Campylobacter jejuni outer membrane protein vaccine

空肠弯曲菌外膜蛋白疫苗

基本信息

批准号：
7918687
负责人：
STUART A THOMPSON
金额：
$ 17.46万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-12 至 2011-04-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：空肠弯曲杆菌是美国细菌胃肠炎的主要原因，由于其能够引起食物传播和水传播疫情，因此已被NIH分类为B类生物恐怖剂。在美国，每年至少有240万例空腹疾病病例，发病率超过沙门氏菌和志贺氏菌的发生率（5）。空肠梭菌感染也是对Guiilain-Barre综合征（GBS）发展的最常见的先行事件，这是一种急性运动麻痹，显然是由针对Jejuni表面抗原的自身免疫反应引起的。因此，一种针对空肠梭菌的有效疫苗是高度可取的，可以保护美国人群免受天然疾病的疾病，并由潜在的生物恐怖袭击引起的。但是，由于对GBS的发展的不确定性，已经提出了基于J. jejuni全细胞制剂的疫苗，因此有必要采用替代方法。因此，由高度保守的外膜蛋白（OMP）组成的疫苗可能是安全诱导保护性免疫的最大希望，而无需诱导GBS。众所周知，空肠梭菌菌株的变化很大，这肯定会影响蛋白质亚基疫苗的发育。适合疫苗包含的蛋白质必须在最大的空肠梭状芽胞杆菌菌株中保存，必须具有免疫原性，并且必须诱导保护性免疫，以防止大量不同的空肠C. jejuni菌株。虽然对空肠梭状芽胞杆菌基因组序列的分析是有助于理解其对OMPs补充的起点，但只有直接识别OMP（通过蛋白质组分析）将提供有关Jejuni C. jejuni菌株实际表达的OMP的详细信息。假设：在所有空肠梭菌菌株中，某些梭状芽孢杆菌外膜蛋白（OPM）将在人类感染期间具有免疫原性，并会产生保护性免疫反应。具体目的1。我们将使用蛋白质组学和质谱法确定几种空肠菌株的外膜的蛋白质成分。具体目的2。我们将确定在我们的初始菌株中保守的OMP是否在大量的空肠菌菌株中也发现了（新鲜的临床分离株和来自美国各地的菌株的档案收集），并将评估感染人类对这些OMP的免疫反应。具体目的3。我们将确定用保守的，纯化的重组OMP对小鼠的免疫能力是否可以防止随后的实验性梭菌感染。