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-乙酰氨基葡萄糖 (PNAG) 是一种 0-1-6 连接的 由多种细菌病原体表达的表面多糖，包括葡萄球菌 金黄色葡萄球菌、大肠杆菌和鼠疫耶尔森氏菌。它很有可能成为一种广泛保护的疫苗 多种病原体，但有特定的糖型，尤其是氨基上缺乏乙酸酯取代基的病原体 需要葡萄糖胺单糖基团来产生最佳免疫力。此外，主动 针对 PNAG 的被动疫苗接种策略已进入早期临床开发，但其实用性 这种抗原作为单组分疫苗可能不是最理想的，此外，病原体衍生的疫苗 PNAG 抗原对于合成引发最有效保护性抗体的疫苗可能不是最佳选择 回复。最后，使用一系列不同的载体蛋白生产结合疫苗可能非常耗时 而且很贵。为了解决这些问题，将生产合成的低聚葡萄糖胺糖型 可以轻松储存并轻松与多种源自靶标的重组载体蛋白缀合 病原体。将评估这些疫苗对耐甲氧西林金黄色葡萄球菌的保护作用。 金黄色葡萄球菌 (MRSA)、肠出血性大肠杆菌 (EHEC) O157 和类似的志贺毒素 (STX) 产生菌株， 和鼠疫耶尔森氏菌。此外，还将评估这些基于 PNAG 的疫苗预防粘液素的能力。 定植和肺炎，这两种关键干预措施尚未经过测试。基于PNAG 结合疫苗将与每种病原体特异的重组蛋白配对，以确定是否 多组分制剂可以产生附加的、协同的、甚至可能是抑制性的免疫效应。 MRSA 结合疫苗将含有合成的 PNAG 寡糖和荚膜多糖 类型 5 (CP5) 和 8 (CP8)。载体蛋白抗原将包括那些有助于保护性的抗原 免疫，例如 α-溶血素类毒素 (Hla) 或凝集因子 B (ClfB)。肠出血性大肠杆菌疫苗将包括 合成 PNAG 寡糖和 STX 的缀合物。合成 PNAG 低聚葡萄糖胺缀合 LcrV、F1 荚膜或它们的融合蛋白将用于靶向鼠疫耶尔森氏菌。我们将调查类型 免疫产生的免疫效应物并评估其预防粘膜病的功能 这些致病菌的定植和感染。