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

作为缀合物成分的免疫调节酵母衍生 β 葡聚糖

• 批准号: 8722668
• 负责人: Michael Edwin Danielson
• 金额: $ 14.95万
• 依托单位: BIOTHERA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722668
• 关键词: Adjuvant; Antibodies; Antifungal Agents; Antifungal Therapy; Antigens; Aspergillosis; Aspergillus; Aspergillus fumigatus; Biological Assay; Biological Response Modifiers; Biological Warfare; Bovine Serum Albumin; Categories; Cell Wall; Cells; Chronic Granulomatous Disease; Clinic; Clinical Trials; Coccidioides; Coccidioidomycosis; Colony-Stimulating Factors; Conjugate Vaccines; Data; Development; Dose; Expenditure; Failure; Feasibility Studies; Fungal Vaccines; Future; Genetic; Glucans; Goals; Health; Health Care Costs; Healthcare; Heating; Homologous Gene; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunologic Adjuvants; Immunologics; Immunomodulators; In Vitro; Individual; Infection; Interferons; Laboratories; Life; Liquid substance; Lung; Lymphocyte Activation; Mannans; Methodology; Military Personnel; Modeling; Modification; Mus; Mycoses; Nature; Oral; Outcome; Particulate; Patients; Persons; Phase; Polysaccharides; Preparation; Production; Proteins; Recombinant Proteins; Regimen; Relapse; Research; Route; Saccharomyces cerevisiae; Safety; Serum; Surrogate Markers; System; Testing; Therapeutic; Toxicology; Transplantation; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Variant; Weight; Work; Yeasts; aluminum sulfate; base; beta-Glucans; commercialization; cytokine; fungus; immunogenic; immunosuppressed; improved; killings; mortality; mouse model; particle; pathogen; patient population; prototype; public health relevance; response; screening; vaccine development; vaccine evaluation

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.

描述（由适用提供）：真菌感染，尤其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。尽管抗真菌疗法有所改善，但失败和继电器很常见。曲霉菌是几个患者人群中这些感染的主要原因：移植，白血病，遗传缺陷，例如慢性肉芽肿性疾病等，死亡率仍然很高。预防性抗真菌疫苗是一种有吸引力的，但尚未实现的选择。该提案的目的是通过将蛋白结合到特定的 - 葡萄糖免疫调节剂（即WGP）（即许多致病性真菌的细胞壁成分）来开发原型葡萄糖蛋白疫苗。单独使用WGP或与非特异性蛋白质牛血清白蛋白（BSA）共轭的初步工作表明，葡萄糖蛋白疫苗对曲霉菌和球蛋白剂具有活性。该提案中描述的工作将研究与曲霉（即ASPF3）相结合的特定的免疫主导重组蛋白与WGP的潜力，并增强疫苗与与非恋爱蛋白共轭的疫苗的保护能力。初步研究表明，这种葡萄糖蛋白疫苗也有可能对其他真菌进行交叉保护。因此，除了针对曲霉菌测试外，还将对疫苗制剂进行测试，该疫苗的制剂对球虫毒剂是正常或免疫抑制个体中严重的原发性真菌病原体，被NIH视为新兴类别C病原体。希望表现出最大的交叉保护，这将为这种谷物蛋白结合疫苗的开发提供基础，作为一种模型的泛素疫苗，既安全又有效，以抵抗由潜水员真菌引起的严重真菌感染。为了进一步了解这些系统中受保护的免疫组织化学的诱导至关重要，细胞因子和抗体谱由受保护的疫苗诱导的抗体和抗体曲线以及较低的保护或非保护的制剂将被研究，以确定疫苗能够确定疫苗的一组替代标记。通往真菌疫苗的最有生产力的途径是一种结合疫苗，将最佳构型葡萄糖与特定的免疫原性蛋白结合在一起。该提案的基本原理来自迄今为止的工作，这表明某些蛋白质可能具有足够的交叉免疫原性，即当与适当的跨免疫原性葡萄糖结合使用时，可能有可能开发泛腐线疫苗。在本阶段应用中提出的研究可能会导致未来的生产和商业化备受推验的泛元疫苗。这种类型的疫苗不仅可以节省大量医疗保健费用，而且会减少许多患者的严重真菌感染，更重要的是挽救生命。