An immunomodulatory yeast-derived beta glucan as a component of a conjugate

描述(由申请人提供)：真菌感染，特别是在免疫功能低下的患者中，是一个严重且日益严重的问题。尽管抗真菌疗法有了很大的进步，但失败和复发是很常见的。烟曲霉菌是导致这些感染的几个患者群体的主要原因：移植、白血病、遗传缺陷，如慢性肉芽肿疾病和其他，死亡率仍然很高。预防性抗真菌疫苗是一个有吸引力但尚未实现的选择。这项提议的目标是通过将蛋白质与颗粒状葡聚糖免疫调节剂(即WGP)相结合来开发葡聚糖蛋白疫苗的原型，WGP是许多致病真菌的细胞壁成分。单独使用WGP或与非特异性蛋白牛血清白蛋白(BSA)结合的初步工作表明，葡聚糖蛋白疫苗对曲霉菌和球孢子虫具有活性。这项建议中描述的工作将检验将来自曲霉的特定的、免疫优势的重组蛋白(即Aspf3)与WGP结合的可能性，并与与非真菌蛋白BSA的结合相比，增强疫苗的保护能力。初步研究表明，这种葡聚糖蛋白疫苗还有可能对其他真菌具有交叉保护作用；因此，除了测试曲霉菌外，疫苗制剂还将测试球孢子虫，这是一种严重的主要真菌病原体，在正常或免疫抑制的个人中，被NIH视为新出现的C类病原体。希望证明最大限度的交叉保护，这将为开发这种葡聚糖-蛋白质结合疫苗作为一种模型全真菌疫苗提供基础，该疫苗对由各种真菌引起的严重真菌感染既安全又有效。为了进一步了解免疫反应的哪一部分对在这些系统中诱导保护性免疫至关重要，将研究保护性疫苗和保护性较低或非保护性制剂诱导的细胞因子和抗体谱，目的是确定一组表明疫苗具有保护性的替代标记。获得真菌疫苗最有效的途径是将优化配置的葡聚糖与特定的免疫原蛋白相结合的结合疫苗。这一提议的基础来自迄今为止的工作，这表明一些蛋白质可能具有足够的交叉免疫原性，当与适当的交叉免疫原性葡聚糖结合时，可能会开发出一种泛真菌疫苗。在这一第一阶段申请中提出的研究有可能导致未来生产和商业化人们非常希望的全真菌疫苗。这种类型的疫苗不仅将节省大量的医疗成本，还将减少许多患者的严重真菌感染，更重要的是，拯救生命。

DESCRIPTION (provided by applicant): Fungal infections, particularly in immunocompromised patients, are a serious and growing problem. Although antifungal therapeutics have improved greatly, failures and relapse are common. Aspergillus fumigatus is a primary cause of these infections in several patient populations: transplants, leukemics, genetic deficiencies such as chronic granulomatous disease and others, with mortality remaining high. Preventative antifungal vaccines are an attractive, but as yet unrealized, option. The goal of this proposal is to develop a prototype glucan-protein vaccine by conjugating a protein to a particulate ¿-glucan immunomodulator (i.e., WGP), a cell wall component of many pathogenic fungi. Preliminary work using WGP alone or conjugated to a non-specific protein, bovine serum albumin (BSA), indicated that a glucan-protein vaccine was active against Aspergillus and Coccidioides. The work described in this proposal will examine the potential of conjugating a specific, immunodominant recombinant protein from Aspergillus (i.e., Aspf3) to WGP and enhancing the protective capacity of the vaccine in comparison to a conjugate with a non-fungal protein, BSA. Preliminary studies demonstrated that such a glucan-protein vaccine would also have the potential to be cross-protective against other fungi; thus, in addition to testing against Aspergillus, the vaccine preparations will be tested against Coccidioides, a serious primary fungal pathogen in normal or immunosuppressed individuals, considered an emerging Category C pathogen by NIH. The hope is to demonstrate maximum cross protection, which would provide the basis for development of this glucan-protein conjugate vaccine as a model panfungal vaccine that is both safe and effective against serious fungal infections caused by diverse fungi. To further the understanding of what part of the immune response is critical to the induction of protective immunity in these systems, cytokine and antibody profiles induced by protective vaccines and less-protective or non-protective preparations will be studied, with a goal of determining a set of surrogate markers indicative that a vaccine would be protective. The most productive route to a fungal vaccine is a conjugate vaccine that combines an optimally configured glucan with a specific immunogenic protein. The rationale for this proposal comes from work to date, which suggests that some proteins may be sufficiently cross-immunogenic that when combined with the appropriate cross-immunogenic glucan it may be possible to develop a pan-fungal vaccine. The studies proposed in this Phase I application have the potential of leading to future production and commercialization of a much desired panfungal vaccine. A vaccine of this type would not only save significant healthcare costs, but would reduce serious fungal infection in numerous patients and more importantly, save lives.