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.

抽象的 尽管消除了数十年的努力，但疟疾仍然是发病率和死亡率的全球原因，与 恶性疟原虫和撒哈拉以南非洲的幼儿造成的最大负担。 一种疟疾疫苗最近已获得世界卫生组织的批准；但是，改进了 需要疫苗，可能是消除疟疾必不可少的。不幸的是，我们对 对疟疾的保护性免疫仍然有限。在人类宿主中，寄生虫通过几个 各种器官的生命周期阶段，在每个阶段都表达众多抗原，其中许多仍然保留 未表征。为了增加挑战，许多表面暴露的抗原都用氨基酸粘贴 导致免疫系统逃避的多态性，某些表位引起免疫反应，而不是 实际保护性。多种遗传多种抗原的血清分析将提高我们对 保护疟疾的免疫力并推动更好的疫苗设计。给予有限的关注 抗体对疟疾的抗体反应的同种型组成，IgA虽然以前不认可，但似乎似乎是 成为一个突出的组成部分。尽管大多数杂型研究研究了对全蛋白的抗体反应，但 研究包含蛋白质的肽对肽的抗体反应允许辨别精确抗体 蛋白质表面上的结合位点，可以为疫苗设计提供信息。这项研究将重点放在IGA和IgG上 两组抗体对疟疾感染的反应：（1）居住在西非马里的婴儿和儿童 紧随其后的三到四年，（2）居住在南部非洲马拉维的婴儿。 出生两年。两组都处于疟疾传播高的设置中，并且具有活性和被动 疟疾感染的监测。对代表数百个恶性疟原虫的肽的抗体反应性 首先和重复的疟疾感染后将测量包括抗原变异的蛋白质 Pepseq，一种新型的肽库平台，以前在疟疾中尚未使用。表位由 将确定疟疾感染后的血清IgA和IgG，纵向研究设计将允许 对疟疾抗体反应的大小，动力学和同型比（IgA/IgG）的研究。总之， 这项工作将回答有关IGA对疟疾感染的反应，确定表位和 作为疫苗候选抗原探索的蛋白质，并提供有关抗体反应的新数据 抗原变体。总体而言，这些发现将提高我们对疟疾的免疫反应的理解， 告知疫苗设计。