Multiplex analysis of IgA and IgG antibody responses to early childhood malaria infections to inform vaccine development

对儿童早期疟疾感染的 IgA 和 IgG 抗体反应进行多重分析，为疫苗开发提供信息

• 批准号: 10647960
• 负责人: Andrea Berry
• 金额: $ 27.65万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647960
• 关键词: Adult; Affect; Affinity; Africa; Africa South of the Sahara; African; Age; Algorithm Design; Amino Acids; Antibodies; Antibody Binding Sites; Antibody Response; Antigen Targeting; Antigens; Area; Attention; Bar Codes; Birth; Blood; Child; Clinical; Country; DNA; Data; Development; Epitopes; Erythrocytes; Future; Genetic Polymorphism; Goals; Human; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Infant; Infection; Investigation; Kinetics; Libraries; Life Cycle Stages; Liver; Longevity; Longitudinal Studies; Malaria; Malaria Vaccines; Malaria prevention; Malawi; Mali; Mass Spectrum Analysis; Measures; Membrane Proteins; Monoclonal Antibodies; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Organ; Outcome; Parasitemia; Parasites; Pattern; Peptide Library; Peptides; Plasmodium; Plasmodium falciparum; Proteins; Research; Research Design; Role; Sampling Studies; Serology; Serum; Site; Southern Africa; Sporozoites; Surface; Target Populations; Time; Vaccine Design; Vaccines; Variant; Work; World Health Organization; circumsporozoite protein; cross reactivity; design; early childhood; experience; geographically distant; high throughput analysis; high throughput technology; improved; malaria infection; malaria transmission; mortality; neural network; novel; novel vaccines; response; tool; vaccine candidate; vaccine development; vaccine trial

ABSTRACT Despite decades of eradication efforts, malaria remains a global cause of morbidity and mortality, with the greatest burden caused by Plasmodium falciparum and largely affecting young children in Sub-Saharan Africa. One malaria vaccine has recently been approved by the World Health Organization; however, improved vaccines are needed and are likely essential for malaria eradication. Unfortunately, our understanding of protective immunity to malaria remains limited. Within the human host, the parasite propagates through several life cycle stages in various organs, expressing multitudes of antigens at each stage, many of which remain uncharacterized. To add to the challenge, many surface-exposed antigens are studded with amino acid polymorphisms that result in immune system evasion, and some epitopes elicit immune responses that are not actually protective. Serum profiling of multiple genetically diverse antigens will improve our understanding of protective immunity to malaria and drive the design of better vaccines. Limited attention has been given to isotype composition of the antibody response to malaria, and IgA, though previously underrecognized, appears to be a prominent component. While most seroprofiling studies examine antibody responses to whole proteins, study of antibody responses to peptides that comprise the proteins allows for discernment of precise antibody binding sites on the protein surface, which can inform vaccine design. This research will focus on IgA and IgG antibody responses to malaria infection in two groups: (1) infants and children living in Mali, West Africa who were followed for three to four years and (2) infants living in Malawi, Southern Africa, who were followed from birth to two years. Both groups were in settings with high malaria transmission and had active and passive surveillance for malaria infections. Antibody reactivity to peptides representing hundreds of P. falciparum proteins including antigenic variants will be measured following first and repeated malaria infections on PepSeq, a novel peptide library platform that has not previously been used in malaria. Epitopes recognized by serum IgA and IgG after malaria infection will be identified, and a longitudinal study design will allow for the study of the magnitude, kinetics, and isotype ratio (IgA/IgG) of the antibody response to malaria. In summary, this work will answer critical questions about the IgA response to malaria infection, identify epitopes and proteins for exploration as vaccine candidate antigens, and provide new data on the antibody response to antigenic variants. Overall, the findings will improve our understanding of the immune response to malaria and inform vaccine design.

摘要 尽管进行了几十年的根除努力，疟疾仍然是全球发病率和死亡率的原因， 恶性疟原虫造成的最大负担，主要影响撒哈拉以南非洲的幼儿。 世界卫生组织最近批准了一种疟疾疫苗；然而，改进后的疫苗 疫苗是必需的，而且很可能是根除疟疾所必需的。不幸的是，我们对 对疟疾的保护性免疫力仍然有限。在人类宿主内，寄生虫通过几个 在不同器官的生命周期阶段，在每个阶段表达大量的抗原，其中许多仍然 没有特征的。增加挑战的是，许多暴露在表面的抗原都含有氨基酸。 导致免疫系统逃避的多态和一些表位引发的免疫反应不是 实际上是保护性的。多种遗传多样性抗原的血清图谱将提高我们对 对疟疾的保护性免疫，并推动更好的疫苗的设计。人们对以下问题的关注有限 疟疾抗体反应的同种类型组成，和IgA，尽管以前没有被认识到，但出现了 成为一个重要的组成部分。虽然大多数血清分析研究都是检查抗体对整个蛋白质的反应， 研究抗体对组成蛋白质的多肽的反应有助于识别准确的抗体 蛋白质表面的结合位点，这可以为疫苗设计提供信息。这项研究将集中在IgA和Ig G上 两组人群对疟疾感染的抗体反应：(1)居住在西非马里的婴儿和儿童 (2)居住在南部非洲马拉维的婴儿，他们从 出生到两岁。这两组人都处于疟疾高传播率的环境中，有主动和被动两种情况 监测疟疾感染情况。对数百种恶性疟原虫多肽的抗体反应性 在首次和反复感染疟疾后，将测量包括抗原变体在内的蛋白质 PepSeq是一种新的多肽文库平台，以前从未用于疟疾。识别的表位 将确定疟疾感染后的血清免疫球蛋白A和免疫球蛋白G，纵向研究设计将允许 疟疾抗体反应的大小、动力学和同型比(IgA/Ig G)的研究。总而言之， 这项工作将回答关于免疫球蛋白A对疟疾感染的反应的关键问题，识别表位和 蛋白质作为疫苗候选抗原的探索，并提供了关于抗体反应的新数据 抗原变异体。总体而言，这些发现将提高我们对疟疾的免疫反应和 告知疫苗设计。