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Prevention and Treatment of Pneumocystis Pneumonia

肺孢子虫肺炎的防治

基本信息

批准号：
10605177
负责人：
Karen A Norris
金额：
$ 75.48万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-21 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605177
关键词：
Acute Address Adverse reactions Aging Animals Antibiotics Antibodies Antibody titer measurement Autoimmune Diseases Bone Marrow Transplantation Cancer Patient Chemotherapy-Oncologic Procedure Chronic Obstructive Pulmonary Disease Clinical Clinical Research Clinical Trials Collagen Crohn&apos s disease Data Defect Development Diagnosis Diagnostic Disease Drug resistance Environment Exposure to Generations Goals Guidelines HIV Hematologic Neoplasms Human Humoral Immunities Hyperimmunoglobulin M Syndrome Immune Immune response Immune system Immunity Immunization Immunocompromised Host Immunosuppression Immunotherapeutic agent Impairment Incidence Individual Infection Infection Control Inflammatory Life Lung Macaca mulatta Memory Modeling Monkeys Monoclonal Antibodies Morbidity - disease rate Nature Obstructive Lung Diseases Opportunistic Infections Organ Organ Transplantation Organism Patients Persons Pharmaceutical Preparations Pneumocystis Pneumocystis Infections Pneumocystis carinii Pneumocystis carinii Pneumonia Pneumonia Population Pre-Clinical Model Prevention Prevention strategy Preventive Prophylactic treatment Prospective Studies Protein Subunits Pulmonary Pathology Recombinant Proteins Regimen Reporting Research Resolution Resource-limited setting Rheumatoid Arthritis Risk Role SIV Severe Combined Immunodeficiency Solid Solid Neoplasm Subunit Vaccines Testing Therapeutic Therapeutic Uses Therapeutic immunosuppression Transplant Recipients Treatment Failure Trimethoprim-Sulfamethoxazole Vaccines Vascular Diseases Virus Diseases Work antiretroviral therapy clinically relevant experience immunosuppressed improved innovation innovative technologies insight lung injury mortality natural antibodies nonhuman primate novel therapeutics opportunistic pathogen organ transplant recipient pathogenic fungus patient population pre-clinical prevent prophylactic protective efficacy public health relevance pulmonary function recurrent infection response seropositive vaccine candidate vaccine development

项目摘要

The fungal opportunistic pathogen, Pneumocystis (Pc) jirovecii is the causative agent of Pneumocystis pneumonia (PCP), which is of increasing concern in persons receiving immunosuppressive therapies, including organ transplant recipients, cancer patients, individuals with inflammatory disease and in persons experiencing natural immunosuppression due to aging, congenital or acquired immunosuppressive states. In addition, in clinical studies and in non-human primate models, we have shown that persistent Pc colonization is also associated with the development of chronic obstructive pulmonary disease (COPD). Long-term goals of our work are to develop vaccine strategies for the prevention of Pc infection and related pulmonary sequelae in immunocompromised populations and to develop innovative strategies for improved therapies for acute PCP in immunocompromised individuals. To achieve these goals, we have developed pre-clinical, non-human primate models of PCP in drug-induced immunosuppressed animals. We have previously identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pc immunity in non-human primates that is durable and protective against PCP following profound immunosuppression induced by simian immunodeficiency virus infection (SIV) and reported that antibodies to KEX1 are associated with prevention of PCP in human immunocompromised individuals. The objectives to be addressed in the proposed studies are 1) to determine the protective efficacy of the KEX1 vaccine in pre-clinical models of therapeutic immunosuppressive regimens, (e.g., as in organ transplantation) and 2), to harness our extensive data regarding the protective nature of the humoral responses to KEX1 for the development and testing of monoclonal antibodies (mAb) for use in treating acute PCP. We hypothesize that the KEX1 vaccine will induce durable and protective immunity against PCP in immunocompromised individuals. We further hypothesize that treatment of acute PCP with KEX1 mAbs will contribute to resolution of pneumonia and mitigate pulmonary damage associated with the infection. Aim 1 will test the hypothesis that immunization with KEX1 vaccine will elicit protective memory responses and will provide protection from PCP in immunocompromised NHPs. We will evaluate the durability and protective efficacy of the immune response during immunosuppressive therapy. NHPs will be challenged via natural exposure to Pneumocystis and evaluated for clinical disease, immunity, pulmonary function and pathology. Aim 2 will test the hypothesis that KEX1-specific mAbs will effectively treat established PCP in an immunosuppression NHP model. Our innovative technology in mAb generation, combined with a unique and clinically relevant model of PCP in immunosuppressed monkeys, will allow us to define the utility of KEX1 mAbs in treating PCP and advance a novel therapeutic avenue for this disease.

肺孢子虫是一种真菌条件致病菌，是肺孢子虫的病原体。肺炎(PCP)，这在接受免疫抑制治疗的人中越来越令人担忧，包括器官移植受者、癌症患者、炎症性疾病患者和由于衰老、先天或后天免疫抑制状态而导致的自然免疫抑制。此外，在临床研究和在非人类灵长类动物模型中，我们已经表明持续的Pc定植也是与慢性阻塞性肺疾病(COPD)的发展相关。我们的长期目标是工作是制定预防丙型肝炎病毒感染和相关肺部疾病的疫苗战略免疫受损人群的后遗症，并制定创新战略，以改善免疫功能低下患者的急性PCP的治疗。为了实现这些目标，我们开发了药物诱导免疫抑制动物的PCP临床前、非人类灵长类动物模型。我们有以前发现了一种重组蛋白亚单位疫苗KEX1，它能诱导小鼠产生强大的抗Pc抗体非人类灵长类动物，经久耐用，对免疫抑制后的PCP具有保护作用由猴免疫缺陷病毒感染(SIV)诱导，并报告KEX1抗体与在人类免疫功能受损的个体中预防PCP。要解决的目标是建议的研究是1)确定KEX1疫苗在临床前模型中的保护效果治疗性免疫抑制方案(如器官移植)和2)，以利用我们广泛的关于对KEX1的体液反应的保护性的数据，用于发展和测试用于治疗急性PCP的单抗。我们假设KEX1疫苗将导致免疫受损个体对PCP的持久和保护性免疫。我们进一步假设应用KEX1单抗治疗急性PCP有助于肺炎的消退和肺的缓解与感染相关的损害。目标1将检验KEX1疫苗免疫将诱导保护性记忆反应，并将在免疫受损的NHP中提供对PCP的保护。我们将评估免疫抑制治疗期间免疫反应的持久性和保护效果。将通过自然暴露于肺孢子虫来挑战NHP，并评估其临床疾病、免疫力、肺功能和病理学检查。目标2将检验KEX1特异性单抗将有效治疗建立免疫抑制NHP模型的PCP。我们在单抗生成方面的创新技术，结合免疫抑制猴子独特的和临床相关的PCP模型，将使我们能够明确KEX1单抗在治疗PCP中的作用，并提出一种治疗该疾病的新途径。