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: 7675566
• 负责人: Steven W. Dow
• 金额: $ 21.49万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675566
• 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; Development; Dose; Evaluation; Exposure to; Francisella; Goals; Human; Immunity; Immunization; Immunoglobulins; Infection; Infection prevention; 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.

该提案的目标是开发能够引起的非复制，迅速发挥作用的粘膜疫苗 有效针对Burkholderia Mallei（BM）和6。Pseudomallei（BPM）肺炎的有效交叉保护 感染。该项目将利用粘膜阳离子脂质体核酸复合物（CLDC）佐剂 用Burkholderia抗原的免疫（鼻内和口服给药）。要评估的抗原 包括7种BM抗原，所有这些抗原都被证明在已发布或 初步研究。我们将检验以下假设，即有效地针对吸入的Mallei和B 可以通过脂质体的脂质体核酸拟耐酸来实现假乳脂的粘膜施用。 含有一到两种免疫原性的burkholderia抗原的疫苗。为了检验这一假设，我们将 承担以下4个特定目标。在AIM 1中。BM抗原引起交叉保护的能力 BM和BPM感染都将被评估。小鼠将用含有CLDC的疫苗免疫 重组BM抗原，并受到BM和6pm的吸入挑战。在AIM 2中。 辅助平台将被优化，以进行有效的粘膜免疫和两个最有效的抗原 将对AIM 1进行高剂量BM和BPM挑战研究的保护能力进行评估 遵循口服和鼻内免疫。负责疫苗诱导的免疫机制 在AIM 3中将评估保护的保护，包括体液和细胞效应器机制。最后，在AIM 4中 我们将确定将粘膜疫苗接种与常规抗菌治疗结合 改善了防止急性感染的保护，并防止建立慢性伯克霍尔德里亚 感染。该研究项目符合RMRCE综合研究的重点，重点是免疫调节， 佐剂和疫苗，并将直接与RP 1.4（Francisella Immunoprotome）和RP 1.2相互作用 （先天佐剂的开发），并将利用动物模型和人类肺部细胞的资源 内核。 RCRME目标。 Burkholderia免疫和新疫苗和佐剂的开发研究是 RMRCE计划的优先级。这里提出的研究将确定新的Burkholderia疫苗 抗原和提前开发广泛有效的粘膜疫苗佐剂，适合保护 伯克霍尔德感染的平民和军事人口。疫苗佐剂平台是 此处开发的也适用于针对许多其他细菌和病毒病原体的免疫。