Synthetics PNAG and multi-component vaccines against emerging pathogens

针对新兴病原体的合成 PNAG 和多组分疫苗

• 批准号: 8233448
• 负责人: Gerald B Pier
• 金额: $ 48.27万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233448
• 关键词: Acetates; Address; Adhesives; Animal Model; Antibodies; Antibody Formation; Antigens; Bacillus (bacterium); Bacteremia; Bacteria; Bacterial Infections; Carrier Proteins; Chimeric Proteins; Clinical; Complement Factor B; Conjugate Vaccines; Development; Diarrhea; Effectiveness; Escherichia coli; Escherichia coli EHEC; Escherichia coli Infections; Escherichia coli O157; Evaluation; Generations; Glucosamine; Hemolysin; Herd Immunity; Human; Immune; Immune Sera; Immunity; Immunization; In Vitro; Individual; Infant; Infection; Intervention; Iron; Link; Modeling; Monosaccharides; Mus; New England; Nose; O Antigens; Oligosaccharides; Organ; Oryctolagus cuniculus; Passive Immunotherapy; Plague; Pneumonia; Pneumonic Plague; Polysaccharides; Preparation; Prevention; Public Health; Recombinant Proteins; Recombinants; Rodent Model; Shiga Toxin; Shiga-Like Toxin I; Staphylococcus aureus; Structure; Surface; Surface Antigens; Surgical Wound Infection; Systemic infection; Testing; Time; Toxoids; Vaccines; Work; Yersinia pestis; amino group; base; biodefense; capsule; factor A; foodborne; killings; methicillin resistant Staphylococcus aureus; pathogen; pathogenic bacteria; poly-N-acetyl glucosamine; preclinical evaluation; prevent; protective efficacy; renal abscess; transmission process; vaccination strategy; vaccine candidate; vaccine efficacy

Poly-N-acetyl glucosamine (PNAG) is a 0-1-6 linked surface polysaccharide that is expressed by a broad range of bacterial pathogens, including Staphylococcus aureus, Escherichia coli, and Yersinia pestis. It has high potential to be a widely protective vaccine against a diverse array of pathogens, but specific glycoforms, notably ones lacking acetate substituents on the amino groups of the glucosamine monosaccharide are needed to produce optimal immunity. Additionally, active and passive vaccination strategies targeting PNAG have moved into early clinical development, but the utility of this antigen as a single component vaccine is likely to be suboptimal, Furthermore, pathogen-derived PNAG antigen may be suboptimal for synthesizing vaccines that elicit the most effective protective antibody response. Finally, producing conjugate vaccines using an array of different carrier proteins can be time consuming and expensive. To address these issues, synthetic oligoglucosamine glycoforms will be produced that can be easily stored and readily conjugated to a variety of recombinant carrier proteins derived from targeted pathogens. These vaccines will be evaluated for engendering protection against methicillin-resistant S. aureus (MRSA), enterohemorrhagic E. coli (EHEC) O157 and similar Shiga toxin (STX)-prpducing strains, and Y. pestis. Moreover, these PNAG-based vaccines will also be evaluated for the ability to prevent mucpsal colonization as well as pneumonia, two critical interventions that have not yet been tested. PNAG-based conjugate vaccines will be paired with recombinant proteins specific to each of the pathogens to determine if additive, synergistic or possibly even inhibitory immune effects can be engendered by multicomponent preparations. Conjugate vaccines for MRSA will contain synthetic PNAG oligosaccharides plus capsular polysaccharide types 5 (CP5) and 8 (CP8). Carrier protein antigens will include those that contribute to protective immunity, such as alpha-hemolysin toxoid (Hla) or clumping factor B (ClfB). Vaccines for EHEC will include conjugates of synthetic PNAG oligosaccharides and STX. Synthetic PNAG oligoglucosamines conjugated to LcrV, F1 capsule or a fusion protein of these will be used to target Y. pestis. We will investigate the type of immune effectors generated by immunization and evaluate their functionality for the prevention of mucosal colonization and infection by these pathogenic bacteria.

聚-N-乙酰葡萄糖（PNAG）是0-1-6链接的 表面多糖由广泛的细菌病原体表达，包括葡萄球菌 金黄色葡萄球菌，大肠杆菌和耶尔森氏菌。它具有广泛保护性疫苗的高潜力 各种各样的病原体，但特定的糖型，尤其是在氨基上缺乏醋酸酯取代基的病原体 需要单糖的基团以产生最佳的免疫力。另外，有效 针对PNAG的被动疫苗接种策略已进入早期临床开发，但实用程序 该抗原作为单个成分疫苗可能是次优的，此外，病原体衍生的 PNAG抗原对于引起最有效的保护性抗体的合成疫苗可能是优越的 回复。最后，使用一系列不同的载体蛋白生产共轭疫苗可能很耗时 而且昂贵。为了解决这些问题，将产生合成的寡葡萄糖糖胺 可以很容易地存储并容易将其缀合到源自目标的各种重组载体蛋白 病原体。这些疫苗将被评估以促进耐甲氧西林的保护。 金黄色葡萄球菌（MRSA），Enterohemorrhagic E. coli（EHEC）O157和类似的Shiga Toxin（STX） - PRPDUCING菌株， 和Y. Pestis。此外，还将评估这些基于PNAG的疫苗，以防止粘液 殖民化和肺炎，两种尚未测试的关键干预措施。基于PNAG 结合疫苗将与针对每种病原体的重组蛋白配对，以确定是否是否 多组分制剂可以产生添加剂，协同或甚至可能的抑制免疫作用。 MRSA的共轭疫苗将含有合成的PNAG寡糖加囊多糖 5型（CP5）和8（CP8）。载体蛋白抗原将包括有助于保护性的抗原 免疫力，例如α-羟蛋白毒素毒素（HLA）或结块因子B（CLFB）。 EHEC的疫苗将包括 合成PNAG寡糖和STX的共轭物。合成的PNAG寡葡萄糖胺与 LCRV，F1胶囊或这些融合蛋白将用于靶向鼠疫。我们将研究的类型 免疫产生的免疫效应子并评估其预防粘膜的功能 这些致病细菌的定殖和感染。