Mimetic Peptides-Mediated Protection Against Coxiella burnetii Infection

摘要 伯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。它是一种研究不足的B类选择剂，可以通过气雾剂传播。现有的 福尔马林灭活疫苗I期全细胞疫苗(PIV)致敏后出现严重副作用 在美国，尚无预防人类Q热的疫苗可供商业使用。因此， 创造一种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 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的新方法。 急性和慢性Q热。有趣的是，我们的初步研究表明，一种模拟C。 锁孔帽状血蓝蛋白偶联Burnetii相脂多糖表位(M1E41920) (m1E41920-KLH)在小鼠和豚鼠模型中均对伯氏梭菌感染具有保护作用。 这些发现支持m1E41920作为预防人类Q热的候选疫苗的实用性。因此， 本修订R01应用的目的是定义和优化PI-内毒素模拟多肽和重组 提供与PIV相同水平保护的蛋白质组合疫苗。为了达到这一目标，我们 提出三个具体目标来检验中心假设，即m1E41920与其他 模拟PI-内毒素和重组伯氏弧菌蛋白抗原的保护肽将赋予相同水平的 作为PIV的保护。Aim 1将使用伯氏梭菌气溶胶感染小鼠模型来定义和优化PI- 模拟内毒素多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保护性表位是否将提供 在豚鼠气溶胶感染模型中提供足够的保护。Aim 3将使用人性化的老鼠模型来 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。在此之前 完成拟议的研究，我们预计将确定第一个针对Q热靶向的多价疫苗 PI-内毒素和PI蛋白的新的中和敏感表位。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 以及针对Q热病的易处理疫苗。

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.