Naturally Occurring Lipid A based Adjuvants

基于天然脂质 A 的佐剂

• 批准号: 7675898
• 负责人: Richard Peters Darveau
• 金额: $ 38.64万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675898
• 关键词: Adjuvant; Antibody Formation; Antigens; Autophagocytosis; Bacteroides thetaiotaomicron; Biological Assay; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Centers of Research Excellence; Characteristics; Clonal Expansion; Communicable Diseases; Dendritic Cells; Development; Emerging Communicable Diseases; Endotoxins; Epitopes; Escherichia coli; Family; Fatty Acids; Funding Mechanisms; Fusobacterium nucleatum; Gene Expression; Generations; Goals; Gram-Negative Anaerobic Bacteria; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunologic Adjuvants; In Vitro; Legal patent; Leukocytes; Lipid A; Lipids; Lipopolysaccharides; Location; Measurement; Minnesota; Modeling; Mus; Natural Immunity; Organism; Pathway interactions; Pattern; Play; Porphyromonas gingivalis; Prevotella intermedia; Production; Proteins; Research; Research Personnel; Resistance; Role; Salmonella; Serum; Source; Structure; TLR2 gene; TLR4 gene; Testing; Toxic effect; Transfection; Tularemia; Vaccine Adjuvant; Vaccines; Virus; Yersinia pestis; aluminum sulfate; base; biodefense; cytokine; functional group; immunogenic; improved; inorganic phosphate; killer T cell; member; microbial; monophosphoryl lipid A; mouse model; novel; novel vaccines; oral bacteria; pathogen; prophylactic; response; tumor

There is a need for more effective vaccine adjuvants. Historically alum has been the only approved adjuvant for human use and has been effective and safe when administered with whole-cell or virus-based vaccines. However increased recognition of bacterial pathogenic mechanisms has led to the development of newer vaccines to pathogens that contain a more defined, microbial component selective composition that often is less immunogenic. Simultaneously, adjuvant research has advanced with the identification of monophosphoryl lipid A (MPL), a vaccine adjuvant that can safely boost the immune response. MPL was obtained by selective structural degradation of toxic bacterial lipopolysaccharide (LPS), often referred to as endotoxin. MPL, as a modified LPS, retained its immunogenic characteristics while significantly reducing its toxic effects. However, LPS obtained from several species of anaerobic gram negative bacteria have been shown to contain a naturally occurring low toxicity lipid A. Recently, we demonstrated that two naturally occurring low toxicity lipid A's obtained from Porphyromonas gingivalis can boost the immune response and are effective vaccine adjuvants in two different tumor models in mice (Porphyromonas gingivalis 1435/1449 LPS as an immune modulator, Patent US2007/0134170A1). In this proposal our hypothesis is: "Naturally occurring low toxicity lipid A's represent a new class of vaccine adjuvants". We will test this hypothesis by isolating and characterizing low toxicity lipid A's (LT lipid A) from several species of anaerobic gram negative bacteria (Aim 1). We will then examine their adjuvant potential in in vitro (Aim 2) and mouse models of non specific (Aim 3) and specific immunity (Aim 4). These studies will determine if naturally occurring LT lipid A's represent a new class of safe and effective vaccine adjuvants.

需要更有效的疫苗佐剂。历史上明矾是唯一被批准的佐剂 用于人类使用，并且当与全细胞或基于病毒的疫苗一起施用时是有效和安全的。 然而，对细菌致病机制的认识增加导致了新的 针对病原体的疫苗含有更明确的微生物组分选择性组合物， 免疫原性更低。与此同时，辅助研究也随着 单磷酰脂质A（MPL），一种疫苗佐剂，可以安全地增强免疫反应。MPL是 通过有毒细菌脂多糖（LPS）的选择性结构降解而获得，通常被称为 内毒素MPL作为修饰的LPS，保留了其免疫原性特征，同时显著降低了其免疫原性。 毒性作用。然而，从几种厌氧革兰氏阴性菌获得的LPS已经被广泛应用于临床。 显示含有天然存在的低毒性脂质A。最近，我们证明了两个自然的 从牙龈卟啉单胞菌获得的低毒性脂质A可以增强免疫应答， 是小鼠两种不同肿瘤模型中有效的疫苗佐剂（牙龈卟啉单胞菌1435/1449 LPS作为免疫调节剂，专利US 2007/0134170 A1）。在本提案中，我们的假设是： 天然存在的低毒性脂质A代表了一类新的疫苗佐剂。我们将测试 这一假设通过分离和表征低毒性脂质A（LT脂质A）从几个物种， 厌氧革兰氏阴性菌（Aim 1）。然后我们将在体外研究它们的佐剂潜力（目的2） 非特异性免疫（Aim 3）和特异性免疫（Aim 4）小鼠模型。这些研究将确定， 天然存在的LT脂质A代表了一类新的安全有效的疫苗佐剂。