Staphylococcus aueaus vaccine development

金黄色葡萄球菌是导致血液、下呼吸道、皮肤和软组织感染的主要原因 在美国，有超过一半的感染和抗生素耐药菌株（MRSA）被分离出来， 社区和医院感染。对入侵性S.金黄色葡萄球菌病 自从发现这种微生物以来，一直是首要的研究目标。虽然几个信封组件 已经研究了分泌产物作为疫苗抗原（表面蛋白，荚膜 多糖、外泌多糖、α-溶血素和杀白细胞素），没有单一抗原促进 形成长期的保护性免疫力。此外，迄今为止的调查没有得出明确的结论， 了解宿主免疫应答的特征，这些特征是产生这种免疫应答所必需的。 保护性免疫这一发现基于三个基本发现。1. S.金黄色葡萄球菌调节 在感染过程中的免疫反应，并防止保护性免疫的发展。近期 ESS和AGR途径中能够产生保护性的葡萄球菌变体的分析 活疫苗接种模型中的免疫性现在能够通过遗传修饰来表征保护性抗原， 减法2.动物模型中针对葡萄球菌感染的保护性免疫水平是 当两种或多种抗原结合时增加。相互作用的现象也是如此：遗传 减去一种以上的疫苗抗原（毒力因子）， 葡萄球菌毒力3.对于肺中的感染过程，α-溶血素的分泌是必需的。 葡萄球菌的毒力属性，使独特的疫苗和免疫设计成为可能 战略布局基于这些发现，我们提出了一种合理的疫苗测试方法， 包括单个亚基必须基于三个标准，（i）指定疫苗抗原的基因必须 存在于相关临床分离的S.金黄色。(ii)缺乏这些基因的葡萄球菌突变体必须 揭示了这些成分对S.金黄色葡萄球菌感染，（iii）免疫接种 与单个亚单位组分或亚单位的组合一起必须产生免疫应答， 改善S.金黄色葡萄球菌感染时，测试与多种动物模型的疾病。

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.