interacts with rapidly changing malaria parasites to provide natural protection against malaria infection in the field. This information will be used to better understand how to make a vaccine that could protect against the many diverse forms of malaria parasites found in nature.