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，明矾一直是唯一被批准的佐剂 供人类使用，与全细胞疫苗或以病毒为基础的疫苗一起使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更新的 针对含有更明确的微生物成分选择性成分的病原体的疫苗，这种成分通常是 免疫原性较低。同时，佐剂研究随着对 单磷脂A(MPL)，一种可以安全地增强免疫反应的疫苗佐剂。MPL是 通过选择性地降解有毒细菌脂多糖(LPS)的结构而获得的，通常被称为 内毒素。MPL作为一种修饰的脂多糖，在保持其免疫原性的同时，显著降低了其免疫原性。 有毒的影响。然而，从几种厌氧革兰氏阴性细菌中获得的内毒素已被 显示含有一种天然产生的低毒脂质A。最近，我们证明了两种天然的 从牙龈卟啉单胞菌中提取的低毒类脂A可以增强免疫应答和 在两种不同的小鼠肿瘤模型(牙龈卟啉单胞菌1435/1449)中是有效的疫苗佐剂 作为免疫调节剂的脂多糖，专利US2007/0134170A1)。在这个提议中，我们的假设是： 自然产生的低毒类脂A代表了一类新的疫苗佐剂。我们将测试 这一假设是通过从几个物种中分离和鉴定低毒的类脂A(LT类脂A)来实现的 厌氧革兰氏阴性菌(目标1)。然后我们将在体外检测它们的佐剂潜力(目标2)。 以及非特异性(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LT类脂A代表了一类新的安全有效的疫苗佐剂。