Development of a Vaccine for the Prevention of Pulmonary Aspergillosis

 描述(由申请人提供)：这项建议的主要目标是开发一种烟曲霉VesiVax(R)疫苗。在这项第一阶段申请中提出的研究将具体涉及使用定义的候选抗原(即Aspf3、Aspf9和Aspfhemolysin)来提炼基于脂质体的疫苗，该候选抗原将提供针对曲霉病的保护性免疫反应。我们的中心假设是，分子快递公司(VesiVax(R))开发的一种高度免疫原性的脂质体递送系统可以用于快速设计和设计针对烟曲霉菌的候选疫苗。脂质体曲霉菌疫苗候选将在相关的免疫低下小鼠模型中进行测试，以了解它们抵御肺曲霉菌攻击的能力。使用Aspf3、Aspf9和Aspf溶血素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Aspf蛋白的最小数量和最佳疫苗剂量来继续这些研究。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，烟曲霉菌可以突破接种疫苗的患者的宿主免疫，这些患者也是免疫低下的(例如，正在接受化疗的患者)。我们将测试感染前接种Aspf疫苗是否可以改善感染后使用抗真菌治疗的真菌感染。我们将测定肺部、支气管肺泡灌洗(BAL)和肾脏中的菌落形成单位，以评估曲霉真菌感染的程度。除了存活和疾病体征外，我们还将测量BAL和肺中的细胞因子水平，以确定感染小鼠的BAL和肺组织中的炎性细胞因子是否减少。将对肺部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。根据SBIR第一阶段申请中描述的这些研究，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。商业化的目的是使用我们的ASPF疫苗来预防或改善初级患者群体中的疾病，这些患者是免疫受损的宿主，例如那些正在接受实体器官移植、骨髓移植或癌症化疗的人。在这些患者中，有机会在出现最严重的免疫抑制之前为患者接种疫苗，目的是使疫苗产生的获得性耐药性在免疫抑制过程中持续下去，从而降低患者死亡率和曲霉菌感染。

 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.