Effect of presentation methods on the molecular mechanism of combinatorial adjuvants

呈现方法对组合佐剂分子机制的影响

• 批准号: 9882950
• 负责人: KRISHNENDU ROY
• 金额: $ 51.93万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882950
• 关键词: AIDS/HIV problem; Acute; Adjuvant; Adjuvanticity; Affect; Alpha Particles; Animals; Antigens; Bacteria; Biochemical; Biological Assay; Biomimetics; Blood Circulation; Cells; Charge; Civilization; Clinical; Data; Dendritic Cells; Development; Diffuse; Disease; Dose; Emerging Communicable Diseases; Emulsions; Exhibits; Formulation; Genes; Health; Human; Hydrophobicity; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunization; In Vitro; Infection; Injections; Intervention; Intramuscular; Kinetics; Knowledge; Lead; Ligands; Lipid A; MF59; Malignant Neoplasms; Mediating; Methods; Molecular; Mus; Nucleic Acids; Outcome; Parasites; Particle Size; Particulate; Pathway interactions; Patients; Pattern; Peripheral; Property; Reagent; Recording of previous events; Research; Side; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Skin; Structure; T-Lymphocyte; TLR4 gene; TLR7 gene; Technology; Testing; Therapeutic; Time; Toll-like receptors; Transgenic Organisms; Tropism; Vaccination; Vaccine Adjuvant; Vaccines; Variant; Virus; adaptive immune response; adaptive immunity; aluminum sulfate; base; biodegradable polymer; clinical translation; clinically relevant; combinatorial; cytokine; density; design; draining lymph node; experience; fungus; hydrophilicity; improved; in vitro Assay; in vivo; interest; molecular imaging; mortality; nano; particle; pathogen; physical property; polarized cell; public health intervention; public health relevance; response; small molecule; subcutaneous; synergism; systemic toxicity

 DESCRIPTION (provided by applicant): Vaccination is one of the most successful public health interventions in human history. Despite the fact that many incurable and high-mortality diseases are fully controlled, and in some cases eliminated from human civilization, many other diseases remain elusive to vaccine interventions. Our ability to better understand how natural infectious pathogens trigger and control mammalian immunity by activating multiple immune-pathways and generating a combinatorial response, will greatly help the design and clinical translation of more effective vaccines against emerging infectious diseases, HIV/AIDS, cancer, etc. Most of our knowledge in stimulating vaccine adjuvants, molecules that stimulate the immune system to generate protective or therapeutic immunity against antigens, comes from pathogen/danger-associated molecular patterns (PAMPs/DAMPs) of viruses, bacteria, fungi or parasites. In natural infections, multiple adjuvants and Ag are carried inside a particle-like structure and innate immune cells experience adjuvant and antigens as a combination entity in single particles, which acts to localize and concentrate a set of synergistic stimulatory signals. Thus, we argue, that (a) in order to develop more efficacious vaccines we must understand the molecular mechanisms by which multiple adjuvants act on innate immune cells and in tandem, control adaptive immunity; and (b) the most prudent way of presenting combinations of adjuvants in vivo is through particulate carriers that mimic pathogens (Pathogen-like particles, PLPs). Variation of these carriers' properties (e.g. size, charge, composition) will affect how adjuvants interact with innate immune cells and modulate the resulting immune response; an aspect that likely occurs in natural infections as well. Our overarching hypotheses are that the combinatorial in vivo effects of two clinically-relevant adjuvants, CpG and Monophosphoryl Lipid A (MPLA), can be (a) precisely modulated by the mode of presentation (soluble, vs particulate carriers of different physical properties) and (b) better predicted by in vitro assays when delivered together as particulate carriers. To test these, we propose the following aims. Aim 1: Develop and characterize CpG/MPLA co-loaded pathogen-like-particle (PLP) adjuvants of various sizes and adjuvant- density. Aim 2: Investigate in-vitro, the molecular mechanisms involved in how various DC subsets respond to combination adjuvant formulations. Aim 3: Identify in vivo, the molecular mechanisms behind synergistic systemic immune-responses to combination adjuvant formulations. Collectively, the proposed studies will (a) greatly advance our understanding of molecular mechanisms that mediate potent priming of adaptive immunity by combination-adjuvants, (b) identify key physico-chemical parameters that control adjuvanticity of combination-adjuvants and PLPs, and (c) lead to the development of new platform technologies and reagents for combinatorial-adjuvant based human vaccines with immediate translational potential and clinical use.

 描述（由申请人提供）：疫苗接种是人类历史上最成功的公共卫生干预措施之一，尽管许多无法治愈和高死亡率的疾病已得到完全控制，在某些情况下从人类文明中消除，但许多其他疾病仍然难以捉摸。我们能够更好地了解自然传染性病原体如何通过激活多种免疫途径并产生组合反应来触发和控制哺乳动物的免疫力，这将极大地有助于针对新出现的传染病的更有效的疫苗的设计和临床转化， HIV/艾滋病、癌症等。我们在刺激疫苗佐剂（刺激免疫系统产生针对抗原的保护性或治疗性免疫力的分子）方面的大部分知识来自病毒、细菌的病原体/危险相关分子模式（PAMP/DAMP）在自然感染中，多种佐剂和抗原被携带在颗粒状结构内，先天免疫细胞将佐剂和抗原作为单个颗粒的组合实体，其作用是定位和集中一组佐剂。因此，我们认为，（a）为了开发更有效的疫苗，我们必须了解多种佐剂作用于先天免疫细胞并协同控制适应性免疫的分子机制；以及（b）最谨慎的方式。在体内呈现佐剂组合的方法是通过模拟病原体的颗粒载体（病原体样颗粒，PLP）来改变这些载体的特性（例如大小、电荷、成分）将影响佐剂如何与先天免疫细胞相互作用并调节由此产生的免疫反应；我们的总体假设是两种临床相关佐剂（CpG 和单磷酰脂质）的组合体内效应。 A (MPLA)，可以 (a) 通过呈现模式精确调节（可溶性载体与不同物理特性的颗粒载体），以及 (b) 在递送时通过体外测定更好地预测为了测试这些，我们提出以下目标：开发和表征不同尺寸和佐剂密度的 CpG/MPLA 共负载病原体样颗粒 (PLP) 佐剂。体外，涉及各种 DC 亚群如何响应组合佐剂制剂的分子机制 目标 3：确定体内协同全身免疫反应背后的分子机制。总的来说，拟议的研究将（a）极大地促进我们对通过组合佐剂介导适应性免疫的有效启动的分子机制的理解，（b）确定控制组合佐剂的佐剂性的关键物理化学参数和PLP，(c) 导致开发基于组合佐剂的人类疫苗的新平台技术和试剂，具有直接转化潜力和临床应用。