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，但疫苗接种可能不会产生强劲的效果 抗体反应，即使在多次注射后也是如此。然而，在健康人群中，2-10%的疫苗接种未能导致 保护性免疫，在乙肝疫苗的特定例子中，慢性炎症性 肥胖等状态与10%-30%的抗体反应较差的人有关，导致 他们没有受到保护。此外，肥胖等慢性炎症性疾病的患病率也在稳步上升 在世界范围内，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，这种情况正在增加 比如新冠肺炎。更好地了解疫苗体液反应差的机制是当务之急 需要的。疫苗反应包括由B细胞诱导亲和力成熟的抗体，这需要帮助 来自生发中心的T滤泡辅助细胞(TFH)的CD4细胞。我们之前发现了循环中的TFH，称为 CTfh在体外为B细胞提供帮助，在转录和表型上与淋巴系Tfh相似， 并以抗原特异性的方式对流感疫苗做出反应，给了我们一个了解淋巴状态的“窗口” 和活动。然而，了解cTfh和B细胞对乙肝疫苗的反应是如何建立的，并 随着时间的推移，变化是有限的，特别是在人类身上。在这里，我们建议研究乙肝疫苗对 使用系统了解与保护性抗体反应强度相关的因素 免疫学方法在慢性炎症环境下接种乙肝疫苗的前瞻性临床研究 是由肥胖引起的。在目标1中，我们将通过研究Tfh-B来评估反复抗原暴露的效果 细胞轴纵向为表型和谱系，以确定哪些特征是最 对最终抗体应答的预测。在目标2中，我们将比较接受佐剂乙肝疫苗的受试者 对于那些接受传统乙肝疫苗接种的人，以确定cTfh和B细胞反应如何由于 佐剂，使用多模式单细胞图谱。最后，在目标3中，我们将测试慢性病的机制 宿主中的炎症通过直接进行淋巴活检来影响乙肝疫苗的应答 多重免疫荧光研究。总之，这些实验将探索重复的影响 抗原暴露、佐剂和cTfh-B细胞轴上的慢性炎症，并建议未来的策略 改进了疫苗设计。

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.