Immune Response to Cryptococcal Infections

对隐球菌感染的免疫反应

基本信息

批准号：
9264958
负责人：
Stuart Michael Levitz
金额：
$ 49.25万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264958
关键词：
Acquired Immunodeficiency Syndrome Address Adjuvant Adoptive Transfer Antibodies Antibody Response Antigens Attenuated Attenuated Vaccines Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Carbohydrates Carrier Proteins Cell Wall Cell physiology Cells Combined Vaccines Conjugate Vaccines Cryptococcal Meningitis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Cryptococcus neoformans infection Development Diphtheria Toxoid Disease Encapsulated Endemic Diseases Escherichia coli Formulation Funding Glucans Goals Graft Rejection HIV Health Priorities Hematologic Neoplasms Immune Immune response Immune system Immunocompetent Immunocompromised Host Incidence Individual Infection Left Link Mass Spectrum Analysis Mediating Modeling Mus Neurologic Pacific Northwest Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phenotype Polysaccharides Populations at Risk Preclinical Testing Proteins Proteome Recombinants Risk Factors Role Site Survivors T cell response T-Lymphocyte TNFRSF10A gene Testing Transgenic Mice United States National Institutes of Health Vaccinated Vaccination Vaccine Antigen Vaccines Yeasts alkalinity arm beta-Glucans design disability fungus global health immunoreactivity immunosuppressed killings mortality novel vaccines particle polyglucosan preclinical development prevent public health relevance response vaccine candidate vaccine development vaccine evaluation vaccine response vaccine-induced immunity

Acquired Immunodeficiency Syndrome Address Adjuvant Adoptive Transfer Antibodies Antibody Response Antigens Attenuated Attenuated Vaccines Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Carbohydrates Carrier Proteins Cell Wall Cell physiology Cells Combined Vaccines Conjugate Vaccines Cryptococcal Meningitis Cryptococcus Cryptococcus gattii Cryptococcus neoformans Cryptococcus neoformans infection Development Diphtheria Toxoid Disease Encapsulated Endemic Diseases Escherichia coli Formulation Funding Glucans Goals Graft Rejection HIV Health Priorities Hematologic Neoplasms Immune Immune response Immune system Immunocompetent Immunocompromised Host Incidence Individual Infection Left Link Mass Spectrum Analysis Mediating Modeling Mus Neurologic Pacific Northwest Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phenotype Polysaccharides Populations at Risk Preclinical Testing Proteins Proteome Recombinants Risk Factors Role Site Survivors T cell response T-Lymphocyte TNFRSF10A gene Testing Transgenic Mice United States National Institutes of Health Vaccinated Vaccination Vaccine Antigen Vaccines Yeasts alkalinity arm beta-Glucans design disability fungus global health immunoreactivity immunosuppressed killings mortality novel vaccines particle polyglucosan preclinical development prevent public health relevance response vaccine candidate vaccine development vaccine evaluation vaccine response vaccine-induced immunity

