Conjugate vaccines for prevention and treatment of cryptococcosis

隐球菌病是由新生隐球菌属真菌引起的一种侵袭性真菌病。在第二个 20世纪的前半叶，隐球菌病在医学上的重要性急剧增加，因为它与 随着艾滋病病毒感染、器官移植和免疫抑制引起的医学进步。通过以下方式治疗 抗真菌药物仍然不令人满意，特别是在非艾滋病毒病例中，因为感染往往是慢性的， 治疗后难以根除和复发。目前还没有疫苗可用于预防 隐球菌病，或任何其他真菌病。宿主对新生隐孢子虫感染的防御包括体液免疫 和细胞机制。新生梭菌的不同寻常之处在于，它是唯一被包裹的人类病原体，而且 多糖胶囊是毒力的绝对必需品。主要的包膜多糖是 葡萄糖醛酸氧甘露聚糖(GXM)。针对荚膜多糖的抗体具有保护性，提供了一种强大的 开发针对这种抗原的疫苗的理论基础。这项提议寻求资金来发展一部小说。 基于合成和天然低聚糖的结合疫苗，它将集中产生的免疫 反应变成只产生保护性抗体。结合疫苗在以下方面取得了显著的成功 减少几种细菌包裹的病原体的发生率，对于 隐球菌病。我们计划利用我们对抗体介导的免疫的所有了解 开发一种新型结合疫苗来对抗一种主要的人类真菌病原体。在……里面 此外，两个新的发展为解决这个问题提供了新的途径：1)合成有机材料的进展 化学导致了代表GXM基序的化学定义的寡糖的产生；以及2) 发现新生葡萄球菌在培养中产生大量寡糖，这些寡糖是生产 疫苗建设。以天然和合成低聚糖为形式的新材料的可用性 结合疫苗的多糖成分带来了使高度免疫原性的前景 将免疫反应集中在只诱导保护性抗体的化合物。提出了三个目标：1. 建立新型弧菌GXM中保护性和非保护性抗体识别的表位； 构建一套基于天然和人工合成的新型蛋白质-多糖结合疫苗 表达新生弧菌GXM结构基序的寡糖；3.建立其免疫原性和 新型结合疫苗对实验性新生葡萄球菌感染的效力。

Cryptococcosis is an invasive mycotic disease caused by the fungus Cryptococcus neoformans. In the second half of the 20th century, cryptococcosis increased dramatically in medical importance because of its association with HIV infection, organ transplantation and immunosuppression caused by medical advances. Therapy with antifungal drugs remains unsatisfactory, particularly in non-HIV cases, as the infection tends to be chronic, difficult to eradicate and recur after therapy. There are no vaccines available for the prevention of cryptococcosis, or for any other mycoses. Host defense against C. neoformans infection involves both humoral and cellular mechanisms. C. neoformans is unusual in that it is the only encapsulated human pathogen and the polysaccharide capsule is an absolute requirement for virulence. The major capsular polysaccharide is glucuronoxylomannan (GXM). Antibodies to the capsular polysaccharide are protective providing a strong rationale for the development of vaccines that target this antigen. This proposal seeks funds to develop a novel conjugate vaccine based on synthetic and natural oligosaccharides, which will focus the resulting immune response into making only protective antibodies. Conjugate vaccines have been remarkably successful in reducing the incidence of several bacterial encapsulated pathogens and the same should be possible for cryptococcosis. We plan to take advantage of all that we have learned about antibody-mediated immunity against C. neoformans to develop a novel conjugate vaccine against a major human fungal pathogen. In addition, two new developments provide a new approach to this problem: 1) advances in synthetic organic chemistry have led to the generation of chemically defined oligosaccharides representing GXM motifs; and 2) the discovery that C. neoformans makes large amounts of oligosaccharides in culture that are raw materials for vaccine construction. The availability of new materials in the form of natural and synthetic oligosaccharides for the polysaccharide component of the conjugate vaccine bring the promise of making highly immunogenic compounds that focus the immune response to elicit only protective antibodies. Three aims are proposed: 1. To establish the epitopes in C. neoformans GXM recognized by protective and non-protective antibodies; 2. To generate a set of novel protein-polysaccharide conjugate vaccines based on natural and synthetic oligosaccharides of expressing C. neoformans GXM structural motifs; 3. To establish the immunogenicity and efficacy novel conjugate vaccines against experimental C. neoformans infection.