A genetic template for generating universally protective responses to influenza

用于产生针对流感的普遍保护性反应的遗传模板

基本信息

批准号：
10017642
负责人：
Maya Sangesland
金额：
$ 2.9万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2021-07-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017642
关键词：
Adoptive Transfer Affinity Amino Acids Animals Antibodies Antibody Response Antibody titer measurement Antigens B-Lymphocytes Binding C57BL/6 Mouse CDR1 gene Cell Lineage Cessation of life Collaborations Data Development Ensure Epitopes Failure Gene Amplification Gene Targeting Genes Genetic Genetic Recombination Genetic Template Genotype Glycoproteins Hemagglutinin Human Immune response Immune system Immunization Immunoglobulin G Immunoglobulins Immunologics In Vitro Industry Standard Influenza Influenza A Virus, H5N1 Subtype Influenza Hemagglutinin Influenza vaccination Leucine Measures Modeling Mus Nature New Mexico Pathway interactions Peptides Phenylalanine Population Positioning Attribute Public Health RNA Phages Reaction Receptors, Antigen, B-Cell Recombinants Reproducibility Site Specificity Structure of germinal center of lymph node Suggestion System Testing Transgenic Mice V(D)J Recombination Vaccination Vaccine Design Vaccines Viral Virus-like particle Work antigen binding clinical development humanized mouse influenza virus vaccine influenzavirus mouse model neutralizing antibody pandemic disease preservation reconstitution response stem universal influenza vaccine universal vaccine

项目摘要

Project Summary/Abstract The majority of vaccine-elicited antibody responses to influenza are dominated by off-target, immunodominant, and non-neutralizing activities. However, recent work indicates that human B cell receptors (BCRs) containing the antibody VH gene IGHV1-69 possess V gene-encoded specificity for a functionally conserved site of vulnerability, the stem-epitope of the influenza glycoprotein hemagglutinin (HA), a target of broadly neutralizing antibody (bnAb) responses. To experimentally evaluate IGHV1-69 stem-epitope targeting as a gene-encoded template for building a universal influenza vaccine, our lab has generated transgenic mice in which antibody development proceeds via normal human VDJ recombination, but is constrained to a single V gene, IGHV1-69. My preliminary data indicates that IGHV1-69 usage in itself is sufficient to refocus the antibody response to the HA stem epitope and is protective from an unmatched viral challenge. This is a major paradigm shift in rational vaccine design, namely that broad protection may be generated through activation and amplification of gene- encoded antibody responses. I now propose to assess the breadth of the IGHV1-69 protective response as well as examine if this encoded targeting activity is regulated by a single amino acid change, present in 15% of the global population, using an IGHV1-69 SNP constrained mouse model. Additionally, to define a means for clinical development, I have applied a RNA bacteriophage platform for peptide display and affinity selection to derive multivalent virus like particles (VLPs) that specifically engage IGHV1-69 germline BCRs, allowing for selective expansion of IGHV1-69 precursors from the full human immunoglobulin repertoire. I propose to evaluate selective IGHV1-69 priming in two models: 1). C57BL/6 mice adoptively transferred with IGHV1-69 B cells, and 2). The Trianni mouse, the latest industry-standard humanized vaccine model. Priming will then be followed by boosting with HA immunogens to amplify HA stem-epitope targeting antibody responses. This study will define a genetically encoded basis for bnAb elicitation and aims to overcome the failure of traditional approaches to influenza vaccination.

项目概要/摘要大多数疫苗引发的流感抗体反应主要是脱靶、免疫显性、和非中和活动。然而，最近的研究表明，人类 B 细胞受体 (BCR) 含有抗体 VH 基因 IGHV1-69 具有 V 基因编码的特异性，针对功能保守位点脆弱性，流感糖蛋白血凝素（HA）的干表位，广泛中和的目标抗体（bnAb）反应。通过实验评估 IGHV1-69 干表位靶向作为基因编码为了构建通用流感疫苗的模板，我们的实验室已经培育出转基因小鼠，其中抗体发育通过正常人类 VDJ 重组进行，但仅限于单个 V 基因 IGHV1-69。我的初步数据表明 IGHV1-69 的使用本身足以重新集中抗体反应 HA 干表位，可抵御无与伦比的病毒攻击。这是理性范式的重大转变疫苗设计，即可以通过基因的激活和扩增来产生广泛的保护编码抗体反应。我现在建议评估 IGHV1-69 保护性反应的广度：以及检查这种编码的靶向活性是否受到单个氨基酸变化的调节，该变化存在于 15% 的使用 IGHV1-69 SNP 约束小鼠模型对全球人群进行研究。此外，定义一种方法临床开发中，我应用了 RNA 噬菌体平台进行肽展示和亲和力选择衍生出专门与 IGHV1-69 种系 BCR 结合的多价病毒样颗粒 (VLP)，从而允许从完整的人免疫球蛋白库中选择性扩展 IGHV1-69 前体。我建议在两个模型中评估选择性 IGHV1-69 启动：1)。 C57BL/6 小鼠过继转移 IGHV1-69 B 细胞，2)。 Trianni 小鼠，最新的行业标准人源化疫苗模型。然后将进行底漆然后用 HA 免疫原加强，以放大 HA 干表位靶向抗体反应。这研究将定义 bnAb 诱导的基因编码基础，旨在克服传统方法的失败流感疫苗接种的方法。