(Poly)glycerolphosphate-based, cross-protective anti-staphylococcal vaccine

描述（由申请方提供）：葡萄球菌是美国菌血症、手术伤口感染和假体材料感染的主要原因，也是医院感染的第二大原因。因此，葡萄球菌感染代表了发病率和死亡率的主要来源，以及巨大的经济负担。目前，临床上还没有抗葡萄球菌疫苗。葡萄球菌表达表面暴露的，含有高度保守的（聚）甘油磷酸（pgp）骨架的细胞壁脂磷壁酸。Pgp特异性单克隆抗体在实验动物中对葡萄球菌感染具有被动保护作用，目前正在III期临床试验中进行测试。已经开发了一种有效和大规模生产合成pgp的方法。合成的pgp和破伤风类毒素（pgp-TT）的共价结合物的产生，在二次免疫后，在小鼠中引起加强的血清IgG抗pgp抗体。与用不相关的缀合物疫苗免疫的小鼠相比，用pgp-TT免疫的小鼠表现出葡萄球菌从血液中的快速清除。因此，基于pgp的结合疫苗代表了针对葡萄球菌病原体（包括S.金黄色葡萄球菌和表皮 许多因素影响偶联疫苗的最佳设计。在这方面，该建议将使用小鼠作为模型系统，确定含有不同链长的甘油磷酸单体的pgp的免疫原性和保护能力，以及pgp与载体蛋白的摩尔比，几种不同蛋白缀合化学的效果，不同蛋白载体和佐剂的效力，纯合成的pgp-PADRE（Pan DR辅助T细胞表位）缀合物疫苗的效力，以及优化的pgp缀合物疫苗引发针对两种S.金黄色葡萄球菌和表皮总的来说，这些研究将建立一种pgp结合疫苗设计，该疫苗设计将适用于人体试验，并有可能提供针对葡萄球菌感染的抗体介导的主动保护。 这个项目是一个合作的努力，合成化学家生产的合成pgp，生物化学家的抗原结合，和细菌免疫学家测试疫苗的免疫原性和宿主保护。 公共卫生相关性：在美国，葡萄球菌是菌血症、手术伤口感染和假体材料感染的主要原因，也是医院感染的第二大原因，导致严重的发病率、死亡率和经济负担。目前，临床上还没有抗葡萄球菌疫苗。在该提案中，将开发一种新型结合疫苗，并在小鼠中进行测试，以诱导对合成产生的高度保守的葡萄球菌细胞壁抗原（聚）甘油磷酸盐具有特异性的保护性IgG抗体。

DESCRIPTION (provided by applicant): Staphylococci are the leading cause of bacteremia, surgical wound infections, and infection of prosthetic materials in the United States, and the second leading cause of nosocomial infections. Thus, Staphylococcal infections represent a major source of morbidity and mortality, and a large economic burden. Currently, there exists no anti-Staphylococcal vaccine in clinical use. Staphylococci express surface-exposed, cell wall lipoteichoic acid containing a highly-conserved (poly)glycerolphosphate (pgp) backbone. A monoclonal antibody specific for pgp confers passive protection against Staphylococcal infection in experimental animals, and is currently being tested in a phase III clinical trial. A method has been developed for efficient and large-scale production of synthetic pgp. A covalent conjugate of synthetic pgp and tetanus toxoid (pgp-TT) was produced that elicited boosted serum IgG anti-pgp antibodies in mice after secondary immunization. Mice immunized with pgp-TT exhibited rapid clearance of Staphylococci from the blood, in contrast to mice immunized with an irrelevant conjugate vaccine. Thus, a pgp-based conjugate vaccine represents a promising approach for active immunization against Staphylococcal pathogens, including S. aureus and S. epidermidis. Numerous factors impact on the optimal design of a conjugate vaccine. In this regard, this proposal will determine, using the mouse as a model system, the immunogenicity and protective ability of pgp that contains different chain lengths of glycerol phosphate monomers, and molar ratios of pgp to carrier protein, the effect of several different - protein conjugation chemistries, the potency of distinct protein carriers and adjuvants, the efficacy of a purely synthetic pgp-PADRE (Pan DR helper T cell epitopes) conjugate vaccine, and the relative capacity of optimized pgp conjugate vaccines to elicit protective antibodies against both S. aureus and S. epidermidis. Collectively, these studies will establish a pgp conjugate vaccine design that will be suitable for testing in humans and that has the potential to confer active, antibody-mediated protection against Staphylococcal infections. This project is a collaborative effort of a synthetic chemist for production of synthetic pgp, a biochemist for antigen conjugation, and a bacterial immunologist for testing vaccine immunogenicity and host protection. PUBLIC HEALTH RELEVANCE: Staphylococci are the leading cause of bacteremia, surgical wound infections, and infection of prosthetic materials in the United States, and the second leading cause of nosocomial infections, incurring substantial morbidity, mortality, and economic burden. Currently, there exists no anti-Staphylococcal vaccine in clinical use. In this proposal a novel conjugate vaccine will be developed, and tested in mice, for induction of protective IgG antibodies specific for the highly-conserved Staphylococcal cell wall antigen, (poly)glycerolphosphate, produced synthetically.