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

• 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
• 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

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.

项目摘要/摘要 大多数疫苗吸收的抗体反应对流感疫苗的反应主要由脱靶，免疫降低， 和非中和活动。但是，最近的工作表明人类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，用于功能保守的位点 脆弱性，流感糖蛋白血凝集素（HA）的茎 - 质量，广泛中和的靶标 抗体（BNAB）反应。通过实验评估IGHV1-69词干 - 作为基因编码 用于构建通用流感疫苗的模板，我们的实验室产生了转基因小鼠，其中抗体 开发通过正常的人VDJ重组进行，但受到单个V基因IGHV1-69的约束。 我的初步数据表明，IGHV1-69本身足以重新调整对抗体的反应 HA茎表位，可保护无与伦比的病毒挑战。这是理性的重大范式转变 疫苗设计，即可以通过激活和扩增基因来产生广泛的保护 编码的抗体反应。我现在建议将IGHV1-69保护性响应的广度评估为 同时检查这种编码的靶向活性是否受单个氨基酸的变化调节，其中15％ 使用IGHV1-69 SNP约束的小鼠模型，全球人群。此外，定义一种手段 临床开发，我已经应用了一个RNA噬菌体平台，以显示肽显示和亲和力选择 推导多价病毒（例如颗粒）（VLP），这些病毒特异性地参与IGHV1-69种系BCR，从而允许 从人类免疫球蛋白库中选择性扩展IGHV1-69前体。我建议 评估两个模型中的选择性IGHV1-69启动：1）。 C57BL/6小鼠通过IGHV1-69 B传递 细胞，2）。 Trianni Mouse，是最新的行业标准人性化疫苗模型。然后启动将是 然后使用HA免疫原子增强靶向抗体反应的HA茎 - 发射剂。这 研究将定义遗传编码的BNAB启发的基础，并旨在克服传统的失败 流感疫苗接种的方法。