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

基于（聚）甘油磷酸盐的交叉保护性抗葡萄球菌疫苗

• 批准号: 8074028
• 负责人: CLIFFORD M SNAPPER
• 金额: $ 22.72万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074028
• 关键词: Active Immunization; Adjuvant; Aldehydes; Animals; Antibodies; Antibody-mediated protection; Antigen Targeting; Antigens; Bacteremia; Bacteria; Binding; Biological Models; Blood; CD4 Positive T Lymphocytes; Carrier Proteins; Cell Wall; Chemistry; Clinical; Clinical Trials; Conjugate Vaccines; Data; Economic Burden; Exhibits; Genus staphylococcus; Glycerol; Glycerophosphates; Helper-Inducer T-Lymphocyte; Human; Immunoglobulin G; Immunologist; Infection; Length; Ligands; Methods; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nosocomial Infections; Phase III Clinical Trials; Production; Property; Prosthesis; Proteins; Relative (related person); Secondary Immunization; Secondary to; Serum; Source; Staphylococcal Infections; Staphylococcal Vaccines; Staphylococcus aureus; Staphylococcus epidermidis; Surface; Surgical Wound Infection; T-Lymphocyte Epitopes; Testing; Tetanus Toxoid; United States; Vaccine Design; Vaccines; Vertebral column; aluminum sulfate; anti-IgG; base; cross reacting material 197; design; experience; immunogenicity; inorganic phosphate; large scale production; lipoteichoic acid; monomer; mortality; novel; pathogen; public health relevance; vaccine evaluation

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.

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，也是巨大的经济负担。目前，尚无抗葡萄球菌疫苗投入临床使用。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）磷酸甘油（pgp）主链。一种针对 pgp 的单克隆抗体可为实验动物提供针对葡萄球菌感染的被动保护，目前正在 III 期临床试验中进行测试。已经开发出一种高效、大规模生产合成 pgp 的方法。产生了合成 pgp 和破伤风类毒素 (pgp-TT) 的共价缀合物，在二次免疫后可在小鼠体内引发增强的血清 IgG 抗 pgp 抗体。与用不相关的结合疫苗免疫的小鼠相比，用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针对葡萄球菌病原体（包括金黄色葡萄球菌和表皮葡萄球菌）主动免疫的有前途的方法。 许多因素影响结合疫苗的优化设计。对此，本提案将以小鼠为模型系统，测定含有不同链长磷酸甘油单体的pgp的免疫原性和保护能力，以及pgp与载体蛋白的摩尔比，几种不同蛋白的作用结合化学、不同蛋白载体和佐剂的效力、纯合成 pgp-PADRE（泛 DR 辅助 T 细胞表位）结合疫苗的功效以及相对优化的 pgp 结合疫苗引发针对金黄色葡萄球菌和表皮葡萄球菌的保护性抗体的能力。总的来说，这些研究将建立一种 pgp 结合疫苗设计，该设计适合在人体中进行测试，并且有可能提供针对葡萄球菌感染的主动、抗体介导的保护。 该项目是生产合成 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的合作成果。 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，会造成大量的发病率、死亡率和经济负担。目前，尚无抗葡萄球菌疫苗投入临床使用。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，以诱导合成产生的高度保守的葡萄球菌细胞壁抗原（聚）甘油磷酸特异的保护性 IgG 抗体。