Programming Durable Immune Responses To Vaccination

摘要 流感病毒每年在全球造成多达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抗体，从而可以 中和不同的流感病毒株；第二，它必须诱导长期的抗体反应，以维持 长期的保护性免疫。获得许可的季节性流感病毒疫苗两者都不起作用--抗体 反应的广度有限，疫苗诱导的免疫似乎持续时间较短。早期的工作有 确定了诱导血凝素(HA)特异性抗体对于保护是必要的和充分的。 尽管在过去八年里为抗击流感付出了广泛的努力和资源 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细胞的理解存在很大差距 人类接种流感病毒疫苗(MBC)的反应：(1)接种流感疫苗会导致GC吗？ 引流淋巴结中的反应？(2)如果是，这种反应与 能引起更持久的血清抗体反应的疫苗？3)都是在 接种GC来源的疫苗？4)如果是，GC来源的抗原特异性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 驻留在骨髓中的LLPC？6)抗原特异性GC B细胞的频率与 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 与人类接种疫苗后的持久抗体反应相关的成分。在我们的 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 分析流感疫苗诱导的甲肝特异性B细胞反应，不仅从容易分离的 可接近的血室，也包括从引流的淋巴结和骨髓中分离出来的那些 车厢。我们的初步数据显示，疫苗诱导的B细胞至少有两个不同的亚群 在血液中出现的动力学、同型分布和分化潜能不同的亚群。 此外，我们的转录分析揭示了关键转录因子的差异表达，例如 Tcf-1与同型转换和自我更新能力广泛相关。澄清其来源和 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和我们的发现 将可能揭示不仅决定寿命的细胞和分子决定因素，而且 在人类中对流感疫苗--以及可能的其他疫苗--产生抗体反应的广度。

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.