Innate-like BCR activity as a template for universal vaccination against influenza virus

类先天 BCR 活性作为流感病毒通用疫苗接种的模板

• 批准号: 10402386
• 负责人: Bryce C Chackerian
• 金额: $ 54.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402386
• 关键词: Adaptive Immune System; Affinity; Amino Acids; Animal Model; Animals; Antibodies; Antibody Repertoire; Antibody Response; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Biology; Cell Lineage; Clinical Pathways; Complementarity Determining Regions; Data; Development; Directed Molecular Evolution; Epitopes; Evolution; Failure; Funding Opportunities; Gene Amplification; Genes; Genetic; Genetic Recombination; Genetic Template; Grant; Hemagglutinin; Heterozygote; Human; Immunity; Immunization; Immunize; Immunologic Receptors; Industry Standard; Influenza; Influenza Hemagglutinin; Influenza vaccination; Institutes; Instruction; Medical Faculty; Microbiology; Mission; Modeling; Molecular Genetics; Mus; New Mexico; Pathway interactions; Pattern; Pattern Recognition; Peptides; Phenylalanine; Positioning Attribute; Proteins; RNA Phages; Regimen; Research; Shapes; Signal Transduction; Single Nucleotide Polymorphism; Site; Specificity; Structure; System; Technology; Testing; Transgenic Mice; United States National Institutes of Health; Universities; V(D)J Recombination; Vaccination; Vaccine Design; Vaccines; Viral; Virus; Virus-like particle; Work; antigen binding; base; booster vaccine; clinical development; design; experimental study; humanized mouse; in vivo; influenzavirus; medical schools; member; mid-career faculty; mouse model; nanoparticle; neutralizing antibody; preservation; prevent; professor; rational design; receptor; reconstitution; response; sensor; stem; tool; universal influenza vaccine; universal vaccine; vaccine discovery; vaccine platform

Project Summary / Abstract This proposal describes the framework of an R01 grant by Dr. Daniel Lingwood, an Assistant Professor at Harvard Medical School and faculty member of the Ragon Institute of MGH, MIT and Harvard, and Dr. Bryce Chackerian, an Associate Professor in the Department of Molecular Genetics & Microbiology at the University of New Mexico School of Medicine. Their research centers on B cell receptor (BCR) antigen recognition biology (Lingwood) and directed evolution of virus-like particle (VLP) vaccine platforms (Chackerian). Together they propose to develop a new strategy for universal influenza vaccine design. Most vaccine-elicited antibody responses to this virus are dominated by immunodominant off-target, non-neutralizing activities. However, recent work from Dr. Lingwood indicates that human BCRs assembled using the antibody gene IGHV1-69 possess V region-encoded (innate-like) specificity for a functionally conserved site of vulnerability, the stem- epitope of the influenza spike protein hemagglutinin (HA) and target of broadly neutralizing antibody (bnAb) responses. To experimentally evaluate this as a gene-encoded template for building a universal vaccine, Dr. Lingwood has generated transgenic mice in which antibody development proceeds via normal human VDJ recombination, but where V region use is constrained to IGHV1-69. Preliminary data indicate that IGHV1-69 usage itself refocuses the antibody response to the stem epitope, a feature that Dr. Lingwood finds is dependent on a single gene-encoded amino acid in the stem-contacting CDRH2 of IGHV1-69. To now transduce this into bnAb elicitation, Dr. Lingwood proposes to immunize his humanized mice with rationally- designed trimeric and nanoparticle displays of influenza HA stem which trigger innate-like stem-epitope signaling by the reconstituted germline IGHV1-69 BCR. Through these experiments Dr. Lingwood will provide a major paradigm shift in rational vaccine design, namely that broad protection may be generated through `activation' and `amplification' of gene-encoded antibody responses. To define a pathway for clinical development, Drs. Lingwood and Chackerian have applied RNA bacteriophage peptide display and affinity selection technology to derive a VLP vaccine with multivalent affinity to the V region of IGHV1-69 germline BCR, in essence a V region-specific primer to selectively expand innate-like stem targeting activity that is otherwise normally diluted by human BCR diversity. Selective IGHV1-69 priming will be evaluated in the Trianni mouse, the latest industry-standard humanized mouse vaccine model. V region priming will then be boosted with IGHV1-69-engaging HA stem immunogens, to stimulate a now immunodominant innate-like HA stem sensing antibody response. Exploiting a genetic basis for bnAb elicitation aims to overcome the failure of traditional approaches to influenza vaccination and is consistent with the purpose of this funding opportunity and broader mission of the NIH.

项目概要/摘要 该提案描述了由 Daniel Lingwood 博士（Daniel Lingwood 助理教授）提供的 R01 资助的框架。 哈佛医学院、麻省总医院、麻省理工学院和哈佛大学 Ragon 研究所的教员以及 Bryce 博士 Chackerian，该大学分子遗传学与微生物学系副教授 新墨西哥医学院。他们的研究重点是 B 细胞受体 (BCR) 抗原识别 生物学（Lingwood）和病毒样颗粒（VLP）疫苗平台的定向进化（Chackerian）。一起 他们建议制定通用流感疫苗设计的新策略。大多数疫苗引发的抗体 对这种病毒的反应主要是免疫显性的脱靶、非中和活动。然而， Lingwood 博士最近的研究表明，人类 BCR 使用抗体基因 IGHV1-69 进行组装 具有V区编码的（先天性的）特异性，针对功能保守的脆弱位点，茎 流感尖峰蛋白血凝素 (HA) 的表位和广泛中和抗体 (bnAb) 的靶标 回应。为了通过实验评估其作为构建通用疫苗的基因编码模板，博士。 Lingwood 培育出转基因小鼠，其中抗体通过正常人类 VDJ 进行发育 重组，但 V 区的使用仅限于 IGHV1-69。初步数据表明IGHV1-69 使用本身重新集中了抗体对茎表位的反应，Lingwood 博士发现的一个特征是 依赖于 IGHV1-69 的茎接触 CDRH2 中单个基因编码的氨基酸。到现在 将其转化为 bnAb 诱导，Lingwood 博士建议用合理的方法对他的人源化小鼠进行免疫： 设计了流感 HA 干的三聚体和纳米颗粒展示，可触发先天样干表位 重组种系 IGHV1-69 BCR 的信号传导。通过这些实验，林伍德博士将提供 合理疫苗设计的重大范式转变，即可以通过以下方式产生广泛的保护 基因编码抗体反应的“激活”和“放大”。定义临床途径 发展，博士。 Lingwood 和 Chackerian 应用了 RNA 噬菌体肽展示和亲和力 选择技术衍生出对 IGHV1-69 种系 V 区具有多价亲和力的 VLP 疫苗 BCR，本质上是一种 V 区特异性引物，用于选择性扩展先天样干靶向活性，即 否则通常会被人类 BCR 多样性稀释。选择性 IGHV1-69 启动将在 Trianni小鼠，最新的行业标准人源化小鼠疫苗模型。 V 区启动将是 使用 IGHV1-69 接合 HA 干免疫原进行增强，以刺激现在免疫主导的先天性 HA 干感应抗体反应。利用 bnAb 诱导的遗传基础旨在克服 流感疫苗接种的传统方法与本次融资机会的目的一致 以及 NIH 更广泛的使命。