Preclinical studies of a Cryptococcus vaccine for AIDS patients

针对艾滋病患者的隐球菌疫苗的临床前研究

基本信息

批准号：
10598929
负责人：
Stuart Michael Levitz
金额：
$ 75.38万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-11 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598929
关键词：
AIDS Vaccines AIDS-Related Opportunistic Infections Acquired Immunodeficiency Syndrome Address Antifungal Agents Antigens CD4 Positive T Lymphocytes Cell Count Cells Cessation of life Chitin deacetylase Chitosan Cryptococcosis Cryptococcus Cryptococcus neoformans Data Dendritic Cells Development Effector Cell Exhibits Funding Future Generations Genes Genetic Engineering Goals HIV Human Immune response Immunity Immunologics Individual Infection Inflammatory Response Ligands Mediating Mus Nature Patients Persons Phase Production Pulmonary Inflammation Risk Role T-Lymphocyte Testing Time Vaccinated Vaccination Vaccine Design Vaccines Variant cell type cytokine design falls global health macrophage mucosal vaccine mutant pre-clinical pre-clinical research preclinical study recruit research clinical testing response tool vaccine development

AIDS Vaccines AIDS-Related Opportunistic Infections Acquired Immunodeficiency Syndrome Address Antifungal Agents Antigens CD4 Positive T Lymphocytes Cell Count Cells Cessation of life Chitin deacetylase Chitosan Cryptococcosis Cryptococcus Cryptococcus neoformans Data Dendritic Cells Development Effector Cell Exhibits Funding Future Generations Genes Genetic Engineering Goals HIV Human Immune response Immunity Immunologics Individual Infection Inflammatory Response Ligands Mediating Mus Nature Patients Persons Phase Production Pulmonary Inflammation Risk Role T-Lymphocyte Testing Time Vaccinated Vaccination Vaccine Design Vaccines Variant cell type cytokine design falls global health macrophage mucosal vaccine mutant pre-clinical pre-clinical research preclinical study recruit research clinical testing response tool vaccine development

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项目摘要

Project Summary/Abstract An estimated 15% of AIDS-related deaths are due to cryptococcosis. We have genetically engineered a Cryptococcus neoformans strain, designated cda1∆2∆3∆, that it is deficient in three genes encoding for chitin deacetylases (CDA). Remarkably, mice given a single intrapulmonary vaccination with live or heat-killed cda1∆2∆3∆ develop long-term protection against an otherwise lethal C. neoformans challenge, even if CD4+ T cells are depleted at the time of fungal challenge. Other cryptococcal strains mutant in chitosan production, or wild type strains grown in different media, also are protective, although some elicit deleterious proinflammatory responses. The three specific aims are focused on developing a mechanistic understanding of the immunological and vaccine determinants of protection. The long-term objective is to develop a cryptococcal vaccine to protect at risk individuals, particularly persons living with HIV. Aim 1 is to determine correlates of cda1∆2∆3∆ vaccine-mediated protection in CD4+ T cell-sufficient mice. We hypothesize that vaccination with cda1∆2∆3∆ results in the generation and expansion of Th1-skewed antigen-specific CD4+ T cells which orchestrate vaccine immunity by producing cytokines which recruit and/or activate antifungal effector cells. We will dissect the cellular and cytokine response following vaccination and infection, interrogate the role of macrophage and dendritic cells skewing, and define the cells and cytokines required for protection. Aim 2 is to determine the effector mechanisms responsible for vaccine-mediated protection when CD4+ T cells are depleted during the challenge phase. Our preliminary data demonstrate that CD4+ T cells are required for mice vaccinated with cda1∆2∆3∆ to develop protective immunity, but then become dispensable when mice receive a lethal challenge of C. neoformans. This plasticity suggests a strategy whereby persons with HIV can be vaccinated when their CD4+ T cells are elevated and still be protected from cryptococcosis when their CD4+ T cells counts fall. We will further define the requirement for CD4+ T cells and identify the effector mechanisms that compensate for the loss of CD4+ T cells. Aim 3 is to determine the components of C. neoformans which drive disparate host responses, focusing on the highly inflammatory response versus the protective response. This aim follows up our discovery that whole cell cryptococcal vaccines can exhibit marked variations in the amount of lung inflammation they induce. We will characterize the nature of the protective and inflammatory response and determine the fungal ligands that drive these responses. We anticipate that at the end of the funding period, we will have a mechanistic understanding of the host and fungal factors responsible for protection of CD4+ T cell-sufficient and -deficient mice by the cda1∆2∆3∆ vaccine strain. The proposal addresses a major global health need for the development of cryptococcal vaccines and could establish proofs of principle applicable to other AIDS-related opportunistic infections and mucosal vaccines.

项目摘要/摘要估计有15％的与艾滋病相关的死亡是由于隐球菌病。我们一般设计了加密环球菌株，设计的CDA1Δ2Δ3Δ，它在三种编码的基因中不足脱乙酰基酶（CDA）。值得注意的是，对单个肺内疫苗接种进行活或热杀死的小鼠 CDA1Δ2Δ3Δ开发了对原本致命的C. Neoformans挑战的长期保护，即使CD4+ T 在真菌挑战时，细胞会耗尽。壳聚糖产生中的其他加密秒菌株突变体或在不同媒体中生长的野生型菌株也受到保护，尽管有些引起删除的促炎性回答。这三个具体目的侧重于对机械理解建立对免疫学和疫苗确定保护。长期目标是开发一个隐球菌疫苗保护处于危险的人，尤其是艾滋病毒的人。目标1是确定相关性 CDA1Δ2Δ3∆疫苗介导的CD4+ T细胞充足小鼠的保护。我们假设与 CDA1Δ2Δ3Δ导致Th1链的抗原特异性CD4+ T细胞的产生和膨胀通过产生募集和/或激活抗真菌效应细胞的细胞因子来编排疫苗免疫。我们将在疫苗和感染后剖析细胞和细胞因子反应，询问巨噬细胞和树突状细胞歪曲，并定义保护所需的细胞和细胞因子。目标2是确定当CD4+ T细胞为疫苗介导的保护的效应器机制在挑战阶段耗尽。我们的初步数据表明，小鼠需要CD4+ T细胞通过CDA1Δ2Δ3Δ接种以发展受保护的免疫力，但是当小鼠接受一个 Neoformans的致命挑战。这种可塑性表明了一种艾滋病毒患者可以是一种策略当CD4+ T细胞升高时接种疫苗，并在CD4+ T时仍受到保护免受隐球菌的保护细胞数量下降。我们将进一步定义CD4+ T细胞的需求并确定效应器机制这可以补偿CD4+ T细胞的损失。 AIM 3是确定Neoformans的成分驱动不同的宿主反应，重点是高度炎症反应与受保护的反应。这个目的遵循我们发现，整个细胞隐球菌疫苗可以在它们影响的肺部感染量。我们将表征受保护和炎症的性质响应并确定驱动这些反应的真菌配体。我们预计在结束时资金期，我们将对宿主和真菌因素有一个机械理解通过CDA1Δ2Δ3ΔVACCINE菌株保护CD4+ T细胞充足和缺陷小鼠。提案解决了全球健康的主要健康需求，以开发隐球菌疫苗，并可以建立证据适用于其他与AIDS相关的机会感染和粘膜疫苗的原则。