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）：空肠弯曲菌是美国细菌性胃肠炎的主要原因，由于其能够引起食源性和水源性爆发，因此被 NIH 归类为 B 类生物恐怖主义制剂。美国每年至少有 240 万例空肠弯曲菌病例，发病率超过沙门氏菌和志贺氏菌的总和 (5)。空肠弯曲菌感染也是吉兰-巴利综合征 (GBS) 发展的最常见先决事件，吉兰-巴利综合征是一种急性运动麻痹，显然是由针对空肠弯曲菌表面抗原的自身免疫反应引起的。因此，非常需要一种针对空肠弯曲菌的有效疫苗，以保护美国人口免受自然发生的空肠弯曲菌疾病和潜在生物恐怖袭击引起的疾病的影响。已经提出了基于空肠弯曲菌全细胞制剂的疫苗，然而，由于 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诱导保护性免疫，而不会诱导 GBS。众所周知，空肠弯曲菌菌株具有高度变异性，这肯定会影响蛋白质亚单位疫苗的开发。适合疫苗包含的蛋白质必须在最大可能比例的空肠弯曲菌菌株中保守，必须具有免疫原性，并且必须诱导针对大量不同的空肠弯曲菌菌株的保护性免疫。虽然对空肠弯曲菌基因组序列的分析有助于作为了解其 OMP 补充的起点，但只有直接鉴定 OMP（通过蛋白质组分析）才能提供有关空肠弯曲菌菌株实际表达的 OMP 的详细信息。假设：某些空肠弯曲菌外膜蛋白 (OMP) 在所有空肠弯曲菌菌株中都是保守的，在人类感染期间具有免疫原性，并会产生保护性免疫反应。具体目标 1. 我们将使用蛋白质组学和质谱法鉴定几种空肠弯曲菌菌株外膜的蛋白质成分。具体目标 2. 我们将确定在我们的初始菌株中保守的 OMP 是否也存在于大量空肠弯曲菌菌株（新鲜的临床分离株和来自美国各地的菌株档案库）中，并将评估免疫反应感染者对这些 OMP 的影响。具体目标 3. 我们将确定用保守的、纯化的重组 OMP 免疫小鼠是否可以防止随后的实验性空肠弯曲菌感染。