Staphylococcus aueaus vaccine development

金黄色葡萄球菌是引起血液循环、下呼吸道、皮肤和软组织的主要原因。 在美国的感染和耐药菌株(MRSA)中，超过一半的人被分离出来 社区和医院感染。寻找对侵袭性金黄色葡萄球菌病的保护性免疫 自从发现这种微生物以来，一直是首要的研究目标。而几个信封组件 和分泌产物已被研究为疫苗抗原(表面蛋白、囊膜 多糖、胞外多糖、a-溶血素和杀白素)，没有单一的抗原促进 发展长期保护性免疫。此外，到目前为止，调查还没有产生明确的 了解宿主免疫反应的特征，这是产生这种免疫反应所必需的 保护豁免权。这一提议基于三个基本发现。1.金黄色葡萄球菌 在感染期间的免疫反应，并防止保护性免疫的发展。最近的 ESS和AGR途径中能够产生保护性的葡萄球菌变异株的分析 活疫苗接种模型中的免疫现在能够通过基因来表征保护性抗原 减法。2.动物模型对葡萄球菌感染的保护性免疫水平为 当两个或更多的抗原结合时增加的。互惠现象也是真实的：遗传 减去一个以上的疫苗抗原(毒力因子)会导致相应的减少 葡萄球菌毒力。3.对于肺部的感染过程，a-溶血素的分泌是必不可少的 葡萄球菌的毒力属性，使独特的疫苗和免疫疗法的设计成为可能 战略。基于这些发现，我们提出了一种合理的疫苗测试方法，即 包括个别亚基必须基于三个标准：(1)指定疫苗抗原的基因必须 出现在金黄色葡萄球菌的相关临床分离株中。(Ii)缺乏这些基因的葡萄球菌突变株必须 揭示这些成分在金黄色葡萄球菌感染发病机制中的作用：(Iii)免疫 单独的亚基成分或亚基的组合必须产生免疫反应 在多种动物模型的疾病试验中，改善金黄色葡萄球菌感染的结果。

Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States and antibiotic resistant strains (MRSA) are isolated in more than half of all community and hospital infections. The search for protective immunity against invasive S. aureus disease has been a premier research goal since the discovery of this microbe. While several envelope components and secreted products have been investigated as vaccine antigens (surface proteins, capsular polysaccharide, exopolysaccharide, a-hemolysin, and leukocidins), no single antigen has facilitated the development of long-term protective immunity. Furthermore, investigations to date have not yielded a clear understanding of the features of the host immune response that are requisite for the generation of such protective immunity. This proposal is based on three fundamental discoveries. 1. S. aureus modulates immune responses during infection and prevents the development of protective immunity. The recent analysis of staphylococcal variants in the ess and agr pathways that are capable of generating protective immunity in live vaccination models now enables the characterization of protective antigens via genetic subtraction. 2. Levels of protective immunity against staphylococcal infection in animal models are increased when two or more antigens are combined. The reciprocal phenomenon is also true: genetic subtraction of more than one vaccine antigen (virulence factor) leads to a commensurate reduction of staphylococcal virulence. 3. For infectious processes in the lung, secretion of a-hemolysin is an essential virulence attribute of staphylococci, enabling the design of unique vaccine and immunotherapeutic strategies. Based on these discoveries, we propose a rational approach for vaccine testing, whereby the inclusion of individual subunits must be based on three criteria, (i) Genes specifying vaccine antigens must be present in relevant clinical isolates of S. aureus. (ii) Staphylococcal mutants lacking these genes must reveal a contribution of these components to the pathogenesis of S. aureus infections, (iii) Immunization with individual subunit components or a combination of subunits must generate immune responses that improve the outcome of S. aureus infections when tested with multiple animal models of disease.