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 该补充将新型隐球菌的范围更改为人体临床试验的总体范围。 目标是研究人类恢复期血浆在预防和治疗严重疾病中的新应用 急性综合征呼吸道冠状病毒 2 (SARS-CoV-2)，可引起冠状病毒病 (COVID-19)。 在研制出针对 COVID-19 的疫苗之前，这是必要的。因此，该项目的中心假设是： COVID-19 恢复期血浆可成功用作减轻传播和传播的治疗策略 这项随机开放标签试验将评估正在进行的 COVID-19 大流行的疗效和死亡率。 抗 SARS-CoV-2 恢复期血浆在出现急性呼吸道症状的住院患者中的安全性 以及在高风险暴露中预防感染的特异性血清学检测。 用于评估血浆捐献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 句话被截断……没有可用的疫苗。 用于预防隐球菌病或任何其他真菌病宿主防御新型隐球菌感染。 C. neoformans 的不同寻常之处在于它是唯一有荚膜的 人类病原体的荚膜多糖是毒力的绝对要求。 多糖是葡萄糖醛酸木甘露聚糖 (GXM)，荚膜多糖的抗体具有保护作用。 该提案为开发针对该抗原的疫苗提供了强有力的理由。 开发一种基于合成和天然寡糖的新型结合疫苗，该疫苗将重点关注 由此产生的仅产生保护性抗体的免疫反应令人不快。 成功地减少了几种细菌包膜病原体的发生率，并且同样应该 我们计划利用我们所了解的有关抗体介导的所有知识。 针对新型隐球菌的免疫力，开发针对主要人类真菌的新型结合疫苗 此外，两项新进展为解决这一问题提供了新方法：1）在病原体方面的进展。 有机合成化学导致了化学定义的低聚糖的产生，这些低聚糖代表 GXM 基序；2) 新型隐球菌在培养物中产生大量寡糖的发现 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成分带来了制造的希望 高免疫原性化合物，集中免疫反应仅引发保护性抗体。 提出的目标是： 1. 建立新型隐球菌 GXM 中保护性和非保护性识别的表位。 2. 构建一套新型的蛋白质-多糖结合疫苗； 表达新型隐球菌 GXM 结构基序的天然和合成寡糖； 3. 建立 针对实验性新型隐球菌感染的免疫原性和功效新型结合疫苗。