Naturally Occurring Lipid A based Adjuvants

基于天然脂质 A 的佐剂

• 批准号: 8236987
• 负责人: Samuel I Miller
• 金额: $ 17.52万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236987
• 关键词: Adjuvant; Cells; Centers of Research Excellence; Characteristics; Development; Emerging Communicable Diseases; Endotoxins; Funding Mechanisms; Goals; Gram-Negative Anaerobic Bacteria; Human; Immune; Immune response; Immunity; In Vitro; Legal patent; Lipid A; Lipids; Lipopolysaccharides; Modeling; Mus; Porphyromonas gingivalis; Research; Research Personnel; Structure; Testing; Toxic effect; Vaccine Adjuvant; Vaccines; Virus; aluminum sulfate; base; biodefense; immunogenic; improved; microbial; monophosphoryl lipid A; mouse model; novel; novel vaccines; pathogen; prophylactic; 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。从历史上看，明矾一直是唯一获得批准的佐剂 用于人类使用，并在用全细胞或基于病毒的疫苗中施用时是有效且安全的。 但是，对细菌病原机制的认识增加导致了更新的发展 对病原体的疫苗，该病原体含有更明确的微生物组件选择性组成，通常是 免疫原性较少。同时，辅助研究在确定 单磷酸脂质A（MPL），一种可以安全增强免疫反应的疫苗佐剂。 Mpl是 通过有毒细菌脂多糖（LPS）的选择性结构降解获得，通常称为 内毒素。 MPL作为修饰的LP，保留了其免疫原性，同时显着降低了其免疫原性 有毒作用。但是，从几种厌氧革兰氏阴性细菌获得的LP已 显示出包含天然存在的低毒性脂质A。最近，我们证明了两个天然 发生从卟啉单胞菌获得的低毒性脂质A可以增强免疫反应和 是小鼠的两个不同肿瘤模型中的有效疫苗佐剂（牙龈卟啉单胞菌1435/1449 LPS作为免疫调节器，专利US2007/0134170A1）。在此提案中，我们的假设是： “天然存在的低毒性脂质A代表了新的疫苗佐剂”。我们将测试 通过隔离和表征低毒性脂质A（LT脂质A）的假设 厌氧革兰氏阴性细菌（AIM 1）。然后，我们将在体外检查它们的辅助潜力（AIM 2） 和非特异性（AIM 3）和特定免疫力（AIM 4）的小鼠模型。这些研究将确定是否 天然存在的LT脂质A代表了一类新的安全有效疫苗佐剂。