A subunit Cryptococcus vaccine

隐球菌亚单位疫苗

• 批准号: 10669795
• 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/10669795
• 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; Population Heterogeneity; Populations at Risk; Proteins; Public Health; Recombinants; Research; Risk Factors; Role; Sister; Subunit Vaccines; System; T cell response; T-Lymphocyte; Testing; Transplant Recipients; Vaccination; Vaccine Antigen; Vaccines; Virulent; Work; Yeasts; arm; capsule; design; experimental study; follow-up; fungus; gain of function; global health; immunogenicity; in vivo; insight; loss of function; manufacture; mouse model; pre-clinical; preclinical development; protective efficacy; response; tissue resident memory T cell; 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.

项目总结/摘要 隐球菌病，由于感染的包囊酵母隐球菌新生和C。gattii，是最 是世界范围内培养阳性脑膜炎的常见病因辅助性T（Th）细胞对宿主防御至关重要。 该项目的首要目标是亚单位疫苗的临床前进展，以保护风险 群体（例如，HIV+，移植受者，流行地区的居民）从隐球菌病。我们的工作 假设使用精心设计的小鼠和人类研究，我们可以合理地开发一个亚基， 多抗原疫苗用于最终的人体试验。我们进一步假设，鉴于人类中的HLA多样性， 由于隐球菌菌株的数量和多样性，成功的人类隐球菌“T细胞疫苗”将 由三种蛋白抗原与有效的Th刺激佐剂组合组成。目标1.确定 使用小鼠模型的佐剂化单抗原候选抗原的保护效力 隐球菌病我们已经鉴定了七种隐球菌蛋白，当在E. 大肠杆菌，并包装成疫苗，显着保护两个近交系小鼠品系，否则致命的 挑战C。新人类我们将评估这些抗原的保护效力，这些抗原用我们的 主要佐剂，CAF 01，针对世界范围内发现的代表性强毒隐球菌菌株。目标二。解剖 鼠和人对候选疫苗抗原的免疫应答。我们将在体外研究 对候选抗原的免疫应答和免疫系统臂的体内作用。肺回忆CD 4 + 和CD 8 + T细胞（包括记忆）应答。 疫苗保护研究将在小鼠具有CD 4 + T细胞损害的条件下进行， 从而模拟隐球菌病，特别是HIV的主要人类危险因素。抗体的作用将是 通过功能获得和功能丧失实验进行研究。人CD 4+和CD 8 + T细胞对免疫抑制剂的应答 将使用来自具有和不具有以下特征的受试者的人PBMC比较7种候选疫苗抗原： 隐球菌病目标3.用抗原组合测试免疫原性和保护性。我们将选择 从这七种抗原中，得到由在CAF 01中佐剂化的三种抗原组成的先导疫苗制剂。这 根据前两个目标中的研究，通过优先考虑顶级抗原， 在小鼠模型中测试含有抗原组合的疫苗的免疫原性和保护性， 隐球菌病我们预计到授权期结束时，我们将有一个亚单位隐球菌疫苗 准备好进行进一步的临床前开发和最终的临床试验。拟议的研究 解决隐球菌疫苗开发的主要全球卫生需求， 隐球菌病免疫发病机理，并建立了适用于其他疫苗的原理证据- 可预防的疾病。