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.

项目摘要/摘要 这份提案描述了由助理教授Daniel Lingwood博士提供的R01赠款的框架 哈佛医学院，麻省理工学院和哈佛大学拉贡研究所的教员，以及布莱斯博士 Chackerian是该大学分子遗传学和微生物学系的副教授 新墨西哥医学院的。他们的研究重点是B细胞受体(BCR)抗原识别 生物学(Lingwood)和定向进化病毒样颗粒(VLP)疫苗平台(Chackerian)。同舟共济 他们建议开发一种通用流感疫苗设计的新策略。疫苗引发的抗体最多 对这种病毒的反应主要是由免疫优势的非靶标、非中和活性决定的。然而， Lingwood博士最近的研究表明，人类BCRs是通过抗体基因IGHV1-69组装起来的 具有V区编码的(天生的)针对功能保守的脆弱部位的专一性，茎- 流感尖峰蛋白血凝素(HA)表位和广谱中和抗体靶标(BNab) 回应。为了将其作为构建通用疫苗的基因编码模板进行实验评估，Dr。 Lingwood已经培育出转基因小鼠，抗体的产生通过正常的人类VDJ进行 重组，但V区的使用被限制在IGHV1-69。初步数据表明，IGHV1-69 使用本身将抗体反应重新聚焦到干细胞表位，林伍德博士发现的一个特征是 依赖于IGHV1-69与茎接触的CDRH2中的单个基因编码的氨基酸。到现在为止 将其转化为bNab诱导，林伍德博士建议用理性的- 设计三聚体和纳米颗粒展示触发天然类茎表位的流感血凝素茎 利用重组生殖系IGHV1-69BCR进行信号传递。通过这些实验，林伍德博士将提供 理性疫苗设计的重大范式转变，即通过 “激活”和“放大”基因编码的抗体反应。为临床定义一条路径 发展中，Lingwood博士和Chackerian博士已经应用了RNA噬菌体展示和亲和力 获得与IGHV1-69种系V区多价亲和力的VLP疫苗的筛选技术 BCR，本质上是一种V区特异性引物，用于选择性地扩大先天类干靶向活性，即 否则通常会被人类的BCR多样性冲淡。选择性IGHV1-69底漆将在 Trianni小鼠，最新的行业标准人源化小鼠疫苗模型。然后将V区启动 用IGHV1-69结合HA干细胞免疫原增强，以刺激现在免疫显性的先天HA 干感抗体反应。利用遗传基础进行bNab的诱导旨在克服 流感疫苗接种的传统方法，并与这一筹资机会的目的一致 以及美国国家卫生研究院更广泛的使命。