Serological markers of natural immunity to Plasmodium falciparum infection

对恶性疟原虫感染的自然免疫的血清学标志物

• 批准号: 10643851
• 负责人: DeAnna Friedman-Klabanoff
• 金额: $ 17.89万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643851
• 关键词: Alleles; Anopheles Genus; Antibodies; Antibody titer measurement; Antigens; B-Lymphocytes; Berry; Binding; Biological Assay; Bite; Blood; Child; Childhood; Circulation; Classification; Clinical; Clinical Immunology; Clinical Research; Cohort Studies; Collection; Communicable Diseases; Culicidae; Custom; DNA; Data; Data Science; Databases; Dedications; Detection; Development; Development Plans; Disease; Doctor of Medicine; Epitopes; Erythrocytes; Exposure to; Funding; Generations; Genetic Variation; Geographic Locations; Goals; Household; Human; Humoral Immunities; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunodominant Epitopes; Immunology; Impairment; In Vitro; Individual; Infection; International; Invaded; K-Series Research Career Programs; Laboratories; Leadership; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Malawi; Maryland; Membrane Proteins; Mentors; Mentorship; Methods; Microarray Analysis; Microsatellite Repeats; Modeling; Molecular Epidemiology; Natural Immunity; Outcome; Parasites; Peptides; Plasmodium; Plasmodium falciparum; Plasmodium falciparum genome; Positioning Attribute; Proteins; Research; Research Design; Research Personnel; Role; Salivary Glands; Sampling; Serology; Serum; Source; Specialist; Sporozoites; T-Lymphocyte Epitopes; Testing; Training; Travel; United States National Institutes of Health; Universities; Vaccines; Variant; Work; acquired immunity; career; career development; design; epidemiology study; global health; human DNA; improved; in silico; in vitro Model; in vivo; insight; interest; large datasets; machine learning algorithm; malaria infection; malaria mosquito; medical schools; member; novel; novel vaccines; participant enrollment; pathogen; polyclonal antibody; predictive tools; prevent; random forest; response; serological marker; skills; surveillance data; tool; translational scientist; transmission process; vaccine candidate; vaccine development; vaccinology

PROJECT SUMMARY Plasmodium falciparum is the most common and deadly cause of malaria. An effective malaria vaccine has the potential to make a pivotal change in malaria control and eradication. For a vaccine to contribute significantly to malaria eradication, it must target the early, pre-erythrocytic part of the lifecycle to block both symptomatic disease and asymptomatic infection, which perpetuates transmission. Naturally acquired immunity to pre- erythrocytic infection is acquired with exposure but remains poorly understood and continues to impede vaccine efforts. DeAnna Friedman-Klabanoff, M.D., a pediatric infectious disease specialist at the University of Maryland School of Medicine, developed this career development award proposal to use novel high-throughput tools to define naturally acquired humoral immunity to diverse pre-erythrocytic epitopes associated with protection, which could lead to novel vaccine candidates. Dr. Friedman-Klabanoff’s long-term goal is to become an independent clinical and translational researcher dedicated to the development of a malaria vaccine, applying immunology and data science to inform and optimize vaccine development. To gain the skills necessary to achieve this goal, Dr. Friedman-Klabanoff proposes a career development plan that includes mentoring from Drs. Miriam Laufer, Shannon Takala Harrison, Michael Cummings, Andrea Berry, Kathleen Neuzil, and John Adams, leaders in the fields of international research design and leadership, molecular epidemiology, data science for analysis of large data sets, use of peptide microarrays to study malaria, vaccinology, and in vitro models of pre-erythrocytic immunity. This project will utilize samples and data from a cohort study of malaria in Malawi led by Dr. Laufer, the primary mentor for this proposal. Household members were followed monthly for detection of malaria infection and mosquitoes were collected from the houses to identify bloodmeal sources. Bloodmeal sources will be identified by matching the human DNA found in the mosquito bloodmeals to DNA from enrolled participants . Mosquito salivary glands will also be tested for P. falciparum infection to determine if the mosquitoes were infectious. Children will be defined as protected or infected based on whether they develop blood-stage infection during the month after an infectious bite. Aim 1 of this proposal will be to identify serologic responses associated with natural protection against P. falciparum infection after exposure to an infectious bite. Serum from the day of exposure will be probed on a custom-developed peptide microarray designed from diverse, field-derived sequences to characterize pre-exposure immunity to pre-erythrocytic antigens. Aim 2 of this proposal is to assess the functional role of antibodies targeting P. falciparum pre-erythrocytic antigens of interest. B- and T- cell epitope prediction tools will be used to find predicted epitopes in pre-erythrocytic proteins and their variants, and in vitro liver models will be used to assess the functional role of antibodies to these epitopes to validate and down select the potential epitopes. The practical implications of this work will be to identify promising epitopes that are targets of protective immunity.

项目摘要 恶性疟原虫是疟疾最常见和最致命的原因。一种有效的疟疾疫苗 在控制和消灭疟疾方面作出重大改变的潜力。要想让一种疫苗 为了根除疟疾，它必须针对生命周期的早期，红细胞前期部分， 疾病和无症状感染，使传播永久化。自然获得的免疫力， 红细胞感染是通过暴露获得的，但仍然知之甚少，并继续阻碍疫苗 努力DeAnna Friedman-Klabanoff，医学博士，马里兰州大学的儿科传染病专家 医学院，开发了这个职业发展奖的建议，使用新颖的高通量工具， 定义了与保护相关的多种红细胞前表位的天然获得性体液免疫， 可能会产生新的候选疫苗。Friedman-Klabanoff博士的长期目标是成为一名独立的 临床和转化研究员，致力于疟疾疫苗的开发，应用免疫学 和数据科学，为疫苗开发提供信息和优化。为了获得实现这一目标所需的技能， 博士弗里德曼-克拉班诺夫提出了一个职业发展计划，其中包括米里亚姆·劳弗博士的指导， Shannon Takala Harrison，Michael Cummings，Andrea Berry，Kathleen Neuzil和John亚当斯， 国际研究设计和领导领域，分子流行病学，分析大型 数据集，使用肽微阵列研究疟疾，疫苗学，以及红细胞前 免疫力该项目将利用Laufer博士领导的马拉维疟疾队列研究的样本和数据， 这个提议的主要指导者每月对家庭成员进行跟踪，以检测疟疾 从房屋中收集感染和蚊子，以确定血餐来源。血粉来源将 通过将蚊子血餐中发现的人类DNA与登记参与者的DNA进行匹配来识别。 还将对蚊子唾液腺进行恶性疟原虫感染检测，以确定蚊子是否感染了恶性疟原虫。 传染性儿童将根据他们是否发展为血液阶段感染而被定义为受保护或感染 在感染性咬伤后的一个月内。本提案的目的1是确定与免疫相关的血清学反应， 在暴露于感染性叮咬后，对恶性疟原虫感染具有天然保护作用。当天的血清 暴露将在定制开发的肽微阵列上进行探测， 序列来表征对红细胞前抗原的暴露前免疫性。本提案的目标2是 评估靶向感兴趣的恶性疟原虫红细胞前抗原的抗体的功能作用。B-和T- 细胞表位预测工具将用于发现红细胞前蛋白及其变体中的预测表位， 体外肝脏模型将用于评估抗体对这些表位的功能作用， 向下选择潜在的表位。这项工作的实际意义将是确定有前途的表位 保护性免疫的目标