Targeting trained immunity and Th1/Th17 axis with combination adjuvants

项目摘要/摘要 缺乏针对大多数传染病的有效疫苗在很大程度上是由于我们从根本上缺乏 对保护性免疫机制的理解。加入疫苗配方中的佐剂 通过调节和延长宿主免疫反应对疫苗效力产生重大影响；然而，我们的 对它们驱动特定免疫参数的潜在机制(S)的了解还不完整。 虽然疫苗是预防和控制传染病的最有效方法，但许多能够 严重影响人类健康的疾病仍然没有有效的疫苗。例如，世界上四分之一的 人群潜伏感染结核病(TB)的病原体结核分枝杆菌(Mtb)1， 世界上最大的传染病杀手。对于结核病和其他主要传染病(例如， 艾滋病和疟疾)，新的佐剂或佐剂组合对于指导保护性免疫是必不可少的 回应。我们和其他人已经证明，针对1型T辅助细胞(Th1)和17型T辅助细胞 (Th17)细胞增强疫苗诱导的对TB5-8的免疫。此外，我们最近还现场演示了 疫苗(如卡介苗)和佐剂(如β-葡聚糖)产生先天性记忆反应，称为训练免疫， 通过单核/巨噬细胞的表观遗传重新编程，从而提供对结核分枝杆菌的保护 感染9，10.这些数据共同表明，针对这两种天然免疫的联合佐剂经过训练 适应性Th1/Th17细胞应答可增强对病原体的保护性免疫。因此， 确定联合佐剂产生有效的训练性免疫和保护性的作用机制 Th1/Th17轴，是这项提案的总体目标。在目前的提案中，我们假设组合 驱动Th1应答的佐剂(AS01或UM-1007，一种新型的TLR7/8激动剂)和Th17应答(β- 葡聚糖、纳米乳剂或新型Mincle激动剂UM-1098)将导致Th1/Th17适应性反应和/或 增强训练有素的免疫力。我们将通过以下四个具体目标实现这些总目标。特定的 目的1：探讨联合佐剂诱导Th1/Th17免疫应答的机制。 特定目的2.确定联合佐剂对造血干细胞的影响和训练 豁免权。具体目标3.确定联合佐剂的使用是否能改善Th1/Th17的回忆 对挑战作出反应并训练免疫力。具体目标4.确定...的作用机制 临床前类人猕猴模型中的联合佐剂。总之，这项研究的目标将是 绘制出有效驱动Th1/Th17反应的佐剂组合诱导的途径，并进行培训 豁免权。通过结核分枝杆菌挑战研究，我们将证明Th1/Th17和Th1/Th17 受过训练的免疫力被激发，参与对病原体挑战的保护。虽然我们将使用结核病作为 模型系统，我们设想，剖析佐剂介导的免疫机制将具有更广泛的影响 关于许多其他传染病的研究。

PROJECT SUMMARY/ABSTRACT The lack of effective vaccines against most infectious diseases is largely a result of our fundamental lack of understanding of mechanisms involved in protective immunity. Adjuvants incorporated into vaccine formulations have a major impact on vaccine efficacy via modulating and prolonging host immune responses; however, our understanding of their underlying mechanism(s) of action in driving specific immune parameters is incomplete. While vaccines are the most effective way to prevent and control infectious diseases, many pathogens that significantly impact human health remain without an effective vaccine. For example, one-fourth of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB)1, the leading infectious disease killer in the world. It is likely that for TB, and other major infectious diseases (e.g. AIDS and malaria), new adjuvants or adjuvant combinations will be essential for instructing a protective immune response. We and others have shown that targeting both the type 1 T helper (Th1) cells and type 17 T helper (Th17) cells enhance vaccine-induced immunity for TB5-8. Additionally, we have recently demonstrated that live vaccines (e.g. BCG) and adjuvants (e.g. β-glucan) generate innate memory response, termed trained immunity, via epigenetic reprogramming of monocytes/macrophages, thereby conferring protection against Mtb infection9,10. These data together suggest that combination adjuvants targeting both innate trained immunity and adaptive Th1/Th17 cellular responses can enhance protective immunity against pathogens. Thus, defining the mechanisms of action of combination adjuvants that generate potent trained immunity and protective Th1/Th17 axis, are the overall goals of this proposal. In the current proposal, we hypothesize that combinations of adjuvants that drive Th1 responses (AS01 or UM-1007, a novel TLR7/8 agonist) and Th17 responses (β- glucan, nanoemulsion, or UM-1098, a novel Mincle agonist) will result in Th1/Th17 adaptive responses and/or enhance trained immunity. We will achieve these overall goals through the following four Specific Aims. Specific Aim 1: To determine the mechanisms by which combination adjuvants elicit Th1/Th17 immune responses. Specific Aim 2. To determine the impact of combination adjuvants on hematopoietic stem cells and trained immunity. Specific Aim 3. To determine whether use of combination adjuvants improves recall Th1/Th17 responses and trained immunity upon challenge. Specific Aim 4. Determine the mechanism of action of combination adjuvants in a pre-clinical human-like rhesus macaque model. Together, the aims of this study will map out the pathways induced by combination of adjuvants that effectively drive Th1/Th17 responses and trained immunity. Through Mtb challenge studies, we will demonstrate whether the mechanisms by which Th1/Th17 and trained immunity are elicited are involved in protection against pathogen challenge. While we will use TB as a model system, we envision that dissecting the mechanism of adjuvants-mediated immunity has broader impact on many other infectious diseases.