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: 10163789
• 负责人: Bryce C Chackerian
• 金额: $ 51.19万
• 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/10163789
• 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; clinical development; design; experimental study; humanized mouse; in vivo; influenzavirus; medical schools; member; mid-career faculty; mouse model; nanoparticle; neutralizing antibody; preservation; prevent; professor; receptor; reconstitution; response; sensor; stem; tool; universal influenza vaccine; universal vaccine; vaccine discovery

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 该建议描述了R01赠款的框架，由Daniel Lingwood博士 哈佛医学院和MGH，麻省理工学院和哈佛大学Ragon研究所的教职员工，布莱斯博士 Chackerian，大学分子遗传学和微生物学系的副教授 新墨西哥州医学院。他们的研究集中于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（Chackerian）的定向演变。一起 他们建议为普遍流感疫苗设计制定新的策略。大多数疫苗吸收的抗体 对该病毒的反应主要由免疫脱离靶向，非中和活动的活性主导。然而， Lingwood博士的最新工作表明，使用抗体基因IGHV1-69组装的人类BCR 具有v区域编码的（先天性）特异性，用于功能保守的脆弱性部位，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 回答。为了将其作为用于建造通用疫苗的基因编码模板，博士 Lingwood产生了转基因小鼠，其中抗体发育通过正常的人VDJ进行 重组，但v区域使用的地方约束至IGHV1-69。初步数据表明IGHV1-69 用法本身重新关注对茎表位的抗体反应，Lingwood博士发现的功能是 取决于IGHV1-69的茎连接CDRH2中的单个基因编码的氨基酸。到现在 将其转变为BNAB启发，Lingwood博士提议用理性地免疫他的人源性小鼠 设计的三聚体和纳米颗粒显示了流感的HA茎 通过重构种系IGHV1-69 BCR发出信号。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，即可以通过 基因编码抗体反应的“激活”和“扩增”。定义临床途径 开发，博士。 Lingwood和Chackerian应用了RNA噬菌体肽显示和亲和力 选择具有多价亲和力的VLP疫苗与IGHV1-69种系的VLP疫苗 BCR，从本质上 否则通常会被人类BCR多样性所稀释。选择性IGHV1-69启动将在 Trianni Mouse，最新的行业标准人源化鼠标疫苗模型。 v区域启动将是 用IGHV1-69启动HA茎免疫剂增强，以刺激现在的免疫主导的先天性HA STEM感知抗体反应。为BNAB启发利用遗传基础旨在克服失败 传统的流感疫苗接种方法，与这种资金机会的目的一致 和NIH更广泛的任务。