Conjugate vaccines for prevention and treatment of cryptococcosis - COVID-19 Revision Supplement

用于预防和治疗隐球菌病的结合疫苗 - COVID-19 修订补充资料

• 批准号: 10265635
• 负责人: Arturo Casadevall
• 金额: $ 26.88万
• 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: 2020-06-17 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265635
• 关键词: 2019-nCoV; Acute; Antibodies; Antibody Response; Antibody-mediated protection; Antigen Targeting; COVID-19; COVID-19 pandemic; COVID-19 treatment; Chemicals; Clinical Trials; Conjugate Vaccines; Cryptococcosis; Cryptococcus neoformans; Cryptococcus neoformans infection; Development; Disease; Encapsulated; Epitopes; Funding; Generations; Goals; Grant; Host Defense; Human; Immune response; Incidence; Infection prevention; Life; Monoclonal Antibodies; Mycoses; Oligosaccharides; Organic Chemistry; Patients; Pharmaceutical Preparations; Plasma; Pneumonia; Polysaccharides; Prevention; Prevention therapy; Proteins; Randomized; Respiratory Signs and Symptoms; Safety; Serology test; Structure; Vaccines; Viral; Virulence; base; capsule; convalescent plasma; coronavirus disease; fungus; glucuronoxylomannan; high risk; human pathogen; immunogenic; immunogenicity; mortality; novel; novel strategies; open label; parent grant; pathogen; pathogenic fungus; treatment strategy; vaccine access; vaccine development

Project Summary Supplement The original grant seeks to develop a novel conjugate vaccine based on synthetic and natural oligosaccharides for Cryptococcus neoformans. This supplement changes the scope to a human clinical trial with the overall goal to investigate novel applications of human convalescent plasma in the prevention and therapy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease (COVID-19). This is necessary before a vaccine is realized for COVID-19. Thus, the central hypothesis of this project is that COVID-19 convalescent plasma can be successfully used as a treatment strategy to mitigate the spread and mortality of the ongoing COVID-19 pandemic. This randomized open label trial will assess the efficacy and safety of Anti-SARS-CoV-2 convalescent plasma in hospitalized patients with acute respiratory symptoms as well as in high risk exposures as prevention of infection. Serological assays specific for SARS-CoV-2 will be used to assess the amount of antibodies that are present in the blood of plasma donors and recipients. Project Summary (from Parent Grant): …FIRST 4 sentences truncated…. 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.

项目摘要补充 最初的拨款旨在开发一种基于合成和天然寡糖的新型结合疫苗 新型隐球菌本补充将范围变更为人体临床试验， 目的探讨人恢复期血浆在预防和治疗重症急性胰腺炎中的新应用 急性呼吸道综合征冠状病毒2（SARS-CoV-2），导致冠状病毒病（COVID-19）。这 是实现COVID-19疫苗之前的必要条件。因此，该项目的中心假设是， COVID-19恢复期血浆可以成功地用作一种治疗策略， 持续的COVID-19大流行的死亡率。这项随机开放标签试验将评估疗效， 抗SARS-CoV-2恢复期血浆用于急性呼吸道症状住院患者的安全性 以及在高风险暴露中预防感染。SARS-CoV-2特异性血清学检测将在 用于评估血浆捐赠者和接受者血液中存在的抗体量。 项目摘要（来自家长资助）：......前4句被截断...没有可用的疫苗 用于预防隐球菌病或任何其它真菌病。宿主对C.新生菌感染 涉及体液和细胞机制。C.新形虫是不寻常的，因为它是唯一的封装 人类病原体和多糖胶囊是一个毒力的绝对要求。大囊膜 多糖是葡糖醛酸甘露聚糖（GXM）。抗荚膜多糖抗体具有保护作用 为开发靶向该抗原的疫苗提供了强有力的理论基础。该提案寻求资金 开发一种基于合成和天然寡糖的新型结合疫苗， 导致免疫反应只产生保护性抗体。结合疫苗已经显著地 成功地减少了几种细菌包裹的病原体的发生率， 可能患有隐球菌病。我们计划利用我们所了解的关于抗体介导的 免疫C。新型真菌开发一种新的结合疫苗， 病原体此外，两个新的发展提供了解决这个问题的新方法：1） 合成有机化学导致了化学上确定的寡糖的产生， GXM基序; 2）C.新形虫在培养物中产生大量的寡糖， 是疫苗制造的原材料天然和合成形式的新材料的可用性 低聚糖作为结合疫苗的多糖组分， 高度免疫原性的化合物，其集中免疫应答以仅引发保护性抗体。三 提出了以下目标：1.确定C.新生儿GXM被保护性和非保护性的 保护性抗体; 2.为了产生一组基于以下的新型蛋白质-多糖缀合物疫苗： 表达C. neoformans GXM结构基序; 3.建立 免疫原性和功效针对实验C.新生儿感染。