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（应用程序提供）：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病态疾病受到完全控制，在某些情况下从人类文明中消除了，但许多其他疾病仍然难以捉摸疫苗干预措施。我们更好地了解自然感染性病原体如何通过激活多个免疫轨道并产生组合反应来触发和控制哺乳动物免疫学的能力，这将有助于设计和临床转化更有效的疫苗，以防止新兴感染，艾滋病毒/艾滋病，癌症，癌症等。抗原来自病毒，细菌，真菌或寄生虫的病原体/危险相关的分子模式（PAMP/潮湿）。自然感染，多种调节和AG在粒子状的结构内携带，与生俱来的免疫电池经历了调节和抗原作为单个颗粒中的组合实体，它们的作用是将一组协同的刺激信号定位并集中。我们认为，（a）为了开发更有效的疫苗，我们必须理解多种调整对先天免疫小球和串联，控制适应性免疫学的分子机制； （b）在体内呈现调节器组合的最谨慎方法是通过模仿病原体（病原体样颗粒，PLP）的特定载体。这些携带者特性（例如大小，电荷，组成）的变化将影响调节器与先天免疫细胞相互作用并调节所得的免疫反应；一个可能发生在自然感染中的方面。我们的总体假设是，可以（a）通过表现方式（可溶性，与特定特性的特定特定物质的特定特定物质预测的特定特定式预测）来精确调节两种临床上的辅助辅助物，CpG和单磷酸脂质A（MPLA）的体内效应。为了测试这些，我们提出以下目标。 AIM 1：开发并表征CPG/MPLA共同负载各种大小和调节密度的病原体样粒子（PLP）佐剂。 AIM 2：研究体外，这是各种DC子集对组合响应如何调整公式的分子机制。 AIM 3：识别体内，即协同系统性免疫反应背后的分子机制以调节配方。拟议的研究总的来说，（a）将大力提高我们对通过组合 - 辅助因素介导适应性免疫启动的分子机制的理解，（b）确定关键的物理化学参数，以控制组合 - 辅助和PL的组合调整，以及（c）与新的平台和基于新平台的临时技术的开发，以及（c） 使用。