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: 10301258
• 负责人: DeAnna Friedman-Klabanoff
• 金额: $ 18.91万
• 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/10301258
• 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.

项目总结