Mimetic Peptides-Mediated Protection Against Coxiella burnetii Infection

摘要 贝氏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， 人类它是一种未充分研究的B类选择性病原体，可通过气溶胶传播。现有 福尔马林灭活的I期全细胞疫苗（PIV）在先前致敏的小鼠中诱导严重的副作用 在美国，没有疫苗可用于预防人Q热。因此，我们认为， 开发一种安全有效的疫苗来预防Q热仍然是一项重要的公共卫生和国家政策。 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，一种C。 与匙孔血蓝蛋白缀合的贝氏I相脂多糖（PI-LPS）表位（m1 E41920） （m1 E41920-KLH）对C.在小鼠和豚鼠模型中的贝氏体感染。 这些发现支持m1 E41920作为预防人类Q热的候选疫苗的效用。因此 该修订的R 01申请的目的是定义和优化PI-LPS模拟肽和重组体， 蛋白质组合疫苗，提供与PIV相同的保护水平。为了实现这一目标，我们 提出了三个具体的目标来测试中心假设，即m1 E41920与额外的 PI-LPS保护肽模拟物和重组C.贝氏蛋白抗原将赋予相同水平的 保护PIV。目标1将使用C。贝氏气溶胶感染小鼠模型，以定义和优化PI- LPS-模拟肽和重组蛋白组合疫苗，其将赋予相同的保护水平 就像PIV一样。目的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的充分保护。Aim 3将使用人源化小鼠模型， 确定啮齿动物识别的PIV保护性表位是否会对人类产生保护作用。于 完成拟议的研究后，我们预计将确定第一个针对Q热的多价疫苗 PI-LPS和PI蛋白的新型中和敏感表位。这将产生重大的积极影响 对人类健康的影响，因为它将提供所需的基本信息，最终开发一个安全，有效的 和对付Q热的疫苗

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.