A systems immunology approach for predicting poor responses to Hepatitis B vaccination

项目摘要 疫苗是对抗传染病的有力工具，但疫苗接种可能无法诱导强有力的 抗体反应，即使在多次给药后。然而，在健康人群中，2-10%的疫苗接种未能导致 保护性免疫，以及在B型肝炎病毒（HBV）疫苗的具体实例中，慢性炎性 诸如肥胖的状态与10-30%的具有差的抗体应答的个体相关， 他们不受保护。此外，慢性炎症状态如肥胖症的患病率稳步上升。 在我们比以往任何时候都更加依赖疫苗来预防传染病的时候， 如COVID-19。更好地了解对疫苗的不良体液反应的机制是迫切的。 needed.疫苗反应涉及由B细胞诱导亲和力成熟的抗体，这需要帮助 从T滤泡辅助（Tfh）CD 4细胞在老年中心。我们以前确定了循环Tfh，称为 cTfh在体外为B细胞提供帮助，与淋巴Tfh具有转录和表型相似性， 并以抗原特异性的方式对流感疫苗接种作出反应，为我们提供了一个进入淋巴状态的“窗口”。 和活动。然而，了解cTfh和B细胞对HBV疫苗的应答是如何建立的， 随着时间的推移，变化是有限的，特别是在人类。在这里，我们建议研究乙肝疫苗的反应， 了解与保护性抗体反应强度相关的因素，使用系统 免疫学方法在慢性炎症背景下HBV疫苗接种的前瞻性临床研究中的应用 由肥胖引起的。在目的1中，我们将通过研究Tfh-B来评估重复抗原暴露的效果。 细胞轴纵向的表型和剧目，以确定哪些特点是最重要的 预测最终的抗体应答。在目标2中，我们将比较接受佐剂乙型肝炎疫苗的受试者 对接受传统HBV疫苗的人进行研究，以确定cTfh和B细胞应答如何因 佐剂，使用多模态单细胞谱。最后，在目标3中，我们将测试慢性 宿主的炎症通过进行直接淋巴结活检来影响HBV疫苗应答， 多重免疫荧光研究。总之，这些实验将探索重复的 抗原暴露、佐剂和慢性炎症对cTfh-B细胞轴的影响，并提出了未来的策略， 改进疫苗设计。

Project Summary Vaccines are powerful tools for combating infectious diseases yet vaccination may fail to induce robust antibody responses, even after multiple doses. Yet 2-10% of all vaccinations in healthy people fail to result in protective immunity, and, in the specific example of hepatitis B virus (HBV) vaccine, chronic inflammatory states such as obesity are associated with 10-30% of individuals having poor antibody responses, leaving them unprotected. Moreover, the prevalence of chronic inflammatory states such as obesity is steadily increasing worldwide, at a time where we more than ever depend on vaccines to prevent infectious diseases such as COVID-19. Better understanding of mechanisms of poor humoral responses to vaccines are urgently needed. Vaccine responses involve induction of affinity-matured antibodies by B cells, which requires help from T follicular helper (Tfh) CD4 cells in germinal centers. We previously identified circulating Tfh, termed cTfh, which provided help to B cells in vitro and had transcriptional and phenotypic similarities to lymphoid Tfh, and responded to influenza vaccination in an antigen-specific way, giving us a “window” into lymphoid state and activity. However, understanding of how cTfh and B cell responses to HBV vaccine are established and change over time are limited, particularly in humans. Here, we propose to study the HBV vaccine response to understand factors associated with the strength of the protective antibody response, using a systems immunology approach in a prospective clinical study of HBV vaccination in the setting of chronic inflammation induced by obesity. In Aim 1, we will evaluate the effect of repeated antigen exposure by studying the Tfh-B cell axis longitudinally for phenotype and repertoire, in order to determine which characteristics are most predictive of the final antibody response. In Aim 2, we will compare subjects receiving adjuvanted HBV vaccine to those receiving traditional HBV vaccine to determine how the cTfh and B cell responses differ due to adjuvant, using multi-modality single cell profiling. Finally, in Aim 3, we will test mechanisms of how chronic inflammation in the host affects the HBV vaccine response by performing direct lymph node biopsies for multiplex immunofluorescence studies. Together, these experiments will explore the effects of repeated antigen exposure, adjuvants, and chronic inflammation on the cTfh-B cell axis and suggest future strategies for improved vaccine design.