(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，手术伤口感染和感染假体材料的主要原因，也是医生感染的第二大主要原因。因此，葡萄球菌感染代表了发病率和死亡率的主要来源，也是巨大的经济负担。目前，在临床使用中没有抗稳定球菌疫苗。葡萄球菌表达表面暴露的，细胞壁脂肪甲酸，其中含有高度保存（聚）甘油磷酸（PGP）骨架。 PGP特异性的单克隆抗体赋予了针对实验动物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。已经开发了一种方法来有效，大规模生产合成PGP。在继发性免疫后，产生了一种合成PGP和破伤风毒素（PGP-TT）的共价共轭物（PGP-TT）。用PGP-TT免疫的小鼠表现出血液中葡萄球菌的快速清除，与用无关的结合疫苗免疫的小鼠相比。因此，基于PGP的共轭疫苗代表了针对葡萄球菌病原体（包括金黄色葡萄球菌和表皮链球菌）的主动免疫的有希望的方法。 许多因素会影响共轭疫苗的最佳设计。 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细胞表位）结合疫苗，以及优化的PGP偶联疫苗的相对能力引起针对金黄色葡萄球菌和表皮链球菌的保护性抗体。总的来说，这些研究将建立PGP共轭疫苗设计，适用于人类测试，并且有可能赋予主动抗体介导的保护抗体抗球菌感染。 该项目是合成化学家用于生产合成PGP的合作努力，一种抗原结合的生物化学家，也是测试疫苗免疫原性和宿主保护的细菌免疫学家。 公共卫生相关性：葡萄球菌是美国菌血症，手术伤口感染和肢体材料感染的主要原因，也是医院感染的第二大主要原因，导致了实质性的发病率，死亡率和经济负担。目前，在临床使用中没有抗稳定球菌疫苗。在该提案中，将开发一种新型的结合疫苗并在小鼠中进行测试，以诱导对高度保存的葡萄球菌细胞壁抗原（Poly）甘油磷酸盐（Poly）甘油磷酸盐特异性的保护性IgG抗体，该抗体在合成中产生。