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。历史上明矾是唯一被批准的佐剂 供人类使用，并且与全细胞或基于病毒的疫苗一起施用时有效且安全。 然而，对细菌致病机制的认识不断增强，导致了更新的细菌的开发。 针对病原体的疫苗含有更明确的微生物成分选择性组合物，通常是 免疫原性较低。与此同时，辅助研究也取得了进展，并确定了 单磷酰脂质 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作为一种改良的LPS，保留了其免疫原性特征，同时显着降低了其免疫原性。 毒性作用。然而，从几种厌氧革兰氏阴性菌中获得的 LPS 已被 显示含有天然存在的低毒性脂质 A。最近，我们证明了两种天然存在的脂质 A 从牙龈卟啉单胞菌中获得的低毒性脂质 A 可以增强免疫反应， 是对小鼠两种不同肿瘤模型有效的疫苗佐剂（牙龈卟啉单胞菌 1435/1449 LPS 作为免疫调节剂，专利 US2007/0134170A1）。在这个提案中，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 通过从几种植物中分离和表征低毒性脂质 A（LT 脂质 A），证实了这一假设。 厌氧革兰氏阴性菌（目标 1）。然后我们将在体外检查它们的佐剂潜力（目标 2） 以及非特异性免疫（目标 3）和特异性免疫（目标 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的疫苗佐剂。