Synergistic vaccine adjuvants that stimulate both innate and adaptive immunities

刺激先天免疫和适应性免疫的协同疫苗佐剂

• 批准号: 8020984
• 负责人: Dante Marciani
• 金额: $ 29.48万
• 依托单位: BIO-SYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020984
• 关键词: Active Immunotherapy; Adjuvant; Agonist; Alcohols; Aldehydes; Anabolism; Animals; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Asses; Avidity; Binding; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Carbohydrates; Cell Surface Receptors; Cells; Chemical Structure; Control Animal; Cytosol; Cytotoxic T-Lymphocytes; DNA; Dendritic Cells; Dendritic cell activation; Elderly; Evaluation; Genome; Glycosides; Government; HIV; HIV-1; Imines; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Individual; Infection; Inflammatory; Interferons; Lectin; Ligand Binding; Ligands; Link; Lipid Binding; Macrophage Activation; Malaria; Mannans; Mannose; Membrane Proteins; Modeling; Mucosal Immunity; Mutate; Natural Immunity; Nuclear Translocation; Oligosaccharides; Organism; Pathway interactions; Pattern recognition receptor; Persons; Phase; Play; Polynucleotides; Polysaccharides; Population; Preventive; Process; Production; Protein Kinase; Proteins; Research; Resistance; Role; Saponin; Saponins; Signal Transduction; Soapbush; Sum; T-Cell Activation; T-Lymphocyte; Time; Tissue-Specific Gene Expression; Toll-like receptors; Triterpenes; Up-Regulation; Vaccine Adjuvant; Vaccines; Vertebrates; Viral Vector; Virus; acquired immunity; acyl group; adaptive immunity; amino group; analog; anergy; base; cytokine; design; in vivo; macrophage; monophosphoryl lipid A; mouse model; neutralizing antibody; pathogen; prototype; public health relevance; receptor; response; senescence; therapeutic vaccine; transcription factor; vaccine efficacy

DESCRIPTION (provided by applicant): The objective is to develop a glycoside adjuvant or immune agonist carrying the chemical structures needed to concurrently stimulate in a cooperative manner both innate and adaptive immunities, leading to a synergistic effect on the cellular (Th1) and humoral (Th2) immunities. It is likely that these adjuvants would also stimulate strong mucosal immunity. Studies with HIV-1 model vaccines indicate that a favorable immune protection would entail besides cytotoxic T lymphocytes (CTL), neutralizing antibodies and mucosal immunity. Yet, HIV's vast capacity to mutate may allow its escape from immune control. That HIV up regulates the CD4+ T cells' expression of the inhibitory CTLA-4 receptor, blocking the co-stimulatory ligands B7-1/B7-2 (CD80/CD86) expressed by antigen presenting cells (APCs) and required for T cell activation, means an anergic immune system that would not protect against the virus. Thus, HIV-1 vaccines would demand superior adjuvants to raise the immune response to levels not required before. The synergistic effects of the concerted stimulation of various receptors for innate and acquired immunity, deliver a much higher immune response with antigen and DNA based vaccines. The strategy to develop these adjuvants involves replacing in glycosides with aldehyde- carrying triterpenes their i) natural carbohydrate moieties with oligosaccharides that are ligands of innate immunity receptors, e.g. toll-like receptors (TLRs) and lectins, and ii) hydrophobic acyl group with new lipophilic chains, that may be design to serve as ligands for innate immunity receptors. The aldehyde group by forming imines with the amino groups of certain cell surface receptor(s) provides an alternative co-stimulatory signal needed to elicit Th1/Th2 immunity while the newly added innate immunity ligand, i.e. oligosaccharides and/or lipids, by binding to certain receptors would stimulate innate immunity. The triterpene group plays a role in the delivery of exogenous antigens directly into the cell's cytosol for processing by the endogenous pathway and CTL production, thus avoiding the need for viral vectors and production of interfering antibodies. Result of the concurrent stimulation of the receptors for both adaptive and innate immunities located on the same cell would be a synergistic effect on the immune response; i.e., the response stimulated by this immune agonist would be much higher than the aggregate of the responses elicited by the individual ligands. Phase I Specific Aims are, 1) Synthesize i) an immune agonist, having an aldehyde-carrying triterpene linked covalently to a mannan oligosaccharide and a myristoyl lipophilic chain, and ii) the controls lacking either the oligosaccharide chain or aldehyde; and 2) Study the role of this new adjuvant in i) the activation of DCs and macrophages by studying up-regulation of MHC, co-stimulatory molecules, and increased secretion of pro-inflammatory cytokines, ii) activating a protective immunity in vivo against a pathogen, by evaluating antigen specific CD4, CD8 responses, antigen specific antibodies, and protection against infection in the mouse model. The immune responses would be compared to that stimulated by well-known innate immunity ligands. PUBLIC HEALTH RELEVANCE: Results of this research would allow enhancing Th1and Th2 immunities with production of CTLs as well as antibodies with high avidity. As these compounds should stimulate mucosal immunity, they would provide a first line of defense against HIV-1 infection. They should also allow the improvement of vaccines' efficacy in the elderly population, which because of immune senescence, frequently shows some immune deficiencies, that interferes with the stimulation of an effective immunity. These agonists' capacity to deliver a co-stimulatory signal that is independent of the CD80/86 ligands may have applications in HIV-1 therapeutic vaccines where the CTLA-4 inhibitory receptor blocks the activity of the natural ligands leading to anergy.

