Programming Durable Immune Responses To Vaccination

规划对疫苗接种的持久免疫反应

• 批准号: 10062811
• 负责人: Ali Hassan Ellebedy
• 金额: $ 68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-18 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062811
• 关键词: Address; Adoptive Transfer; Affinity; Antibodies; Antibody Response; Antigens; Appearance; Axillary lymph node group; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; BCL6 gene; Blood; Bone Marrow; Cell Compartmentation; Cells; Cessation of life; ChIP-seq; Clone Cells; Comparative Genomic Analysis; Data; Data Set; Exhibits; Feedback; Fine needle aspiration biopsy; Frequencies; Gene Expression; Genes; Genetic Transcription; Goals; Hemagglutinin; Human; Humoral Immunities; IRF4 gene; Immune response; Immunity; Immunocompromised Host; Immunoglobulin A; Immunoglobulin Class Switching; Individual; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Kinetics; Longevity; LoxP-flanked allele; Maintenance; Memory B-Lymphocyte; Molecular; Mus; Pathway interactions; Peripheral; Phenotype; Plasma Cells; Plasmablast; Public Health; Reaction; Research; Resources; Sampling; Seeds; Series; Serum; Structure of germinal center of lymph node; Surface; Testing; Transcript; Up-Regulation; Vaccination; Vaccine Design; Vaccines; Work; base; cross reactivity; differential expression; draining lymph node; experimental study; fighting; genetic analysis; human pathogen; influenza epidemic; influenza virus strain; influenza virus vaccine; influenzavirus; innovation; insight; mouse model; novel; pandemic disease; peripheral blood; programs; response; seasonal influenza; self-renewal; single-cell RNA sequencing; stem; transcription factor; transcription factor NF-AT c3; transcriptome sequencing; universal influenza vaccine; vaccine-induced immunity

ABSTRACT Influenza viruses cause up to 500,000 deaths around the globe annually. An ideal influenza vaccine must have two essential attributes: one, it should be capable of inducing broadly cross-reactive antibodies that can neutralize diverse influenza virus strains; and two, it must induce long-lived antibody responses to maintain protective immunity for extended periods. Licensed seasonal influenza virus vaccines do neither – the antibody response is of limited breadth and vaccine-induced immunity appears to be of short duration. Early work has established that induction of hemagglutinin (HA)-specific antibodies is essential and sufficient for protection. Despite the extensive efforts and resources that have been deployed to fight influenza over the past eight decades, it remains a major public health threat. There are major gaps in our understanding of memory B cell (MBC) responses to influenza virus vaccination in humans: (1) does influenza vaccination induce a GC reaction in the draining lymph node? (2) if yes, how robust is that response in comparison to those induced by vaccines that elicit more durable serum antibody responses? 3) are all peripheral MBCs that emerge after vaccination GC-derived? 4) if yes, what is the phenotype of GC-derived antigen-specific B cells that are destined to become LLPCs? 5) does influenza vaccination induces a sustained increase in the frequency of bone marrow-resident LLPCs? 6) is there a correlation between the frequency of antigen-specific GC B cells and the increase/maintenance in bone marrow LLPCs? Tackling these gaps will allow us to discern the cellular components that are associated with durable antibody responses following vaccination in humans. In our studies, we will address these outstanding questions through detailed phenotypic, functional and transcriptional analysis of influenza vaccination-induced, HA-specific B cell responses isolated not only from the easily accessible blood compartment, but also those isolated from the draining lymph nodes and the bone marrow compartments. Our preliminary data show that there are at least two distinct subsets of vaccine-induced B cell subsets that differ in the kinetics of their appearance in blood, isotype distribution, and differentiation potential. Additionally, our transcriptional analyses reveal differential expression of key transcription factors, such as TCF-1 that are associated broadly with isotype-switching and self-renewal capacity. Elucidating the origin and fate of influenza vaccines-induced B cell responses is unarguably a major public health need and our findings will potentially reveal the cellular and molecular determinants dictating not only the longevity, but also the breadth of elicited antibody responses to influenza – and potentially other – vaccination in humans.

抽象的 每年在全球造成多达500,000人死亡的流感病毒。理想的影响者疫苗必须具有 两个基本属性：一个，应该能够能够诱导的广泛交叉反应抗体可以 中和潜水员影响病毒菌株；两个，它必须诱导长寿命抗体反应以维持 保护性免疫长期。许可的季节性影响病毒疫苗没有 - 抗体 响应的广度有限，疫苗诱导的免疫力似乎持续时间很短。早期工作 确定诱导血凝素（HA）特异性抗体是必不可少的，足以保护。 尽管已经采取了广泛的努力和资源来打击过去八的影响力 几十年来，它仍然是一个主要的公共卫生威胁。我们对记忆B单元的理解有主要差距 （MBC）影响人类病毒疫苗接种的反应：（1）确实会影响疫苗 图纸淋巴结中的反应？ （2）如果是，与由那些诱导的反应相比，这种响应有多稳健 引起更耐用的血清抗体反应的疫苗？ 3）都是后外的MBC 疫苗接种GC衍生？ 4）如果是，GC衍生的抗原特异性B细胞的表型是什么 注定要成为LLPC？ 5）确实影响疫苗接种会导致频率持续增加 骨髓居民LLPC？ 6）在抗原特异性GC B细胞的频率之间存在相关性 以及骨髓LLPC的增加/维护？解决这些间隙将使我们能够辨别蜂窝 与人类疫苗后耐用抗体反应相关的成分。在我们的 研究，我们将通过详细的表型，功能和转录来解决这些杰出的问题 分析影响疫苗接种诱导的HA特异性B细胞反应，不仅从易于从 可及的血室，以及那些从排水淋巴结和骨髓中隔离的血室 车厢。我们的初步数据表明，疫苗诱导的B细胞至少有两个不同的子集 它们在血液，同种型分布和分化潜力的动力学中不同的子集。 此外，我们的转录分析揭示了关键转录因子的差异表达，例如 TCF-1与同型转换和自我更新能力广泛相关。阐明起源和 影响力疫苗引起的B细胞反应的命运无疑是主要的公共卫生需求，我们的发现 将有可能揭示细胞和分子决定剂不仅决定寿命，还决定 引起的抗体反应的广度对人类的影响（以及其他可能的其他）疫苗接种。