Genetic, structural and functional profiling of the human antibody response to arenavirus infection

人类抗体对沙粒病毒感染反应的遗传、结构和功能分析

• 批准号: 10688292
• 负责人: Raiees Ahmad Andrabi
• 金额: $ 87.03万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688292
• 关键词: Address; Africa; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Area; Arenavirus; Arenavirus Infections; B-Lymphocytes; Basic Science; Binding; Biological Assay; Case Fatality Rates; Case Study; Categories; Cells; Cessation of life; Classification; Clinical; Clonal Expansion; Collaborations; Complex; Country; Development; Disease; Disease Outbreaks; Ebola; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; FDA approved; Family; Foundations; Future; Genetic; Geographic Distribution; Geography; Ghana; Glycoproteins; Goals; Government; Guinea; Heart; Hospitalization; Hospitals; Human; Humoral Immunities; Immune Evasion; Immune response; Immune system; Immunity; Immunogenetics; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunology; Infection; Ivory Coast; Lassa Fever; Lassa virus; Liberia; Mali; Maps; Molecular; Monoclonal Antibodies; Nigeria; Old World Arenaviruses; Pathogenesis; Patients; Phenotype; Phylogenetic Analysis; Population; Productivity; Property; RNA Viruses; Recording of previous events; Research Personnel; Resolution; Risk; Rodent; Serum; Sierra Leone; Site; Specificity; Structure; Surveys; Survivors; Tacaribe Complex Viruses; Techniques; Therapeutic; Togo; Vaccine Design; Vaccinee; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Virus; Vulnerable Populations; Work; Zoonoses; adaptive immunity; cohort; design; effective therapy; genetic analysis; high risk; immunogenic; innovation; interest; long-term sequelae; member; multidisciplinary; multiple omics; neutralizing antibody; novel; pandemic pathogen; pandemic potential; pathogen; priority pathogen; response; segregation; tool; translational study; transmission process; vaccine development; virus host interaction

PROJECT SUMMARY Arenaviruses are a family of zoonotic RNA viruses that are capable of causing severe hemorrhagic fever disease in humans. Lassa virus (LASV), an Old World arenavirus which is endemic in regions of West Africa including Sierra Leone and is the causative agent of Lassa fever (LF), causes thousands of deaths annually. Arenaviruses have repeatedly crossed over into humans over the past several decades, and emerging variants of known arenaviruses often display increased human-to-human transmissibility and broader geographic range. For these reasons, the CDC and WHO have classified several human arenaviruses as high priority pathogens and the PREDICT consortium ranked LASV as the highest risk virus on their watchlist of potential pandemic pathogens. Vaccines and therapeutics against arenaviruses are urgently needed, however, we must first gain a much deeper understanding of the molecular mechanisms that result in protective humoral immunity. Although the discovery of effective clinical countermeasures is the ultimate goal, this collaborative project focuses on leveraging innovative, high-throughput antibody discovery and characterization tools to define the genetic, functional and structural properties of anti-LASV antibodies with broad specificity across human arenaviruses. We have assembled a collaborative, multidisciplinary group of investigators with a long history of productive collaboration in viral immunology and with complementary areas of expertise. Additionally, we have access to a singular cohort of LF survivors at Kenema Government Hospital, which is located in Sierra Leone and is at the heart of the LF zone. We expect our work will result in the discovery of thousands of novel anti-LASV antibodies, characterization of which will reveal conserved sites of viral vulnerability and uncover the precise molecular mechanisms of viral neutralization. These fundamental studies directly address critical gaps in our understanding of the interplay between humoral immunity and hemorrhagic fever-causing arenaviruses and will serve as a foundation for future translational studies.

项目总结

项目成果

A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection.

• DOI: 10.1038/s41467-023-41376-6
• 发表时间: 2023-09-12
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ronk, Adam J.;Lloyd, Nicole M.;Zhang, Min;Atyeo, Caroline;Perrett, Hailee R.;Mire, Chad E.;Hastie, Kathryn M.;Sanders, Rogier W.;Brouwer, Philip J. M.;Saphire, Erica Olmann;Ward, Andrew B.;Ksiazek, Thomas G.;Alvarez Moreno, Juan Carlos;Thaker, Harshwardhan M.;Alter, Galit;Himansu, Sunny;Carfi, Andrea;Bukreyev, Alexander
• 通讯作者: Bukreyev, Alexander