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 尽管进行了数十年的根除努力，疟疾仍然是全球发病率和死亡率的一个原因， 恶性疟原虫造成的最大负担，主要影响撒哈拉以南非洲地区的幼儿。 世界卫生组织最近批准了一种疟疾疫苗；然而，改进了 疫苗是需要的，而且可能对于根除疟疾至关重要。不幸的是，我们的理解 对疟疾的保护性免疫力仍然有限。在人类宿主体内，寄生虫通过多种方式传播 各个器官的生命周期阶段，在每个阶段表达多种抗原，其中许多仍然存在 没有特征的。为了增加挑战，许多表面暴露的抗原都散布着氨基酸 导致免疫系统逃避的多态性，以及一些表位引发的免疫反应并非如此 实际上具有保护作用。多种遗传多样性抗原的血清分析将提高我们对 对疟疾的保护性免疫力并推动更好疫苗的设计。受到的关注有限 对疟疾和 IgA 的抗体反应的同种型组成虽然以前未被充分认识，但现在出现了 成为突出的组成部分。虽然大多数血清分析研究检查抗体对整个蛋白质的反应， 研究抗体对包含蛋白质的肽的反应可以识别精确的抗体 蛋白质表面的结合位点，可以为疫苗设计提供信息。这项研究将重点关注 IgA 和 IgG 两组对疟疾感染的抗体反应：（1）居住在西非马里的婴儿和儿童 被跟踪了三到四年，（2）生活在南部非洲马拉维的婴儿，他们被跟踪来自 出生至二岁。两组均处于疟疾传播率高的环境中，并有主动和被动 监测疟疾感染。抗体对代表数百种恶性疟原虫的肽的反应性 包括抗原变异在内的蛋白质将在首次和重复疟疾感染后进行测量 PepSeq，一种新型肽库平台，以前从未用于疟疾治疗。表位识别 将鉴定疟疾感染后的血清 IgA 和 IgG，纵向研究设计将允许 研究疟疾抗体反应的强度、动力学和同种型比率 (IgA/IgG)。总之， 这项工作将回答有关 IgA 对疟疾感染的反应的关键问题，识别表位和 探索作为疫苗候选抗原的蛋白质，并提供有关抗体反应的新数据 抗原变体。总的来说，这些发现将提高我们对疟疾免疫反应的理解， 告知疫苗设计。