Synthetics PNAG and multi-component vaccines against emerging pathogens

多-N-乙酰氨基葡萄糖(PNAG)是一个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。它有很大的潜力成为一种广泛的保护性疫苗 病原体种类繁多，但有特殊的糖型，特别是氨基上没有醋酸酯取代基的病原体 氨基葡萄糖单糖组是产生最佳免疫力所必需的。此外，活动 针对PNAG的被动疫苗接种策略已经进入早期临床开发，但其效用 将这种抗原作为单一成分的疫苗很可能是次优的，而且是病原体衍生的 PNAG抗原可能不适合合成能诱导最有效的保护性抗体的疫苗 回应。最后，使用一系列不同的载体蛋白生产结合疫苗可能很耗时。 而且很贵。为了解决这些问题，将生产合成的低聚葡糖苷形式 它可以很容易地存储并容易地与从靶向来源的各种重组载体蛋白连接 病原体。这些疫苗将进行评估，以产生对耐甲氧西林葡萄球菌的保护。 金黄色葡萄球菌(MRSA)、肠出血性大肠杆菌(EHEC)O157和类似志贺毒素(STX)的产生菌； 和鼠疫耶尔森氏菌。此外，还将评估这些基于PNAG的疫苗预防粘液的能力 殖民主义和肺炎，这两种关键的干预措施尚未得到检验。基于PNAG的 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 多组分制剂可产生相加的、协同的或甚至抑制的免疫效应。 MRSA结合疫苗将包含合成的PNAG寡糖和荚膜多糖 类型5(CP5)和类型8(CP8)。载体蛋白抗原将包括那些有助于保护 免疫，如α-溶血素类毒素(Hla)或凝集因子B(ClfB)。用于EHEC的疫苗将包括 合成的PNAG寡糖和STX的偶联物。合成的PNAG寡糖胺偶联到 LcrV、F1胶囊或它们的融合蛋白将用于靶向鼠疫杆菌。我们将调查这种类型的 免疫产生的免疫效应物及其预防粘膜功能的评价 这些致病细菌的定植和感染。

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.