Mimetic Peptides-Mediated Protection Against Coxiella burnetii Infection

模拟肽介导的伯氏柯克斯体感染保护

基本信息

批准号：
10005679
负责人：
Guoquan Zhang
金额：
$ 52.67万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-13 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005679
关键词：
Acute Adjuvant Adult Aerosols Antibiotics Antigens Bacteria Categories Cavia Cellular Immunity Centers for Disease Control and Prevention (U.S.)Chemicals Chronic Combined Vaccines Coxiella burnetii Defect Desiccation Development Diagnosis Dose Ensure Epitopes Etiology Exposure to Formalin Goals Gram-Negative Bacteria HLA-DR4 Antigen Health Heart Valves Human Immune system Immunity Immunization Individual Infection Keyhole Limpet Hemocyanin Lead Life Lipopolysaccharides Mediating Modeling Mus Occupational Organism Peptides Phase Prevention Proteins Public Health Q Fever Recombinant Proteins Recombinants Research Rodent Route T-Lymphocyte Testing Transgenic Mice Vaccines Variant Virulent Whole Cell Vaccine base biosafety level 3 facility biosecurity chronic infection flu high risk humanized mouse immunogenicity immunoprophylaxis immunosuppressed mouse model novel novel strategies pathogen peptidomimetics pregnant prevent protective efficacy side effect vaccine candidate weapons

项目摘要

Abstract Coxiella burnetii is an obligate intracellular Gram-negative bacterium that causes acute and chronic Q fever in humans. It is an understudied category B select agent and can be transmitted via aerosol. The existing formalin-inactivated phase I whole-cell vaccine (PIV) induces serious side effects in previously sensitized individuals and no vaccine is commercially available for prevention of human Q fever in the US. Therefore, creation of a safe and effective vaccine to prevent Q fever remains an important public health and national biosecurity goal. Our long-term goal is to develop novel approaches for safe and effective immunoprophylaxis of acute and chronic Q fever. Interestingly, our preliminary studies demonstrated that a peptide mimic of a C. burnetii phase I lipopolysaccharide (PI-LPS) epitope (m1E41920) conjugated to keyhole limpet haemocyanin (m1E41920-KLH) conferred protection against C. burnetii infection in both mouse and guinea pig models. These findings support the utility of m1E41920 as a vaccine candidate to prevent human Q fever. Thus, the objective of this revised R01 application is to define and optimize a PI-LPS-mimetic peptide and recombinant protein combination vaccine that confers the same level of protection as the PIV. To achieve this objective, we propose three specific aims to test the central hypothesis that the combination of m1E41920 with additional protective peptide mimic of PI-LPS and recombinant C. burnetii protein antigens will confer the same level of protection as the PIV. Aim 1 will use a C. burnetii aerosol infection mouse model to define and optimize a PI- LPS-mimetic peptide and recombinant protein combination vaccine that will confer the same level of protection as the PIV. Aim 2 will determine if the protective epitopes of PIV recognized by the mouse model will confer adequate protection in a guinea pig aerosol infection model. Aim 3 will use a humanized mouse model to determine if the protective epitopes of PIV recognized by rodents will confer protection in humans. Upon the completion of the proposed research, we expect to define the first multivalent vaccine for Q fever targeting novel neutralization-sensitive epitopes of both PI-LPS and PI protein. This will have significant positive effects on human health, because it will provide the basic information required to ultimately develop a safe, effective and tractable vaccine against Q fever.

抽象的伯纳特柯克斯体是一种专性细胞内革兰氏阴性细菌，可引起急性和慢性 Q 热人类。它是一种正在研究的 B 类选择剂，可以通过气溶胶传播。现有的福尔马林灭活的 I 期全细胞疫苗 (PIV) 对先前致敏的患者会产生严重的副作用在美国，目前还没有商业上可用于预防人类 Q 热的疫苗。所以，开发安全有效的疫苗来预防 Q 热仍然是一个重要的公共卫生和国家问题生物安全目标。我们的长期目标是开发安全有效的免疫预防新方法急性和慢性Q热。有趣的是，我们的初步研究表明，C. 的肽模拟物。与匙孔血蓝蛋白缀合的伯内氏 I 相脂多糖 (PI-LPS) 表位 (m1E41920) (m1E41920-KLH) 在小鼠和豚鼠模型中提供针对伯内特念珠菌感染的保护作用。这些发现支持 m1E41920 作为候选疫苗预防人类 Q 热的实用性。因此，此修订版 R01 应用程序的目标是定义和优化 PI-LPS 模拟肽和重组体蛋白质组合疫苗，提供与 PIV 相同水平的保护。为了实现这一目标，我们提出三个具体目标来检验中心假设，即 m1E41920 与附加的组合 PI-LPS 和重组伯氏梭菌蛋白抗原的保护性肽模拟物将赋予相同水平的保护作为 PIV。目标 1 将使用 C. burnetii 气溶胶感染小鼠模型来定义和优化 PI- LPS 模拟肽和重组蛋白组合疫苗将提供相同水平的保护作为 PIV。目标 2 将确定小鼠模型识别的 PIV 保护性表位是否会赋予在豚鼠气溶胶感染模型中提供足够的保护。 Aim 3 将使用人源化小鼠模型确定啮齿类动物识别的 PIV 保护性表位是否会对人类提供保护。于完成拟议的研究后，我们预计将确定第一种针对 Q 热的多价疫苗 PI-LPS 和 PI 蛋白的新型中和敏感表位。这将产生显着的积极影响人类健康，因为它将提供最终开发安全、有效的药物所需的基本信息以及针对 Q 热的易处理疫苗。