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.