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

• 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
• 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

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 这是Ragon Institute教职员工Daniel Lingwood博士和Facundo Batista博士的申请 MGH，麻省理工学院和哈佛大学。两个研究者都定义了B细胞抗原识别原理，以告知抗体 疫苗设计，为此，已经开发了两个正交的转基因小鼠模型，这些模型概括了人类 体内抗体反应。研究人员建议应用这些模型来评估种系刺激 人类B细胞谱系已知会引起对流感A的广泛中和抗体（BNAB） 病毒（IAV），占多数流感医院和大流行威胁。大多数抗体 对IAV的响应由脱离目标，非中和活动主导，但是，研究人员的工作 表明从抗体VH基因组装的人BCR IGHV1-69具有自然特异性 脆弱性的保守位点，来自第1组IAV的血凝素尖峰蛋白上的茎-BNAB表位 （IAV亚型：H1，H2，H5，H6，H8，H9，H11，H11，H12，H12，H16）。测试这种遗传因素是否赋予疫苗 可放大的BNAB开发途径，研究人员已经设计了Lingwood Mouse系统， 抗体使用人类抗体VH基因（例如IGHV1-69）和完整的人类CDRH3多样性而形成抗体。 该系统的遗传操纵使体内B细胞滴定与IGHV1-69 B细胞频率匹配 在人类中发现。用SS-NP依次将这些小鼠免疫，SS-NP是一种纳米颗粒，显示BNAB靶标， 在IGVH1-69 BNAB前体的生殖线刺激方面成功了，IGHV1-69依赖性扩展 BNAB响应；通过疫苗接种引起高滴度IAV BNAB的第一个例子。此回应也是如此 为包括大流行鸟类流感在内的1组IAV提供了广泛的保护，支持研究者 中央假设可以通过靶向种系抗体疫苗引起广泛的保护性BNAB。在 AIM 1，调查人员将定义SS-NP是否站立为IGHV1-69编码的通用助推器 将B细胞记忆引入到模拟人类免疫的各种IAV“群”之后的BNAB响应 流感的历史。在AIM 2中，研究人员将定义如何重新聚焦血清抗体针对该特定 BNAB靶标还增强了抗体FC效应子功能，可能通过激活来实现保护 先天免疫。在AIM 3中，Batista Mouse系统将用于评估疫苗扩张 IGHV1-69 BNAB与人类IGHV1-18-和IGHV6-1级BNAB谱系旁边，中和 其余2组IAV亚型（H3，H4，H7，H10，H14，H15）。在该系统中，鼠IgM B细胞带有 每种途径的单个人类BNAB前体共转移至单个受体小鼠。下列的 免疫，谱系膨胀通过其通过B细胞生发中心的进展单独跟踪 然后进入免疫记忆。这些动物将与SS-NP，SS-NP2和SS-NP3共免疫；三 几何相同的纳米颗粒具有每个BNAB前体的不同亲和力。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。