Development of a Vaccine for the Prevention of Pulmonary Aspergillosis

预防肺曲霉病疫苗的开发

基本信息

批准号：
8977244
负责人：
Thai Quoc Do
金额：
$ 32.99万
依托单位：
MOLECULAR EXPRESS, INC.
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：
2015-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977244
关键词：
Acquired Immunodeficiency Syndrome Address Air Alveolar Animals Antibody Response Antifungal Agents Antifungal Therapy Antigen Targeting Antigens Aspergillosis Aspergillus Aspergillus fumigatus Body Weight decreased Bone Marrow Transplantation Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Candida albicans Chemotherapy-Oncologic Procedure Coccidioides immitis Colony-forming units Compost Cryptococcus neoformans Cytotoxic Chemotherapy DNA Data Developed Countries Developing Countries Development Diagnosis Diagnostic tests Disease Disease Management Dose Drug Formulations Duct (organ) structure Economic Burden Environment Epidemiologic Studies Exposure to Extrinsic asthma Formaldehyde Fungal Vaccines Glucans Glycoproteins Goals Healthcare Hemolysin Hospitalization Human Human Herpesvirus 2 Immune response Immune system Immunity Immunocompromised Host Immunosuppression Immunosuppressive Agents Incidence Individual Infection Inflammatory Inflammatory Response Influenza Irrigation Kidney Lead Length of Stay Liposomes Lung Lung diseases Malignant Neoplasms Measures Medical Modeling Molecular Mus Mycoses Organ Organ Transplantation Patients Peptides Persons Pharmaceutical Preparations Pharmacotherapy Phase Prevention Procedures Proteins Public Health Publishing Research Resistance Risk Series Small Business Innovation Research Grant Soil Solid Staging Structure of parenchyma of lung System Systemic disease T-Lymphocyte Temperature Testing Time Tissues United States Vaccinated Vaccination Vaccines Work base cell killing chemotherapy clinically relevant commercialization cost cytokine dosage engineering design follow-up fungus immunogenic immunosuppressed mortality mouse model outcome forecast patient population prevent public health relevance research clinical testing vaccine candidate vaccine development

项目摘要

DESCRIPTION (provided by applicant): The principal objective of this proposal is to develop an Aspergillus fumigatus VesiVax(r) vaccine. The studies proposed in this Phase I Application will specifically address refining a liposomal based vaccine using the defined candidate antigens (i.e., Aspf3, Aspf9 and AspfHemolysin) that will provide protective immune responses against aspergillosis. Our central hypothesis is that a highly immunogenic liposome delivery system developed by Molecular Express (VesiVax(r)) can be used to rapidly design and engineer candidate vaccines against A. fumigatus. The liposomal Aspergillus vaccine candidates will be tested in a relevant immunocompromised mouse model for their ability to protect against a pulmonary Aspergillus challenge. Preliminary data using Aspf3, Aspf9 and Aspf Hemolysin are very encouraging. Here, we intend to follow up those studies by determining the minimum number of Aspf proteins needed for the vaccine and the dosage of vaccine that is optimal. We will also determine whether the Aspf vaccine will provide additional protection to animals requiring antifungal therapy. It is conceivable that A. fumigatus may break-through the host immunity in vaccinated patients that are also immunocompromised (e.g., patients on chemotherapy). We will test whether the Aspf vaccination prior to infection can ameliorate the fungal infection when antifungal therapy is used post infection. We will determine the colony forming units in the lungs, bronchial-alveolar lavage (BAL) and kidneys to assess the extent of Aspergillus fungal infection. In addition to survival and signs of disease, we will measure cytokine levels in the BAL and lungs to determine if there is a decrease of inflammatory cytokines in the BAL and lung tissue in infected mice. Histopathological analysis will be done on the lungs to determine the level of fungal infection and the type and extent of the immune response in these tissues. From these studies described in this SBIR Phase I application, the most effective candidate Aspergillus vaccine candidate will be used for advancement to clinical evaluation and development of a commercial product. Commercialization will be done with the intent of using our Aspf vaccine to prevent or ameliorate disease in the primary patient population, the immunocompromised hosts such as those individuals undergoing a solid organ transplant, bone marrow transplant or cancer chemotherapy. In these patients, the opportunity exists to immunize the patient prior to the onset of the most severe immunosuppression, with the goal that the acquired resistance from the vaccine can carry over through the course of the immunosuppression, thus reducing patient mortality and infection with Aspergillus.

描述（由申请人提供）：该提案的主要目标是开发烟曲霉 VesiVax(r) 疫苗。该第一阶段申请中提出的研究将专门解决使用确定的候选抗原（即 Aspf3）改进基于脂质体的疫苗。、Aspf9 和 AspfHemolysin）将提供针对曲霉病的保护性免疫反应，我们的中心假设是高度免疫原性的脂质体递送。 Molecular Express (VesiVax(r)) 开发的系统可用于快速设计和改造针对烟曲霉的候选疫苗。将在相关免疫功能低下的小鼠模型中测试候选脂质体曲霉疫苗的预防肺部曲霉挑战的能力。使用 Aspf3、Aspf9 和 Aspf 溶血素的初步数据非常令人鼓舞，我们打算通过确定 Aspf 的最小数量来跟进这些研究。疫苗所需的蛋白质和最佳疫苗剂量我们还将确定 Aspf 疫苗是否能为需要抗真菌治疗的动物提供额外的保护。可以想象，烟曲霉可能会突破疫苗患者的宿主免疫力。免疫功能低下的患者（例如接受化疗的患者），我们将测试感染后使用抗真菌治疗时，感染前接种 Aspf 疫苗是否可以改善真菌感染。我们将确定感染后的菌落形成单位。肺部、支气管肺泡灌洗液 (BAL) 和肾脏，以评估曲霉属真菌感染的程度。除了存活率和疾病体征外，我们还将测量 BAL 和肺部的细胞因子水平，以确定炎症细胞因子是否减少。对受感染小鼠的肺泡灌洗液和肺组织进行组织病理学分析，以确定真菌感染的水平以及这些组织中免疫反应的类型和程度。 SBIR 第一阶段应用，最有效的候选曲霉菌疫苗将用于推进临床评估和商业产品的开发，目的是使用我们的 Aspf 疫苗预防或改善主要患者群体的疾病，免疫功能低下的宿主，例如接受实体器官移植、骨髓移植或癌症化疗的个体，在这些患者中，有机会在最严重的免疫抑制发生之前对患者进行免疫，目的是获得获得性耐药。疫苗中的毒素可以在免疫抑制过程中延续，从而降低患者死亡率和曲霉菌感染。