Mimetic Peptides-Mediated Protection Against Coxiella burnetii Infection

模拟肽介导的伯氏柯克斯体感染保护

• 批准号: 10207396
• 负责人: Guoquan Zhang
• 金额: $ 51.26万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207396
• 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; Vaccine Production; 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; porcine model; pregnant; prevent; protective efficacy; side effect; vaccine candidate; weapons

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 Coxiella burnetii是一种强制性细胞内革兰氏阴性细菌，会引起急性和慢性Q热。 人类。它是一个研究的B类选择剂，可以通过气溶胶传输。现有 福尔马林灭活的I期全细胞疫苗（PIV）在先前敏化的 个人和没有疫苗在美国预防人类Q发烧。所以， 创建一种安全有效的疫苗来防止Q发烧，仍然是重要的公共卫生和国家 生物安全目标。我们的长期目标是开发新颖的方法，以进行安全有效的免疫预防 急性和慢性Q热。有趣的是，我们的初步研究表明，一种肽模仿C。 Burnetii I期脂多糖（PI-LPS）表位（M1E41920）与钥匙孔的lig骨血果蛋白结合在一起 （M1E41920-KLH）在小鼠和豚鼠模型中赋予了针对C. burnetii感染的保护。 这些发现支持M1E41920作为预防人类Q发烧的疫苗的效用。因此， 此修订后的R01应用的目的是定义和优化Pi-LPS模拟肽和重组 蛋白质组合疫苗赋予与PIV相同的保护水平。为了实现这一目标，我们 提出了三个特定目的，以检验中心假设，即M1E41920与其他 pi-lps和重组C. burnetii蛋白抗原的保护性肽模仿肽将赋予相同水平 保护为PIV。 AIM 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，该疫苗将提供相同水平的保护水平 作为PIV。 AIM 2将确定小鼠模型识别的PIV的保护表位是否会授予 豚鼠气溶胶感染模型中的适当保护。 AIM 3将使用人源化的鼠标模型 确定啮齿动物识别的PIV的保护表位是否会赋予人类保护。在 拟议研究的完成，我们希望定义第一种用于Q发烧靶向的多价疫苗 PI-LPS和PI蛋白的新型中和敏感表位。这将产生重大的积极影响 关于人类健康，因为它将提供最终开发安全，有效的基本信息 以及可抗Q发烧的疫苗。