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: 10448386
• 负责人: DeAnna Friedman-Klabanoff
• 金额: $ 17.67万
• 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/10448386
• 关键词: Alleles; Anopheles Genus; Antibodies; Antibody titer measurement; Antigens; B-Lymphocytes; Berry; Binding; Biological Assay; Bite; Blood; Blood Circulation; Child; Childhood; Clinical; Clinical Immunology; Clinical Research; Cohort Studies; Collection; Communicable Diseases; Culicidae; Custom; DNA; Data; Data Science; Databases; Detection; Development; Development Plans; Disease; Doctor of Medicine; Enrollment; Epitopes; Erythrocytes; Exposure to; Funding; Generations; Genetic Variation; Geographic Locations; Goals; Household; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunodominant Epitopes; Immunology; Impairment; In Vitro; Individual; Infection; International; Invaded; K-Series Research Career Programs; Laboratories; Lead; Leadership; Liver; Malaria; Malaria Vaccines; Malawi; Maryland; Masks; Membrane Proteins; Mentors; Mentorship; Methods; Microarray Analysis; Microsatellite Repeats; Modeling; Molecular Epidemiology; Natural Immunity; Outcome; Parasites; Participant; 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; base; 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; pathogen; polyclonal antibody; 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致命的原因。有效的疟疾疫苗具有 潜在地改变疟疾控制和消除的潜力。疫苗可以显着贡献 消除疟疾，它必须瞄准生命周期的早期，肉毒杆菌的早期，以阻止这两种症状 疾病和渐近感染，使传播永存。自然获得的免疫力预先 红细胞感染是通过暴露而获得的，但仍然了解不足并继续阻碍疫苗 努力。迪安娜·弗里德曼·克拉巴诺夫（Deanna Friedman-Klabanoff），医学博士，马里兰大学的儿科传染病专家 医学院，制定了这项职业发展奖提案，以使用新颖的高通量工具来 定义自然获得的体液免疫对潜水员的肉芽囊细胞前表位，该表位与保护相关，该表位 可能导致新型疫苗候选物。弗里德曼·克拉巴诺夫（Friedman-Klabanoff）博士的长期目标是成为独立 临床和翻译的研究人员致力于开发疟疾疫苗，采用免疫学 和数据科学，以告知和优化疫苗开发。为了获得实现这一目标所需的技能， 弗里德曼·克拉巴诺夫（Friedman-Klabanoff）博士提出了一项职业发展计划，其中包括医生的指导。 Miriam Laufer， Shannon Takala Harrison，Michael Cummings，Andrea Berry，Kathleen Neuzil和John Adams和John Adams 国际研究设计和领导力领域，分子流行病学，数据科学用于分析大型 数据集，使用胡椒微阵列研究疟疾，疫苗学和体外肉毒杆菌模型 免疫。该项目将利用由劳弗博士领导的马拉维疟疾队列研究的样本和数据， 该提案的主要导师。每月跟踪家庭成员以检测疟疾 从房屋收集感染和蚊子以鉴定血液源。血液消息来源会 可以通过将蚊子血液中发现的人DNA与入学参与者的DNA相匹配。 蚊子唾液腺也将测试恶性疟原虫感染，以确定蚊子是否为 感染力。儿童将根据是否发展为血液阶段感染而被定义为受保护或感染 在感染性叮咬之后的一个月。该建议的目标1将是确定相关的血清学反应 暴露于感染性咬合后，自然保护了恶性疟原虫感染。从一天开始的血清 将在从潜水员，现场衍生的定制肽微阵列上探测暴露 表征暴露前的免疫对肉毒前抗原的免疫的序列。该提议的目标2是 评估靶向恶性疟原虫的抗体前肉毒杆菌抗原感兴趣的抗体的功能作用。 b-和t- 细胞表位预测工具将用于查找预息蛋白及其变体中的预测表位，即 并将使用体外肝模型来评估抗体对这些表位的功能作用，以验证和 向下选择潜在的表位。这项工作的实际含义将是确定有希望的表位 是保护性免疫的靶标。