Multi-componet Vaccine for Staphylcoccus epidermidis

表皮葡萄球菌多成分疫苗

• 批准号: 7537194
• 负责人: Tomas Maira-Litran
• 金额: $ 21.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537194
• 关键词: Active Immunization; Amides; Amino Acids; Animal Model; Animals; Anthrax disease; Antibiotic Resistance; Antibiotics; Antibodies; Antigen Targeting; Bacillus (bacterium); Bacillus anthracis; Bacteremia; Bacteria; Binding; Biological Assay; Blood group antibody D; Carrier Proteins; Catheters; Clinical; Coagulase; Complement; Conjugate Vaccines; Evaluation; Genes; Genus staphylococcus; Glucosamine; Glutamic Acid; Growth; Human; Immune Sera; Immunity; Immunization; Immunotherapeutic agent; Implant; In Vitro; Individual; Infection; Infection prevention; Investigation; Isomerism; Link; Mediating; Medical Device; Microbial Biofilms; Modeling; Molecular Target; Molecular Weight; Mus; Nosocomial Infections; Oryctolagus cuniculus; Pathogenesis; Peptides; Polymers; Polysaccharides; Population; Prevention approach; Production; Proteins; Resistance; Serum; Staphylococcus aureus; Staphylococcus epidermidis; Surface; Synthetic Prostaglandins A; Testing; Tetanus Toxoid; Thick; Vaccines; Virulence Factors; Work; catheter related infection; comparative; extracellular; immunogenic; immunogenicity; in vivo; insight; killings; neutrophil; novel; novel strategies; novel vaccines; pathogen; poly-N-acetyl glucosamine; protective efficacy; research study; vaccine candidate; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): Coagulase-negative staphylococci (CoNS), notably Staphylococcus epidermidis, are a predominant cause of hospital-acquired infections and treatment can be difficult owing to biofilm formation and antibiotic resistance. This ability to form a multi-layered biofilm depends, in part, on the production of the surface polysaccharide termed poly-N-acetyl-glucosamine (PNAG). Previous work has demonstrated that PNAG is an in vivo expressed antigen and the target for protective immunity for both S. epidermidis and Staphylococcus aureus. However, production of PNAG varies widely among clinical isolates of CoNS, potentially limiting the use for this surface polymer as the sole component of a vaccine against staphylococcal strains. Therefore, additional potential vaccine candidates need to be investigated. S. epidermidis and other related CoNS elaborate, as extracellular polymers, poly-?-DL-glutamic acid (DL-PGA) to facilitate growth and survival in the human host. These polymers are also produced by Bacillus spp., including B. licheniformis and more notably B. anthracis, and antibody to the PGA mediates protective immunity to anthrax. Preliminary work has shown that mouse antibodies raised to a B. licheniformis DL-PGA-conjugate vaccine can mediate killing of various S. epidermidis strains by human polymorphonuclear leukocytes and complement in an in vitro opsonophagocytic assay. Moreover, the opsonophagocytic killing was independent of PNAG production, as both PNAG positive and negative clinical isolates were similarly opsonized and killed. The major hypothesis being evaluated is that an optimized vaccine that would target S. epidermidis should be multi-component and include PNAG and D- and/or L-glutamic acid in combination in order to provide maximum coverage against staphylococcal clinical isolates and/or obtain a synergistic effect from the individual components. Multiple vaccines candidates will be synthesized including high molecular weight D- and L-PGA, 20-mer synthetic PGA peptides of either the D or L configuration and dPNAG conjugated to the carrier protein tetanus toxoid. The in vitro opsonophagocytic assay will be used as the first screen for potentially protective antibodies. Highly opsonic antibodies and vaccines that elicit them will be further tested for their immunoprotective efficacy by passive and active immunization against challenge with multiple strains of CoNS in a murine catheter-infection model. Insights gained by these studies will help us to evaluate immunotherapeutic strategies for control and prevention of infection by CoNS. Project Narrative: Over the past 2 decades, Staphylococcus epidermidis has become one of the most prevalent pathogens involved in hospital-acquired infections. Importantly many strains of S. epidermidis are resistant to commonly used antibiotics, underscoring the need to find new approaches to prevention and treatment of infection such as identifying novel molecular targets for vaccine development. This application proposes to investigate the vaccine potential of two different S. epidermidis surface polymers termed poly-DL-glutamic acid and deacetylated poly-N-acetyl-glucosamine (dPNAG) either alone or in combination as components of a novel vaccine against this pathogen.

描述（由申请人提供）：凝固酶阴性葡萄球菌（CONS），尤其是表皮葡萄球菌，是医院获得感染的主要原因，并且由于生物膜的形成和抗生素耐药性而很难进行治疗。这种形成多层生物膜的能力部分取决于称为聚-N-乙酰葡萄糖胺（PNAG）的表面多糖的产生。先前的工作表明，PNAG是体内表达的抗原，也是表皮链球菌和金黄色葡萄球菌的保护性免疫靶标。然而，PNAG的产生在缺点的临床分离株中差异很大，可能会限制该表面聚合物作为疫苗对葡萄球菌菌株的唯一成分。因此，需要研究额外的潜在候选疫苗。表皮链球菌及其他相关的详细说明，如细胞外聚合物，聚 - ？ - dl-谷氨酸（DL-PGA），以促进人宿主的生长和存活。这些聚合物也由芽孢杆菌属杆菌产生，包括扁豆芽孢杆菌和更明显的炭疽芽孢杆菌，以及对PGA的抗体介导对炭疽的保护性免疫。初步工作表明，饲养至扁豆芽孢杆菌DL-PGA偶联物疫苗的小鼠抗体可以通过人类多形核白细胞介导杀死各种表皮链球菌菌株，并补充体外opsonophopococytic分析。此外，由于PNAG阳性和阴性临床分离株均被类似地进行调理和杀死，因此调查性杀伤性杀戮与PNAG的产生无关。评估的主要假设是，将靶向表皮链球菌的优化疫苗应为多组分，包括PNAG和D-和/或L-谷氨酸组合，以提供针对葡萄球菌临床分离株和/或获得的最大覆盖率。来自各个组件的协同作用。将合成多种疫苗候选物，包括高分子量D和L-PGA，D或L构型的20-Mer合成PGA肽，以及与载体蛋白破伤风毒素结合的DPNAG。体外调查性细胞测定法将用作潜在保护性抗体的第一个筛选。在鼠导管感染模型中，通过被动和主动免疫对挑战的被动和主动免疫，将进一步测试引起它们的高度Opsonic抗体和疫苗。这些研究获得的见解将有助于我们评估控制和预防感染的免疫治疗策略。 项目叙述：在过去的二十年中，表皮葡萄球菌已成为参与医院获得的感染的最普遍的病原体之一。重要的是，表皮链球菌的许多菌株对常用抗生素具有抗性，强调了寻找预防和治疗感染的新方法，例如鉴定新的分子靶标的疫苗开发。该应用建议研究称为聚-DL-谷氨酸的两种不同表皮表面聚合物的疫苗电位，单独或单独或组合是新型疫苗的组成部分，称为聚-DL-谷氨酸和脱乙酰化的聚-N-乙酰葡萄糖（DPNAG）。