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Triggering germline-encoded broadly neutralizing antibody responses against influenza virus

触发针对流感病毒的种系编码的广泛中和抗体反应

基本信息

批准号：
10241949
负责人：
Facundo Damian Batista
金额：
$ 52.06万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-19 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241949
关键词：
Adult Affinity Animals Antibodies Antibody Repertoire Antibody Response Antigens Avian Influenza B-Lymphocytes Cell Lineage Centers for Disease Control and Prevention (U.S.)Cessation of life Development Disease Economics Engineering Epitopes Faculty Failure Frequencies Gene Amplification Genes Genetic Template Geometry Hemagglutinin Hospitalization Hot Spot Human Hydrophobicity Immune Immunity Immunization Immunize Immunoglobulin M Immunologic Memory Individual Influenza Influenza A virus Influenza Hemagglutinin Institutes Memory Memory B-Lymphocyte Modeling Mus Natural Immunity Pathway interactions Property Proteins RHOA gene Recording of previous events Research Personnel Seasons Serum Site Specificity Structure of germinal center of lymph node System Testing Time Titrations Transgenic Mice Update Vaccination Vaccine Antigen Vaccine Design Vaccines Viral Virus Work design flu genetic manipulation humanized mouse immune activation in vivo indexing influenza infection influenza virus vaccine influenzavirus member mouse model nanoparticle neutralizing antibody next generation pandemic disease polyclonal antibody reconstitution response seasonal influenza stem universal influenza vaccine universal vaccine vaccine development vaccine evaluation vaccine-induced antibodies

项目摘要

Project Summary / Abstract This is an application by Dr. Daniel Lingwood and Dr. Facundo Batista, faculty members of the Ragon Institute of MGH, MIT and Harvard. Both investigators define B cell-antigen recognition principles to inform antibody vaccine design, and for this, have developed two orthogonal transgenic mouse models that recapitulate human antibody responses in vivo. The investigators propose to apply these models to evaluate germline stimulation of human B cell lineages known to give rise to broadly neutralizing antibody (bnAbs) against influenza A viruses (IAV), which account for the majority of flu-hospitalizations and pandemic threats. Most antibody responses to IAV are dominated by off-target, non-neutralizing activities, however, work from the investigators indicates that human BCRs assembled from the antibody VH gene, IGHV1-69, possess natural specificity for a conserved site of vulnerability, the stem-bnAb epitope on the hemagglutinin spike proteins from Group 1 IAV (IAV subtypes: H1, H2, H5, H6, H8, H9, H11, H12, H12, H16). To test if this genetically endows for vaccine- amplifiable bnAb development pathways, the investigators have engineered the LINGWOOD mouse system, where antibodies develop with human antibody VH genes (e.g. IGHV1-69) and full human CDRH3 diversity. Genetic manipulation of this system enables in vivo B cell titration to match the IGHV1-69 B cell frequency found in humans. Sequentially immunizing these mice with SS-np, a nanoparticle displaying the bnAb target, has succeeded in germline stimulation of IGVH1-69 bnAb precursors and IGHV1-69-dependent expansion of bnAb responses; the first example of eliciting high titer IAV bnAbs through vaccination. This response also provided broad protection against Group 1 IAV, including pandemic bird flu, supporting the investigators' central hypothesis that broadly protective bnAbs can be elicited by germline antibody-targeting vaccines. In Aim 1, the investigators will define whether SS-np stands as a universal booster of the IGHV1-69-encoded bnAb response after introduction of B cell memory to diverse IAV `swarms' that simulate human immune history to influenza. In Aim 2, the investigators will define how refocusing serum antibodies against this specific bnAb target also enhances antibody Fc effector functions, potentially co-enabling protection through activation of innate immunity. In Aim 3, the BATISTA mouse system will be used to evaluate vaccine-expansion of IGHV1-69 bnAbs alongside the human IGHV1-18- and IGHV6-1-class bnAb lineages, which neutralize the remaining Group 2 IAV subtypes (H3, H4, H7, H10, H14, H15). In this system, murine IgM B cells bearing individual human bnAb precursors of each pathway are co-transferred to a single recipient mouse. Following immunization, lineage expansions are individually tracked via their progression through B cell germinal centers and then into immune memory. The animals will be co-immunized with SS-np, SS-np2, and SS-np3; three geometrically identical nanoparticles bearing distinct affinities for each bnAb precursor. Selective + collective expansion of these bnAb lineages aims to overcome failure of traditional influenza vaccine approaches.

项目摘要/摘要