Conjugate vaccines for prevention and treatment of cryptococcosis

用于预防和治疗隐球菌病的结合疫苗

• 批准号: 10339408
• 负责人: Arturo Casadevall
• 金额: $ 69.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-02 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339408
• 关键词: Anti-Retroviral Agents; Antibodies; Antibody Response; Antibody-mediated protection; Antifungal Agents; Antigen Targeting; Antigenic Variation; Antigens; Area; Autoimmune Diseases; Basic Science; Biochemistry; CD4 Lymphocyte Count; Carbohydrates; Chemicals; Chronic; Communicable Diseases; Conjugate Vaccines; Cryptococcosis; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Cryptococcus neoformans infection; Defect; Development; Diarrhea; Disease; Disputes; Encapsulated; Epitopes; Exhibits; Funding; Generations; Goals; HIV; HIV Infections; HIV/TB; Haemophilus influenzae; Haemophilus influenzae type b; Host Defense; Human; Immune; Immune response; Immunology; Immunosuppression; Incidence; Individual; Infection; Influenza B Virus; Knowledge; Laboratories; Life; Lymphopenia; Malaria; Malignant Neoplasms; Mediating; Medical; Meningitis; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mycoses; Neisseria meningitidis; Oligosaccharides; Organ Transplantation; Organic Chemistry; Patients; Pharmaceutical Preparations; Polysaccharides; Prevention; Prevention therapy; Proteins; Recurrence; Research; Risk; Serotyping; Source; Streptococcus pneumoniae; Structure; Target Populations; Tetanus Toxoid; Time; United States National Institutes of Health; Vaccine Design; Vaccines; Virulence; antiretroviral therapy; base; capsule; design; fungus; glucuronoxylomannan; human pathogen; immunogenic; immunogenicity; interest; mortality; novel; novel strategies; pathogen; pathogenic fungus; pathogenic microbe; prevent; response; success; vaccine access; vaccine candidate; vaccine development

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.

隐球菌病是由真菌新型人物引起的一种侵入性的霉菌疾病。在第二个 20世纪的一半，由于其关联，隐球菌病的医学重要性急剧增加 随着艾滋病毒感染，器官移植和由医学进展引起的免疫抑制。治疗 抗真菌药物仍然不令人满意，尤其是在非HIV情况下，因为感染往往是慢性的， 治疗后难以根除和复发。没有可预防的疫苗 隐球菌病，或其他任何mycoses。宿主防御Neoformans感染涉及两种体液 和细胞机制。 C. neoformans是不寻常的，因为它是唯一包裹的人类病原体和 多糖胶囊是毒力的绝对要求。主要囊多糖是 葡萄糖量氧基瘤（GXM）。囊囊多糖的抗体具有保护性 靶向该抗原的疫苗开发的理由。该提议寻求资金开发小说 基于合成和天然寡糖的共轭疫苗，这将集中于产生的免疫 响应仅制作保护性抗体。共轭疫苗在 降低几种细菌封装的病原体的发生率，并且应该有可能 隐球菌病。我们计划利用有关抗体介导的免疫的所有知识 反对新梭菌，以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，两个新的发展为解决这个问题提供了一种新方法：1）合成有机的进步 化学导致了代表GXM基序的化学定义的寡糖产生。和2） C. Neoformans在培养物中生产大量的寡糖的发现是 疫苗结构。以天然和合成寡糖形式的新材料的可用性用于 共轭疫苗的多糖成分带来了使高度免疫原性的承诺 将免疫反应集中于仅引起保护性抗体的化合物。提出了三个目标：1。 在通过保护性和非保护抗体识别的Neoformans GXM中建立表位； 2 基于天然和合成 表达新生梭菌GXM结构基序的寡糖； 3。建立免疫原性和 疗效新型结合疫苗针对实验性梭状芽胞杆菌感染。