Programming Durable Immune Responses To Vaccination

规划对疫苗接种的持久免疫反应

• 批准号: 10539283
• 负责人: Ali Hassan Ellebedy
• 金额: $ 65.49万
• 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/10539283
• 关键词: 1918 influenza pandemic; 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 vaccination; Kinetics; Licensing; Longevity; LoxP-flanked allele; Maintenance; Memory B-Lymphocyte; Molecular; Mus; Pathway interactions; Peripheral; Phenotype; Plasma Cells; Plasmablast; Public Health; Reaction; Research; Resources; Sampling; Series; Serum; Structure of germinal center of lymph node; Surface; Testing; Transcript; Up-Regulation; Vaccination; Vaccines; Work; 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; rational design; 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.

摘要 流感病毒每年在地球仪各地造成多达50万人死亡。理想的流感疫苗必须具备 两个基本属性：第一，它应该能够诱导广泛的交叉反应性抗体， 中和不同的流感病毒株;第二，它必须诱导长寿命的抗体反应，以维持 长期保护性免疫。已获许可的季节性流感病毒疫苗两者都没有-抗体 反应的广度有限，疫苗诱导的免疫似乎持续时间短。早期的工作 建立了血凝素（HA）特异性抗体的诱导对于保护是必要的并且是足够的。 尽管在过去八年，政府已作出广泛的努力和调配资源对抗流感， 几十年来，它仍然是一个重大的公共卫生威胁。在我们对记忆B细胞的理解上存在着重大的空白 (MBC)人类对流感病毒疫苗接种的反应：（1）流感疫苗接种是否诱导GC 引流淋巴结有反应吗(2)如果是，与 能引发更持久的血清抗体反应的疫苗？3)都是外周肌红细胞， 疫苗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)接种流感疫苗是否会导致 骨髓中的LLPC 6)抗原特异性GC B细胞的频率 以及骨髓LLPC的增加/维持？解决这些差距将使我们能够辨别细胞 这些成分与人类接种疫苗后的持久抗体应答相关。在我们 研究，我们将通过详细的表型，功能和转录来解决这些悬而未决的问题。 流感疫苗诱导的HA特异性B细胞应答的分析不仅从容易分离的 可接近的血液隔室，但也包括从引流淋巴结和骨髓中分离的那些 隔间我们的初步数据表明，至少有两种不同的疫苗诱导的B细胞亚群， 在血液中出现的动力学、同种型分布和分化潜能方面不同的亚群。 此外，我们的转录分析揭示了关键转录因子的差异表达，如 TCF-1与同种型转换和自我更新能力广泛相关。阐明起源和 流感疫苗诱导的B细胞反应的命运无疑是一个主要的公共卫生需求，我们的研究结果 将有可能揭示不仅决定寿命，而且决定寿命的细胞和分子决定因素 在人类中，对流感疫苗和潜在的其他疫苗接种引起的抗体反应的广度。