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：
10028586
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/10028586
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 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

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.

项目概要/摘要这是拉贡研究所教员 Daniel Lingwood 博士和 Facundo Batista 博士的申请麻省总医院、麻省理工学院和哈佛大学。两位研究人员都定义了 B 细胞抗原识别原理以告知抗体疫苗设计，为此，开发了两种正交转基因小鼠模型，再现了人类体内抗体反应。研究人员建议应用这些模型来评估生殖细胞刺激已知可产生针对甲型流感病毒的广泛中和抗体 (bnAb) 的人类 B 细胞谱系病毒 (IAV)，它是流感住院和大流行威胁的主要原因。大多数抗体对 IAV 的反应主要是脱靶、非中和活动，然而，研究人员的工作表明由抗体 VH 基因 IGHV1-69 组装而成的人类 BCR 对脆弱性保守位点，第 1 组 IAV 血凝素刺突蛋白上的茎 bnAb 表位（IAV 亚型：H1、H2、H5、H6、H8、H9、H11、H12、H12、H16）。为了测试这是否在基因上赋予了疫苗- 为了实现可扩增的 bnAb 开发途径，研究人员设计了 LINGWOOD 小鼠系统，其中抗体利用人类抗体 VH 基因（例如 IGHV1-69）和完整的人类 CDRH3 多样性进行开发。该系统的基因操作使体内 B 细胞滴定能够匹配 IGHV1-69 B 细胞频率在人类中发现。随后用 SS-np（一种显示 bnAb 靶标的纳米颗粒）对这些小鼠进行免疫接种，已成功实现 IGVH1-69 bnAb 前体的种系刺激和 IGHV1-69 依赖性扩增 bnAb 反应；通过疫苗接种引发高滴度 IAV bnAb 的第一个例子。这个回应也提供了针对第一组 IAV 的广泛保护，包括大流行性禽流感，支持研究人员的中心假设是种系抗体靶向疫苗可以引发广泛的保护性 bnAb。在目标 1，研究人员将确定 SS-np 是否是 IGHV1-69 编码的通用增强剂将 B 细胞记忆引入模拟人类免疫的不同 IAV“群”后，bnAb 的反应流感病史。在目标 2 中，研究人员将定义如何重新聚焦针对这种特定的血清抗体 bnAb 靶标还增强抗体 Fc 效应器功能，可能通过激活共同实现保护先天免疫。在目标 3 中，BATISTA 小鼠系统将用于评估疫苗的扩展 IGHV1-69 bnAb 与人类 IGHV1-18 和 IGHV6-1 级 bnAb 谱系一起，中和其余第 2 组 IAV 亚型（H3、H4、H7、H10、H14、H15）。在该系统中，小鼠 IgM B 细胞携带每个途径的单个人类 bnAb 前体被共同转移到单个受体小鼠中。下列的免疫、谱系扩张通过 B 细胞生发中心的进展进行单独追踪然后进入免疫记忆。动物将接受 SS-np、SS-np2 和 SS-np3 联合免疫；三几何形状相同的纳米颗粒对每种 bnAb 前体具有不同的亲和力。选择性+集体这些 bnAb 谱系的扩展旨在克服传统流感疫苗方法的失败。