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.

项目概要 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以下特点。 疫苗有可能在疟疾控制和根除方面做出重大改变。 根除疟疾，必须针对生命周期的早期红细胞前部分，以阻止症状 疾病和无症状感染，从而使传播自然获得免疫力。 红细胞感染是通过接触而获得的，但人们对它知之甚少，并且继续阻碍疫苗接种 DeAnna Friedman 的努力——马里兰大学儿科传染病专家 Klabanoff 医学博士 医学院制定了这项职业发展奖提案，旨在使用新颖的高通量工具 定义了对与保护相关的多种红细胞前表位的自然获得的体液免疫， 弗里德曼-克拉班诺夫博士的长期目标是成为一名独立的科学家。 致力于应用免疫学开发疟疾疫苗的临床和转化研究人员 和数据科学来指导和优化疫苗开发，以获得实现这一目标所需的技能， Friedman-Klabanoff 博士提出了一项职业发展计划，其中包括 Miriam Laufer 博士的指导。 香农·塔卡拉·哈里森 (Shannon Takala Harrison)、迈克尔·卡明斯 (Michael Cummings)、安德里亚·贝里 (Andrea Berry)、凯瑟琳·诺伊齐尔 (Kathleen Neuzil) 和约翰·亚当斯 (John Adams) 国际研究设计和领导力、分子流行病学、大规模数据分析的数据科学等领域 数据集、使用肽微阵列研究疟疾、疫苗学和前红细胞体外模型 该项目将利用由 Laufer 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接受一次疟疾检测跟踪。 从房屋中收集感染和蚊子以确定血粉来源。 通过将蚊子血粉中发现的人类 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。 儿童将根据是否出现血液阶段感染被定义为受保护或感染。 该提案的目标 1 是确定相关的血清学反应。 从接触传染性血清后，对恶性疟原虫感染具有天然的保护作用。 暴露将在定制开发的肽微阵列上进行探测，该微阵列由不同的、现场衍生的设计 该提案的目标 2 是表征对前红细胞抗原的暴露前免疫的序列。 评估针对目标 B 和 T 恶性疟原​​虫前红细胞抗原的抗体的功能作用。 细胞表位预测工具将用于寻找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，以验证和 向下选择潜在的表位这项工作的实际意义将是确定有希望的表位。 这是保护性免疫的目标。