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（由申请人提供）：真菌感染，尤其是免疫功能低下的患者，是一个严重且日益严重的问题。尽管抗真菌治疗已取得很大进步，但失败和复发仍很常见。烟曲霉是多种患者群体感染的主要原因：移植、白血病、慢性肉芽肿病等遗传缺陷等，死亡率仍然很高。预防性抗真菌疫苗是一种有吸引力但尚未实现的选择。该提案的目标是通过将蛋白质与颗粒β-葡聚糖免疫调节剂（即WGP）（许多病原真菌的细胞壁成分）结合来开发原型葡聚糖蛋白疫苗。单独使用 WGP 或与非特异性蛋白牛血清白蛋白 (BSA) 结合的初步研究表明，葡聚糖蛋白疫苗对曲霉菌和球孢子菌具有活性。该提案中描述的工作将检查将来自曲霉属的特定免疫显性重组蛋白（即 Aspf3）与 WGP 缀合的潜力，并与与非真菌蛋白 BSA 的缀合物相比，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，除了针对曲霉属的测试外，疫苗制剂还将针对球孢子菌进行测试，球孢子菌是正常或免疫抑制个体中的一种严重的主要真菌病原体，被 NIH 认为是一种新兴的 C 类病原体。希望展示最大程度的交叉保护，这将为开发这种葡聚糖-蛋白结合疫苗作为模型全真菌疫苗奠定基础，该疫苗既安全又有效，可针对多种真菌引起的严重真菌感染。为了进一步了解免疫反应的哪一部分对于在这些系统中诱导保护性免疫至关重要，将研究由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。真菌疫苗最有效的途径是将最佳配置的葡聚糖与特定免疫原性蛋白质结合在一起的结合疫苗。该提议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，当与适当的交叉免疫原性葡聚糖结合时，有可能开发出泛真菌疫苗。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备受期待的全真菌疫苗。这种类型的疫苗不仅可以节省大量的医疗费用，而且可以减少众多患者的严重真菌感染，更重要的是可以挽救生命。