描述（由申请人提供）：目的是开发一种糖苷佐剂或免疫激动剂，其携带以协同方式同时刺激先天性和适应性免疫所需的化学结构，从而对细胞（Th1）和体液（Th1）产生协同作用。 Th2) 免疫力。这些佐剂很可能也会刺激强大的粘膜免疫。 HIV-1模型疫苗的研究表明，除了细胞毒性T淋巴细胞（CTL）之外，良好的免疫保护还需要中和抗体和粘膜免疫。然而，艾滋病毒巨大的突变能力可能使其逃脱免疫控制。 HIV 上调 CD4+ T 细胞抑制性 CTLA-4 受体的表达，阻断抗原呈递细胞 (APC) 表达的 T 细胞激活所需的共刺激配体 B7-1/B7-2 (CD80/CD86) ，意味着免疫系统无反应，无法抵御病毒。因此，HIV-1 疫苗需要优质佐剂来将免疫反应提高到以前不需要的水平。协同刺激先天性和获得性免疫的各种受体的协同效应，通过基于抗原和 DNA 的疫苗产生更高的免疫反应。开发这些佐剂的策略涉及用携带醛的三萜烯取代糖苷中的i)天然碳水化合物部分，并用寡糖代替，寡糖是先天免疫受体的配体，例如， Toll 样受体 (TLR) 和凝集素，以及 ii) 具有新亲脂链的疏水酰基，可设计用作先天免疫受体的配体。醛基通过与某些细胞表面受体的氨基形成亚胺提供了引发 Th1/Th2 免疫所需的替代共刺激信号，而新添加的先天免疫配体，即寡糖和/或脂质，通过结合某些受体会刺激先天免疫。三萜基团在将外源抗原直接递送到细胞的胞浆中以通过内源途径进行加工和CTL产生中发挥作用，从而避免了对病毒载体和干扰抗体的产生的需要。同时刺激位于同一细胞上的适应性免疫和先天免疫受体的结果将对免疫反应产生协同效应；即，由这种免疫激动剂刺激的反应将比单个配体引起的反应的总和高得多。第一阶段的具体目标是，1) 合成 i) 一种免疫激动剂，其具有与甘露寡糖和肉豆蔻酰亲脂链共价连接的携带醛的三萜，以及 ii) 缺乏寡糖链或醛的对照； 2) 研究这种新佐剂在以下方面的作用：i) 通过研究 MHC、共刺激分子的上调和促炎细胞因子分泌的增加来激活 DC 和巨噬细胞，ii) 激活体内针对通过在小鼠模型中评估抗原特异性 CD4、CD8 反应、抗原特异性抗体和抗感染保护来识别病原体。将免疫反应与众所周知的先天免疫配体刺激的免疫反应进行比较。 公共健康相关性：这项研究的结果将允许通过产生 CTL 以及高亲和力的抗体来增强 Th1 和 Th2 免疫力。由于这些化合物会刺激粘膜免疫，因此它们将成为对抗 HIV-1 感染的第一道防线。它们还应该提高疫苗在老年人群中的功效，由于免疫衰老，老年人群经常表现出一些免疫缺陷，从而干扰有效免疫力的刺激。这些激动剂能够传递独立于 CD80/86 配体的共刺激信号，可应用于 HIV-1 治疗性疫苗，其中 CTLA-4 抑制性受体阻断天然配体的活性，导致无反应性。