Campylobacter jejuni outer membrane protein vaccine

描述（由申请人提供）：空肠弯曲杆菌是美国细菌性胃肠炎的主要原因，并且由于其能够引起食源性和水源性爆发而被NIH分类为B类生物恐怖主义制剂。至少有240万例C。在美国，每年发生1例空肠炎，其发病率超过沙门氏菌和志贺氏菌的总和（5）。C.空肠感染也是吉兰-巴雷综合征（GBS）发展的最常见的前因事件，吉兰-巴雷综合征是一种急性运动麻痹，显然是由针对C.空肠表面抗原一种有效的抗C.因此，空肠是非常需要的，以保护美国人口免受天然存在的C.空肠疾病和潜在的生物恐怖袭击引起的疾病。基于C.已经提出了空肠全细胞制剂，然而，由于关于GBS发展的不确定性，需要替代方法。因此，由高度保守的外膜蛋白（OMP）组成的疫苗可能最有希望安全地诱导保护性免疫，而不会诱导GBS。 C.空肠菌株是高度可变的，这肯定会影响蛋白亚单位疫苗的开发。适合于疫苗包含的蛋白质必须以C的最大可能比例保守。空肠菌株，必须是免疫原性的，并且必须诱导针对大量不同C.空肠菌株。分析了C. jejuni的基因组序列是了解其OMPs的起点，只有直接鉴定OMPs（通过蛋白质组分析）才能提供关于C. jejuni实际表达的OMPs的详细信息。空肠菌株。 假设：确定C。空肠外膜蛋白（OMPs）在所有C.空肠菌株在人感染期间将是免疫原性的，并且将产生保护性免疫应答。 具体目标1。我们将鉴定几种C.空肠菌株的蛋白质组学和质谱分析。 具体目标2。我们将确定在我们的初始菌株中保守的外膜蛋白是否也在大量的C.空肠菌株（新鲜临床分离株和来自美国各地的菌株档案收集），并将评估感染者对这些外膜蛋白的免疫反应。 具体目标3。我们将确定用保守的、纯化的重组外膜蛋白免疫小鼠是否能保护小鼠抵抗随后的实验性C。空肠感染

DESCRIPTION (provided by applicant): Campylobacter jejuni is the leading cause of bacterial gastroenteritis in the U.S., and has been classified by the NIH as a Category B Bioterrorism Agent due to its ability to cause food-borne and water-borne outbreaks. There are at least 2.4 million cases of C. jejuni disease in the U.S. annually, with an incidence exceeding that of Salmonella and Shigella combined (5). C. jejuni infection is also the most common antecedent event to the development of Guiilain-Barre Syndrome (GBS), an acute motor paralysis that apparently results from an autoimmune response directed against C. jejuni surface antigens. An effective vaccine against C. jejuni is therefore highly desirable, to protect the U.S. population from both naturally-occurring C. jejuni disease and that arising from potential bioterrorist attacks. Vaccines based on C. jejuni whole-cell preparations have been proposed, however, due to uncertainties concerning the development of GBS, alternative approaches are warranted. A vaccine consisting of highly conserved outer membrane proteins (OMPs) may therefore hold the most promise for safely inducing protective immunity without the potential for inducing GBS. It is well recognized that C. jejuni strains are highly variable, and this will certainly impact on the development of a protein subunit vaccine. A protein appropriate for vaccine inclusion must be conserved in the largest possible proportion of C. jejuni strains, must be immunogenic, and must induce protective immunity against a large number of diverse C. jejuni strains. While analysis of the C. jejuni genome sequence is helpful as a starting point toward understanding its complement of OMPs, only direct identification of OMPs (by proteome analysis) will provide detailed information about the OMPs actually expressed by C. jejuni strains. Hypothesis: Certain C. jejuni outer membrane proteins (OMPs) will be conserved among all C. jejuni strains, will be immunogenic during human infection, and will generate a protective immune response. Specific Aim 1. We will identify the protein constituents of the outer membranes of several C. jejuni strains using proteomics and mass spectrometry. Specific Aim 2. We will determine whether OMPs that are conserved in our initial strains are also found in a large number of C. jejuni strains (fresh clinical isolates and an archival collection of strains from across the U.S.), and will evaluate the immune responses of infected humans to these OMPs. Specific Aim 3. We will determine whether immunization of mice with conserved, purified recombinant OMPs protects against subsequent experimental C. jejuni infection.