Mucosal immunization for cross-protection against pneumonic burkholderia

该建议的目标是开发非复制型、快速作用的粘膜疫苗， 对鼻疽伯克霍尔德菌（Bm）和6.肺炎性假鼻疽 感染该项目将利用阳离子脂质体-核酸复合物（CLDC）佐剂用于粘膜免疫。 用伯克霍尔德氏菌抗原免疫（鼻内和口服施用）。待评价的抗原 包括7种Bm抗原，所有这些抗原均已在已发表或发表的研究中显示至少能引起部分保护作用。 初步研究。我们将检验对吸入B.鼻疽和B 通过粘膜施用脂质体-核酸佐剂可以实现假鼻疽感染 含有一到两种免疫原性伯克霍尔德氏菌抗原的疫苗。为了验证这个假设，我们将 实现以下四个具体目标。在目标1中。Bm抗原引发抗Bm抗体交叉保护的能力 将评估Bm和BPM感染。将用基于CLDC的疫苗免疫小鼠，所述疫苗含有 重组Bm抗原，并用Bm和6pm进行吸入攻击。在目标2中。CLDC 佐剂平台将被优化用于有效的粘膜免疫和两种最有效的抗原 在高剂量Bm和BPM攻毒研究中，将评估目标1中的所有受试者引发保护的能力 口服和鼻内免疫后。疫苗诱导的免疫学机制 保护，包括体液和细胞效应机制，将在目标3中评估。最后，目标4 我们将确定粘膜接种与常规抗菌治疗相结合是否可以 产生更好的保护免受急性感染，并防止慢性伯克霍尔德氏菌的建立 感染该研究项目符合RMRCE免疫调节综合研究重点， 佐剂和疫苗，并将直接与RP 1.4（弗朗西斯菌免疫蛋白质组）和RP 1.2相互作用 （先天性佐剂的开发），并将利用动物模型和人肺细胞的资源， 丹 RCRME目标。伯克霍尔德氏菌免疫的研究和新疫苗和佐剂的开发 RMRCE计划的优先事项。这里提出的研究将确定新的伯克霍尔德菌疫苗 抗原和推进开发一种广泛有效的粘膜疫苗佐剂， 平民和军人免受雾化伯克霍尔德菌感染。疫苗佐剂平台 这里开发的疫苗也适用于针对许多其他细菌和病毒病原体的免疫。

The goals of this proposal are to develop non-replicating, rapidly acting mucosal vaccines capable of eliciting effective cross-protection against both Burkholderia mallei (Bm) and 6. pseudomallei (Bpm) pneumonic infection. This project will utilize cationic liposome-nucleic acid complex (CLDC) adjuvants for mucosal immunization (intranasal and oral administration) with Burkholderia antigens. The antigens to be evaluated include 7 Bm antigens, all of which have been shown to elicit at least partial protection in published or preliminary studies. We will test the hypothesis that effective cross-protection against inhaled B. mallei and B pseudomallei infection can be achieved bv mucosal administration of liposome-nucleic acid adiuvanted vaccines containing one to two immunogenic Burkholderia antigens. To test this hypothesis, we will undertake the following 4 specific aims. In Aim 1. the ability of Bm antigens to elicit cross-protection against both Bm and Bpm infection will be assessed. Mice will be immunized with CLDC-based vaccines containing recombinant Bm antigens and subjected to inhalational challenge with Bm and 6pm. In Aim 2. the CLDC adjuvant platform will be optimized for efficient mucosal immunization and the two most effective antigens from Aim 1 will be assessed for their ability to elicit protection in high-dose Bm and Bpm challenge studies following oral and intranasal immunization. The immunological mechanisms responsible for vaccine-induced protection, including humoral and cellular effector mechanisms, will be assessed in Aim 3. Finally, in Aim 4 we will determine whether combining mucosal vaccination with conventional antimicrobial therapy can generate improved protection from acute infection and prevent the establishment of chronic Burkholderia infection. This research project fits within the RMRCE Integrated Research Focus on Immunomodulation, Adjuvants and Vaccines, and will interact directly with RP 1.4 (Francisella immunoproteome) and RP 1.2 (Development of innate adjuvants) and will utilize the resources of Animal Models and Human Lung Cell Cores. RCRME objectives. Studies of Burkholderia immunity and development of new vaccines and adjuvants are priorities for the RMRCE program. The studies proposed here will identify new Burkholderia vaccine antigens and advance development of a broadly effective mucosal vaccine adjuvant suitable for protection of civilian and military populations from aerosolized Burkholderia infection. The vaccine adjuvant platform being developed here is also applicable to immunization against a number of other bacterial and viral pathogens.