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

描述（由申请方提供）：有效的血液期恶性疟原虫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负担的婴儿和幼儿。我们建议使用新的分子流行病学和结构疫苗学的方法来了解人类的免疫反应和由此产生的抗原多样性的顶端膜抗原-1（AMA 1），一个领先的疟疾疫苗候选抗原。AMA 1具有高度多态性;抗原变异可能是寄生虫免疫逃逸机制，其允许在面对天然免疫时用不同变体重复感染。我们最近在西非马里的儿童中完成了基于AMA 1的单价疟疾疫苗的第一个2期临床试验。该疫苗具有有限的总体疗效，但对由AMA 1与疫苗株同源的寄生虫引起的临床疟疾具有良好的等位基因特异性疗效，就AMA 1的免疫相关多态性而言。分子流行病学和动物研究表明，AMA 1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，AMA 1等位基因的巨大多样性可能被合并为较小数量的亚组，从而减少了必须包括以实现广泛交叉保护的AMA 1疫苗的变体数量。拟议的转化研究项目将采用我们开发的新型分子流行病学方法，以及一种新型的自转运蛋白表达系统，分析在疟疾流行区前瞻性纵向研究中收集的患者血清样本，目的是确定交叉反应和交叉保护AMA 1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.