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项目摘要

DESCRIPTION (provided by applicant): Cryptococcal meningitis, due to the encapsulated yeast C. neoformans (Cn), is estimated to kill over 600,000 people annually. Most victims have compromised CD4+ T cell function. A closely related species, C. gattii (Cg), causes endemic disease in persons who generally have mild or no immunocompromise. Development of a vaccine to protect against cryptococcosis is a global health priority. The goal of this project is the preclinical development of candidate vaccines to protect at risk populations from cryptococcosis. We hypothesize such a vaccine will have a subunit formulation and consist of cryptococcal antigens (Ags) delivered with adjuvant(s) that stimulate strong and durable T cell and antibody (Ab) responses. Aim 1 is to synthesize candidate cryptococcal vaccine Ags and test the Ags for immunoreactivity. In preliminary studies, we have obtained 100% protection against lethal cryptococcosis by vaccinating mice with glucan particles (GPs) containing alkaline extracts derived from Cn. The proteome of the protective extract has been defined; however, it is not known which Ags are responsible for protection. In Aim 1A, Ags in the extracts will be recombinantly expressed and tested for their capacity to stimulate ex vivo CD4-biased T cell responses using cells from vaccinated mice and cryptococcosis patients. It is recognized that vaccine-mediated protection can involve arm(s) of the immune system that do not have a predominant role in natural infection. In Aim 1B, GXM, the major capsular component of Cn, will be conjugated to diphtheria toxoid. This is predicted to convert the glycan into a potent immunogen capable of eliciting protective Ab responses. Aim 2 is to formulate candidate cryptococcal vaccines and perform preclinical testing. By the end of Aim 1, we anticipate we will have identified ~10 Cn Ags that stimulate T cell responses and we will have made conjugate vaccines that stimulate Ab responses against GXM. In Aim 2A, we will determine which of these candidate Ags stimulate protective responses in models of cryptococcosis. In Aim 2B, we will optimize Ag combinations and vaccine formulations, including testing GPs and CpG alone and in combination. The durability of protection will be explored. In Aim 2C, we will explore the immune mechanisms of vaccine-induced protection. In Aim 2D, recognizing that AIDS is the major risk factor for cryptococcosis, the effect of CD4-depletion on CD8+ and Ab vaccine responses will be defined. Finally, in Aim 2E, we will test whether vaccine-mediated protection can be achieved against Cg infections. We anticipate that at the end of the funding period, we will have created candidate vaccines capable of eliciting robust and durable Ag-specific Ab and Th1-biased responses that protect mice against challenge with Cn and Cg. The studies address an NIH-identified need for development of cryptococcal vaccines and should establish proofs of principle applicable to other vaccine-preventable diseases, particularly those for which T cell defenses are paramount.

描述（由适用提供）：由于包裹的酵母菌Neoformans（CN），估计每年杀死60万以上的人杀死了60万人。大多数受害者都损害了CD4+ T细胞功能。密切相关的物种C. gattii（CG）会在通常患有轻度或没有免疫功能低下的人中引起内在疾病。开发用于预防隐球菌病的疫苗是全球健康的重点。该项目的目的是临床前的候选疫苗，以保护危险人群免受隐球菌病的影响。我们假设这种疫苗将具有亚基配方，并由带有调节的加密秒抗原（AGS）组成，这些抗原（S）刺激了强且耐用的T细胞和抗体（AB）响应。目的1是合成候选候选疫苗AGS并测试AGS的免疫反应性。在初步研究中，我们通过用含有源自CN的饮酒液提取物的谷物颗粒（GPS）接种小鼠，从而获得了100％保护致命的隐球菌病。已定义了受保护提取物的保护群体；但是，尚不清楚哪些AG负责保护。在AIM 1A中，提取物中的AG将重组表达并测试其使用来自接种的小鼠和隐球菌患者的细胞刺激离体CD4偏置的T细胞反应的能力。人们认识到，疫苗介导的保护可以涉及在自然感染中没有主要作用的免疫系统的手臂。在AIM 1B中，GXM是CN的主要囊膜成分，将与白喉毒素偶联。预计这将转化为能够引起受保护AB反应的潜在免疫原。 AIM 2是制定候选隐球菌疫苗并进行临床前测试。到AIM 1结束时，我们预计我们将确定约10个刺激T细胞反应的CN AG，我们将制造共轭疫苗，以刺激针对GXM的AB反应。在AIM 2A中，我们将确定这些候选AG中的哪个刺激隐球菌病模型中的受保护反应。在AIM 2B中，我们将优化AG组合和疫苗制剂，包括单独和组合进行GPS和CPG。将探索保护的耐用性。在AIM 2C中，我们将探索疫苗诱导的保护的免疫力学。在AIM 2D中，认识到AIDS是隐球菌病的主要危险因素，将定义CD4止动物对CD8+和AB疫苗反应的影响。最后，在AIM 2E中，我们将测试是否可以针对CG感染实现疫苗介导的保护。我们预计，在资金期结束时，我们将创建能够引起健壮且耐用的Ag特异性AB和Th1偏置反应的候选疫苗，从而保护小鼠免受CN和CG的挑战。这些研究涉及对NIH识别的隐球菌疫苗开发的需求，并应建立适用于其他可预防疫苗的原理证据，尤其是T细胞防御措施至关重要的疾病。