Development of novel, safe and efficacious Coxiella burnetii vaccine

新型、安全、有效的伯氏柯克斯体疫苗的研制

基本信息

批准号：
8952597
负责人：
Mark A Jutila
金额：
$ 21.6万
依托单位：
MONTANA STATE UNIVERSITY - BOZEMAN
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：
2015-07-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8952597
关键词：
Acute Address Adjuvant Adverse effects Aerosols Affect Antibodies Antibody Response Antibody-mediated protection Antigens Australia B-Lymphocytes Bacteria Biological Bioterrorism CD8B1 gene Cells Chronic Coxiella burnetii Dendritic Cells Development Diagnosis Disease Progression Dose Endocarditis Engineering Epitopes Generations Gram-Negative Bacteria Growth Human Immune response Immunity Immunoglobulin G In Vitro Inactivated Vaccines Individual Infection Inflammation Inflammatory Inflammatory Response Link Lung Mediating Modeling Morbidity - disease rate Mus Nature Peptides Phase Predisposition Q Fever Site Social Welfare Surface T cell response T-Lymphocyte T-Lymphocyte Epitopes TLR4 gene Testing TimeLine Tissues Transgenic Mice Vaccination Vaccine Antigen Vaccines Viral Virulent Virus-like particle Whole Cell Vaccine Work adaptive immunity base booster vaccine cell mediated immune response in vivo macrophage mortality mouse model novel novel vaccines pathogen polypeptide prevent protective efficacy public health relevance research study response reverse genetics toll-like receptor 4 vaccine delivery vaccine development

项目摘要

DESCRIPTION (provided by applicant): Although Q fever was first diagnosed nearly 80 years ago; an efficacious vaccine that provides long- term protection from C. burnetii infection and is safe for repeated booster administrations is still unavailable. We have determined that either CD4 or CD8 T cells alone (without B cells) are sufficient for protection from virulent phase I C. burnetii and that the CD8 T cell response is associated with less deleterious tissue damage. Others have shown that antibodies to phase I C. burnetii LPS may be efficacious as well, and should be considered in any new vaccine formulation. Phase I C. burnetii LPS is known to differently affect its receptor, TLR4, and the downstream immune responses to C. burnetii in mice and humans, diminishing the utility of mice as a model of Q fever in humans. To overcome this deficiency in mice, we will utilize an hTLR4/MD2 transgenic mouse model (expressing human TLR4/MD2), which we have recently shown is more susceptible than wildtype mice to low dose C. burnetii infection. This new mouse will allow us to better analyze the in vivo response to phase I C. burnetii LPS and its utility as a vaccine antigen. To develop a new vaccine for Q fever, we plan on using a novel delivery platform that uses P22 virus-like particles (P22 VLPs), which even in the absence of specific antigen induce adjuvant-like responses that nonspecifically protect mice from different viral and bacterial pathogens and minimize tissue morbidity associated with these pathogens. The P22 VLP can be uniquely engineered to express antigens on both the internal and external surfaces, which we have shown leads to selective enhancement of protective CD8 T cell and B cell responses, respectively. Specifically, our preliminary results suggest that P22 VLPs can be engineered to effectively induce antigen-specific non-damaging immune responses that could accommodate the requirements for a licensable C. burnetii vaccine. Thus, we hypothesize that VLPs can be engineered to generate an effective C. burnetii vaccine that induces only the protective and non-damaging adaptive immune responses (such as both CD8 T cell and antibody responses) locally in the lungs. Due to the non-damaging nature of the immune response elicited by the VLPs, we further hypothesize that this vaccine will be safe for repeatable administration. To test this hypothesis, we will pursue the following Specific Aims. Aim 1) Generate a VLP construct that induces CD8 T cell-mediated protection. This will be done by identification of C. burnetii immunodominant CD8 T cell epitopes that will be expressed on the internal surface of the P22 VLPs. Aim 2) Generate a VLP construct that induces anti-LPS antibody-mediated protection. The efficacy of VLP-delivered phase I C. burnetii LPS will be determined in humanized TLR4/MD2 mice immunized with VLP constructs expressing immunodominant CD8 T cell epitopes on the inside of the P22 VLPs and LPS on the outside of the same VLPs.

描述（由适用提供）：尽管大约80年前首次诊断出Q热；一种有效的疫苗，可长期免受伯内特氏梭菌感染的保护，并且对于重复的助推器管理是安全的。我们已经确定，单独的CD4或CD8 T细胞（无B细胞）足以防止毒性I期C. burnetii，并且CD8 T细胞反应与较小的有害组织损伤有关。其他人则表明，对I期C. burnetii LPS的抗体也可能有效，应在任何新的疫苗配方中考虑。众所周知，I阶段C. burnetii LP会影响其受体TLR4，以及小鼠和人类对Burnetii的下游免疫反应，从而减少了小鼠作为人类Q发烧模型的效用。为了克服小鼠的这种缺乏，我们将利用HTLR4/MD2转基因小鼠模型（表达人TLR4/MD2），我们最近表明，这比野生型小鼠更容易受到低剂量C. burnetii感染。这种新的小鼠将使我们能够更好地分析对I期C. burnetii LPS及其作为疫苗抗原的效用。为了开发一种用于Q发烧的新疫苗，我们计划使用一个使用P22病毒样颗粒（p22 VLP）的新型输送平台，即使没有特定的抗原也会引起调节样的反应，该反应非特异性地保护小鼠免受不同病毒和细菌病原体的影响，并最大程度地减少与这些病原体相关的组织发病率。 P22 VLP可以独特地设计以在内部和外表面上表达抗原，我们已经显示出这将分别选择性增强受保护的CD8 T细胞和B细胞反应的选择性增强。具体而言，我们的初步结果表明，可以设计P22 VLP，以有效诱导抗原特异性的非伤害免疫反应，以适应获得许可的C. burnetii疫苗的要求。这就是我们假设可以设计VLP来生成有效的burnetii疫苗，该疫苗仅诱导肺部局部局部的受保护和无损的适应性免疫反应（例如CD8 T细胞和抗体反应）。由于VLP引起的免疫反应的不损害性质，我们进一步假设该疫苗可以安全地进行重复给药。为了检验这一假设，我们将追求以下特定目标。 AIM 1）生成诱导CD8 T细胞介导的保护的VLP构建体。这将通过鉴定将在p22 VLP的内表面表达的C. burnetii免疫主导CD8 T细胞表位来完成。 AIM 2）生成诱导抗LPS抗体介导的保护的VLP构建体。 VLP传递I期C的效率将在人源化的TLR4/MD2小鼠中确定，该小鼠用VLP构建体在p22 VLPS的内部和同一VLPS外部的LPS内部的VLP构建体中免疫的VLP构建体。