Programming Durable Immune Responses To Vaccination

规划对疫苗接种的持久免疫反应

• 批准号: 10319526
• 负责人: Ali Hassan Ellebedy
• 金额: $ 66.76万
• 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/10319526
• 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; 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; 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