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

描述(由申请人提供)：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，葡萄球菌感染是发病率和死亡率的主要来源，并造成巨大的经济负担。目前，临床上尚无抗葡萄球菌疫苗。葡萄球菌表达表面暴露的、细胞壁脂磷壁酸，含有高度保守的(聚)甘油磷酸(PGP)骨架。一种针对Pgp的单抗在实验动物中提供了对葡萄球菌感染的被动保护，目前正在进行第三阶段临床试验。开发了一种高效、规模化生产合成PGP的方法。合成的PgP与破伤风类毒素的共价结合物(PGP-TT)在二次免疫后可诱导小鼠血清中抗PgP抗体的增强。与免疫无关结合疫苗的小鼠相比，PGP-TT免疫的小鼠表现出从血液中快速清除葡萄球菌。因此，基于PGP的结合疫苗代表了一种对金黄色葡萄球菌和表皮葡萄球菌等病原体进行主动免疫的有前途的方法。影响结合疫苗优化设计的因素很多。在这方面，这项建议将以小鼠为模型系统，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，几种不同蛋白质结合化学的影响，不同蛋白质载体和佐剂的效力，纯合成PGP-PADRE(泛DR辅助T细胞表位)结合疫苗的效力，以及优化的PGP结合疫苗诱导针对金黄色葡萄球菌和表皮葡萄球菌保护性抗体的相对能力。总而言之，这些研究将建立一种PGP结合疫苗设计，该设计将适合在人类身上进行测试，并有可能提供主动的、抗体介导的预防葡萄球菌感染的保护。该项目是由合成PGP的合成化学家、抗原结合的生物化学家和测试疫苗免疫原性和宿主保护的细菌免疫学家共同努力的结果。 公共卫生相关性：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，导致大量的发病率、死亡率和经济负担。目前，临床上尚无抗葡萄球菌疫苗。在这项建议中，将开发一种新的结合疫苗，并在小鼠身上进行测试，以诱导针对高度保守的葡萄球菌细胞壁抗原的保护性免疫球蛋白抗体，合成的(多)甘油磷酸。

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.