Pattern Recognition Molecule Mindin As Adjuvant

说明(申请人提供)：与传统疫苗相比，新一代疫苗提供了更特异的免疫保护和更少的不良影响。与主要由活的减毒或灭活的完整病原体和毒素组成的传统疫苗不同，许多正在开发的新疫苗由合成、重组或高度纯化的亚单位抗原组成。虽然这些亚单位抗原不包含与整个病原体一样多的成分来引起副作用，但它们的免疫原性也可能较低。因此，迫切需要开发新型和改良的疫苗佐剂。尽管已有数百种制剂被列为在动物模型中具有佐剂活性，但铝盐佐剂仍然是美国许可的疫苗中使用的唯一制剂。模式识别分子代表了一类新的佐剂开发候选分子。表达在细胞内、细胞外或细胞表面的模式识别分子识别病原体相关分子模式，在启动先天免疫和获得性免疫反应中发挥重要作用。细胞外基质(ECM)蛋白Mindin是一种模式识别分子，在疫苗接种中可作为分子佐剂发挥作用。Mindin属于ECM蛋白的F-pondin家族，在物种间高度保守。我们的结果表明，Mindin在启动先天和获得性免疫反应中起着关键作用。重要的是，Mindin可以放大对PAMPs刺激的炎症反应，并增强正常巨噬细胞对细菌的吞噬作用。Mindin的这些特性表明，它可以增强对微生物病原体的免疫反应。在这一应用中，我们建议检查Mindin是否可以用作细菌和病毒疫苗的分子佐剂。首先，Mindin将被提纯，并用作流感病毒和B群链球菌疫苗免疫的佐剂。其次，Mindin将与疫苗亚单位或胶囊多糖融合，并将在免疫中对结合产物进行测试。第三，将检测Mindin融合的DNA质粒在保护流感病毒感染方面的有效性。

DESCRIPTION (provided by applicant): New generation vaccines offer promises of more specific immune protection and less adverse effects when compared to traditional vaccines. In contrast to traditional vaccines that are primarily consisted of live attenuated or inactivated whole pathogens and toxins, numerous new vaccines under development are composed of synthetic, recombinant, or highly purified subunit antigens. While these subunit antigens do not contain as much components as whole pathogens to cause side effects, they are also likely less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. Even though hundreds of agents have been listed as having adjuvant activity when used in animal models, aluminum salt-based adjuvant remains to be the sole agent used in U.S.-licensed vaccines. Pattern recognition molecules represent a novel class of candidates for adjuvant development. Pattern recognition molecules expressed intracellularly, extracellularly, or on cell surface recognize pathogen-associated molecular patterns (PAMPs) and play critical roles in the initiation of innate and adaptive immune responses. The extracellular matrix (ECM) protein Mindin is a pattern recognition molecule that may function as a molecular adjuvant in vaccination. Mindin belongs to the F-spondin family of ECM proteins and is highly conserved across species. Our results demonstrate that Mindin plays a key role in the initiation of innate and adaptive immune responses. Importantly, Mindin can amplify the inflammatory response to PAMPs stimulation and enhance phagocytosis of bacteria by normal macrophages. These properties of Mindin suggest that it can enhance immune responses to microbial pathogens. In this application, we propose to examine whether Mindin can be used as a molecular adjuvant for bacterial and viral vaccines. First, Mindin will be purified and used as an adjuvant in immunizations with influenza virus and group B Streptococcus vaccines. Second, Mindin will be fused to vaccine subunits or capsular polysaccharides and the conjugated products will be tested in immunizations. Third, Mindin fused DNA plasmids will be examined for their efficacy in protecting influenza virus infection.