Mucosal immunization for cross-protection against pneumonic burkholderia

粘膜免疫对肺炎伯克霍尔德氏菌的交叉保护

• 批准号: 8261421
• 负责人: Steven W. Dow
• 金额: $ 22.23万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261421
• 关键词: Acute; Acute Pneumonia; Address; Adjuvant; Advanced Development; Animal Model; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Breathing; Burkholderia; Burkholderia Infections; Burkholderia mallei; Burkholderia pseudomallei; Cells; Chronic; Combined Modality Therapy; Complex; DNA; Development; Dose; Evaluation; Exposure to; Francisella; Goals; Human; Immunity; Immunization; Immunoglobulins; Infection; Infection prevention; Intranasal Administration; Joints; Laboratories; Liposomes; Lung; Malleus; Military Personnel; Modeling; Mus; Nucleic Acid Vaccines; Nucleic Acids; Oral; Oral Administration; Population; Populations at Risk; Program Development; Publishing; Recombinant Proteins; Recombinants; Relative (related person); Research; Research Project Grants; Resistance; Resources; Role; T-Lymphocyte; Testing; Vaccine Adjuvant; Vaccine Antigen; Vaccine Design; Vaccines; Viral; Virulent; Yersinia infections; aerosolized; antimicrobial; base; biodefense; immunogenic; immunoregulation; improved; mucosal vaccination; mucosal vaccine; novel; novel vaccines; oral vaccine; pathogen; programs

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.

这项提议的目标是开发非复制的、快速起作用的能够诱导 对伯克霍尔德菌(BM)和6.假鼻疽肺炎(BPM)的有效交叉保护 感染。该项目将利用阳离子脂质体-核酸复合体(CLDC)佐剂用于粘膜 用伯克霍尔德氏菌抗原进行免疫(鼻腔和口服)。待评估的抗原 包括7个BM抗原，所有这些抗原都已被证明至少在已发表的或 初步研究。我们将检验这样一种假设，即对吸入的马利氏杆菌和乙型流感病毒具有有效的交叉保护作用 经粘膜注射脂质体-核酸可致假腮腺感染 含有一到两种免疫原伯克霍尔德氏菌抗原的疫苗。为了检验这一假设，我们将 实现以下4个具体目标。目的1.BM抗原诱导交叉保护的能力。 将对BM和BPM感染进行评估。小鼠将接种以CLDC为基础的疫苗，该疫苗包含 重组BM抗原与BM和6 PM吸入攻击在Aim 2.CLDC中 佐剂平台将进行优化，以实现高效的粘膜免疫和两种最有效的抗原 AIM 1将评估他们在大剂量BM和BPM挑战研究中获得保护的能力 在口服和鼻腔免疫后。疫苗诱导的免疫学机制 目标3将评估保护，包括体液和细胞效应机制。 我们将确定将粘膜疫苗接种与常规抗菌治疗相结合是否可以 加强对急性感染的保护，防止慢性伯克霍尔德氏菌的形成 感染。这项研究项目符合RMRCE免疫调节综合研究重点， 佐剂和疫苗，并将直接与RP 1.4(弗朗西斯杆菌免疫蛋白质组)和RP 1.2相互作用 (开发天然佐剂)，并将利用动物模型和人肺细胞资源 核心。 RCRME目标。伯克霍尔德氏菌的免疫研究以及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氏菌疫苗 抗原性及广谱黏膜疫苗佐剂的研究进展 平民和军人受到气雾化伯克霍尔德氏菌感染。该疫苗佐剂平台 这里开发的也适用于针对其他一些细菌和病毒病原体的免疫接种。