Synthetics PNAG and multi-component vaccines against emerging pathogens

聚-N-乙酰葡糖胺（PNAG）是一种0-1-6连接的 由包括葡萄球菌在内的多种细菌病原体表达的表面多糖 金黄色葡萄球菌、大肠杆菌和鼠疫耶尔森氏菌。它有很高的潜力成为一种广泛保护性疫苗， 多种病原体，但特定的糖型，特别是那些缺乏乙酸酯取代基的氨基 需要葡糖胺单糖的基团来产生最佳免疫力。此外，Active 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 这种抗原作为单一组分疫苗可能是次优的，此外，病原体来源的 PNAG抗原可能不是最佳的合成疫苗，引发最有效的保护抗体 反应最后，使用不同载体蛋白的阵列生产缀合疫苗可能是耗时的 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 其可以容易地储存并容易地缀合至源自靶向的重组载体蛋白， 病原体将评价这些疫苗对耐甲氧西林沙门氏菌的保护作用。 金黄色葡萄球菌（MRSA）、肠出血性大肠杆菌（E.大肠杆菌（EHEC）O 157和类似的产滋贺毒素（STX）菌株， 和Y.鼠疫此外，还将评估这些基于PNAG的疫苗预防粘膜炎的能力。 殖民化以及肺炎，这两个关键的干预措施尚未得到测试。基于PNAG 结合疫苗将与对每种病原体特异的重组蛋白配对，以确定 多组分制剂可产生累加、协同或甚至可能抑制免疫作用。 MRSA的结合疫苗将含有合成的PNAG寡糖和荚膜多糖 5型（CP 5）和8型（CP 8）。载体蛋白抗原将包括有助于保护性免疫的那些。 免疫，如α-溶血素类毒素（Hla）或凝集因子B（Clf B）。肠出血性大肠杆菌疫苗包括 合成PNAG寡糖和STX的缀合物。合成的PNAG寡葡糖胺缀合至 LcrV、F1荚膜或它们的融合蛋白将用于靶向Y。鼠疫我们将调查 通过免疫产生的免疫效应物，并评估其预防粘膜损伤的功能。 这些致病菌的定植和感染。

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.