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（由应用程序提供）：该提案的主要目的是开发一种曲霉Vumigatus vesivax（R）疫苗。在本阶段应用中提出的研究将专门针对使用定义的候选抗原（即ASPF3，ASPF9和ASPFHEMOLYSIN）来精炼基于脂质体的疫苗，该抗原将提供保护抗曲霉病的保护。我们的中心假设是，由Molecular Express（Vesivax（R））开发的高度免疫原性脂质体递送系统可用于快速设计和工程候选候选疫苗，以针对A. fumigatus进行。脂质体曲霉疫苗的候选物将在相关的免疫功能低下的小鼠模型中进行测试，以防止肺曲霉挑战。使用ASPF3，ASPF9和ASPF Hemolysin的初步数据非常令人鼓舞。在这里，我们打算通过确定疫苗所需的最小ASPF蛋白质和最佳疫苗剂量来跟进这些研究。我们还将确定ASPF疫苗是否会为需要抗真菌治疗的动物提供额外的保护。可以想象的是，烟曲霉可能会在接种疫苗的患者中脱离宿主免疫学，这些患者也可以免疫功能低下（例如，接受化学疗法的患者）。我们将测试当感染后使用抗真菌治疗时，在感染前的ASPF疫苗是否可以改善真菌感染。我们将确定肺部，支气管 - 肺泡灌洗（BAL）和肾脏中的菌落形成单位，以评估真菌曲霉感染的程度。除了生存和疾病迹象外，我们还将测量BAL和肺部的细胞因子水平，以确定受感染小鼠的BAL和肺组织中炎症细胞因子的降低。组织病理学分析将来自此SBIR I期应用中描述的这些研究，最有效的候选曲霉疫苗候选者将用于促进商业产品的临床评估和开发。商业化的目的是使用我们的ASPF疫苗预防或改善初级患者人群，免疫功能低下的宿主，例如那些接受固体器官移植，骨髓移植或癌症化学疗法的人。在这些患者中，存在机会在最严重的免疫抑制发作之前对患者进行免疫接种，其目标是，从疫苗中获得的抗药性可以通过免疫抑制过程来延续，从而降低了患者的死亡率和曲霉感染。