Conjugate vaccines for prevention and treatment of cryptococcosis

用于预防和治疗隐球菌病的结合疫苗

基本信息

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
项目类别：
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

项目摘要

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.

隐球菌病是一种由新型隐球菌引起的侵袭性真菌病。在第二个 20 世纪上半叶，隐球菌病因其相关性而在医学上的重要性急剧增加随着医学进步引起的HIV感染、器官移植和免疫抑制。治疗与抗真菌药物仍然不能令人满意，特别是在非艾滋病毒病例中，因为感染往往是慢性的，难以根除，治疗后易复发。目前尚无疫苗可用于预防隐球菌病或任何其他真菌病。宿主对新型隐球菌感染的防御涉及体液和细胞机制。新型隐球菌的不同寻常之处在于，它是唯一有荚膜的人类病原体，而且多糖胶囊是毒力的绝对要求。主要荚膜多糖是葡萄糖醛酸木甘露聚糖（GXM）。荚膜多糖抗体具有保护作用，可提供强大的保护作用开发针对该抗原的疫苗的理由。该提案寻求资金来开发一种新颖的基于合成和天然寡糖的结合疫苗，它将集中产生的免疫反应为仅产生保护性抗体。结合疫苗在以下领域取得了巨大成功减少几种细菌包膜病原体的发生率，对于隐球菌病。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新型隐球菌，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，两项新进展为解决这一问题提供了新方法：1）合成有机方面的进展化学导致了代表 GXM 基序的化学定义寡糖的产生；和 2) 发现新型隐球菌在培养物中产生大量寡糖，这些寡糖是疫苗建设。天然和合成低聚糖形式的新材料的可用性结合疫苗的多糖成分有望实现高免疫原性集中免疫反应以仅引发保护性抗体的化合物。提出了三个目标： 1. 建立新型隐球菌 GXM 中保护性和非保护性抗体识别的表位； 2. 到产生一套基于天然和合成的新型蛋白质-多糖结合疫苗表达新型隐球菌GXM结构基序的寡糖； 3. 确定免疫原性和针对实验性新型隐球菌感染的功效新型结合疫苗。