Conjugate vaccines for prevention and treatment of cryptococcosis

隐球菌病是一种由新型隐球菌引起的侵袭性真菌病。在第二 世纪的一半，隐球菌病在医学上的重要性急剧增加， 与艾滋病病毒感染、器官移植和免疫抑制等医学进步有关。治疗 抗真菌药物仍然不能令人满意，特别是在非HIV病例中，因为感染往往是慢性的， 难以根除，治疗后复发。没有疫苗可用于预防 隐球菌病或任何其他真菌病。宿主对C.新形式感染涉及体液和 和细胞机制。C.新形虫是不寻常的，因为它是唯一的封装人类病原体， 多糖荚膜是毒力的绝对要求。主要的荚膜多糖是 葡糖醛酸甘露聚糖（GXM）。针对荚膜多糖的抗体是保护性的， 开发针对该抗原的疫苗的基本原理。这项提案寻求资金，以开发一部小说， 基于合成和天然寡糖的结合疫苗，其将集中产生的免疫 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： 减少几种细菌包封的病原体的发生率， 隐球菌病我们计划利用我们所了解的有关抗体介导免疫的所有知识 针对C.新型真菌开发一种针对主要人类真菌病原体的新型结合疫苗。在 此外，两个新的进展为解决这一问题提供了新的途径：1）合成有机 化学导致产生代表GXM基序的化学上确定的寡糖;以及2） 发现C.新形式的人在培养物中产生大量的低聚糖， 疫苗建设。天然和合成低聚糖形式的新材料的可用性， 缀合物疫苗的多糖组分带来了制备高免疫原性 这些化合物集中免疫反应，只引发保护性抗体。提出了三个目标：1。到 确定C.由保护性和非保护性抗体识别的新型GXM; 2.到 产生一组基于天然和合成的新型蛋白质-多糖缀合物疫苗， 表达C. neoformans GXM结构基序; 3.确定免疫原性， 针对实验C.新生儿感染。

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.