A subunit Cryptococcus vaccine

隐球菌亚单位疫苗

• 批准号: 10539210
• 负责人: Stuart Michael Levitz
• 金额: $ 61.98万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539210
• 关键词: Address; Adjuvant; Antibodies; Antigens; Area; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cessation of life; Clinical Trials; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Data; Data Protection; Development; Disease; Encapsulated; Escherichia coli; Etiology; Flow Cytometry; Funding; Genetic Variation; Goals; Grant; HIV; HLA Antigens; Helper-Inducer T-Lymphocyte; Host Defense; Human; Immune response; Immune system; Inbred Strains Mice; Infection; Lead; Lung; Mediating; Memory; Meningitis; Modeling; Mus; Patients; Peripheral Blood Mononuclear Cell; Persons; Phase; Population Heterogeneity; Populations at Risk; Proteins; Public Health; Recombinants; Research; Risk Factors; Role; Sister; Subunit Vaccines; System; T cell response; T memory cell; T-Lymphocyte; Testing; Transplant Recipients; Vaccination; Vaccine Antigen; Vaccines; Virulent; Work; Yeasts; arm; base; capsule; design; experimental study; follow-up; fungus; gain of function; global health; immunogenicity; in vivo; insight; loss of function; mouse model; pre-clinical; preclinical development; protective efficacy; response; vaccine candidate; vaccine evaluation; vaccine formulation

Project Summary/Abstract Cryptococcosis, due to infection by the encapsulated yeast Cryptococcus neoformans and C. gattii, is the most common cause of culture-positive meningitis worldwide. T helper (Th) cells are paramount to host defenses. The overarching goal of this project is the preclinical advancement of a subunit vaccine to protect at risk populations (e.g., HIV+, transplant recipients, residents of endemic areas) from cryptococcosis. Our working hypothesis is using carefully designed mouse and human studies, we can rationally develop a subunit multiantigen vaccine for eventual human testing. We further postulate that given HLA diversity in the human population and diversity amongst cryptococcal strains, a successful human cryptococcal “T cell vaccine” will consist of three protein antigens combined with a potent Th-stimulating adjuvant. Aim 1. Determine the protective efficacy of adjuvanted single antigen candidate antigens using mouse models of cryptococcosis. We have identified seven cryptococcal proteins which, when expressed recombinantly in E. coli and packaged into vaccines, significantly protected two inbred mouse strains against an otherwise lethal challenge with C. neoformans. We will evaluate the protective efficacy of these antigens formulated with our lead adjuvant, CAF01, against representative virulent cryptococcal strains found worldwide. Aim 2. Dissect murine and human immunologic responses to candidate vaccine antigens. We will investigate ex vivo immune responses to candidate antigens and the in vivo role of arms of the immune system. Lung recall CD4+ and CD8+ T cell (including memory) responses following murine vaccination and challenge will be determined. Vaccine protection studies will be undertaken under conditions where mice have CD4+ T cell compromise, thereby modeling the major human risk factors for cryptococcosis, especially HIV. The role of antibody will be studied with gain of function and loss of function experiments. Human CD4+ and CD8+ T cell responses to the seven candidate vaccine antigens will be compared using human PBMCs from subjects with and without cryptococcosis. Aim 3. Test immunogenicity and protection with antigen combinations. We will select from the seven antigens a lead vaccine formulation consisting of three antigens adjuvanted in CAF01. This goal will be accomplished by prioritizing the top antigens based on the studies in the first two aims and then testing vaccines containing antigen combinations for immunogenicity and protection in mouse models of cryptococcosis. We anticipate by the end of the granting period we will have a subunit cryptococcal vaccine ready to be moved forward for further preclinical development and eventual clinical trials. The proposed studies address a major global health need for the development of cryptococcal vaccines, provide insights into the immunopathogenesis of cryptococcosis, and establish proofs of principle applicable to other vaccine- preventable diseases.

项目摘要/摘要 密码球菌是由于封装的酵母菌虫和gattii的感染而引起的，是最多的 全球培养阳性脑膜炎的常见原因。 T助手（Th）细胞对宿主防御至关重要。 该项目的总体目标是亚基疫苗的临床前促进，以保护处于风险的风险 来自隐球菌病的人群（例如HIV+，移植受者，内在地区的居民）。我们的工作 假设正在使用精心设计的鼠标和人类研究，我们可以合理地发展一个亚基 最终人类测试的多蛋白疫苗。我们进一步指出，鉴于人类的HLA多样性 人口和多样性在隐球菌菌株中，成功的人类隐球菌“ T细胞疫苗”将 由三种蛋白质抗原组成，结合了可调节的潜在th刺激。目标1。确定 使用小鼠模型的调整后单抗原候选物的保护效率 隐球菌病。我们已经确定了七个加密噬菌蛋白，当这些蛋白在E中重组时。 大肠杆菌并包装成疫苗，显着保护了两种近交小鼠菌株，以否则致死 挑战Neoformans。我们将评估使用我们的这些抗原的受保护效率 铅佐剂CAF01，反对代表全球发现的强大隐球菌菌株。目标2。解剖 鼠类和人类免疫学对候选疫苗抗原的反应。我们将调查离体 免疫对候选抗原的反应和免疫系统臂的体内作用。肺部回忆CD4+ 将确定鼠疫苗接种和挑战后的CD8+ T细胞（包括记忆）反应。 疫苗保护研究将在小鼠患有CD4+ T细胞损害的条件下进行 从而对隐球菌病，尤其是艾滋病毒的主要人力风险因素进行建模。抗体的作用将是 研究了功能增长和功能实验的丧失。人CD4+和CD8+ T细胞对 使用有或没有的受试者的人类PBMC比较7种候选疫苗抗原 隐球菌病。目标3。通过抗原组合测试免疫原性和保护。我们将选择 从七个抗原中，由CAF01调整的三种抗原组成的铅疫苗配方。这 目标将根据前两个目标的研究优先考虑顶部抗原，然后 在小鼠模型中测试含有抗原组合的免疫原性和保护的疫苗 隐球菌病。我们预计到授予期结束时，我们将有一种亚基隐球菌疫苗 准备前进，以进行进一步的临床前开发和最终的临床试验。提出的研究 满足全球健康需求，以开发隐球菌疫苗，为您提供见解 隐球菌病的免疫病发生，并建立适用于其他疫苗的原理证明 可预防的疾病。