Mucosal Immunity, Vaccines and Microbiota Interplay in Humans and Animal

人类和动物的粘膜免疫、疫苗和微生物群的相互作用

• 批准号: 8119519
• 负责人: Marcelo B. Sztein
• 金额: $ 289.92万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119519
• 关键词: Mucosal; Immunity; Vaccines; Microbiota; Interplay; Mucosal; Immunity; Vaccines; Microbiota; Interplay

DESCRIPTION (provided by applicant): Vaccines are widely viewed as cost-effective interventions to prevent and control classical endemic and epidemic infectious diseases, as well as to limit the transmission and impact of emerging infections and certain bioterror agents. However, the development of new and improved vaccines against some of these agents is hampered by a lack of information concerning the "true" (i.e., operative) immunological mechanisms underlying the protection elicited by natural infection and by candidate vaccines. This is particularly true with regard to pathogens that enter the host via mucosal surfaces, including the gastrointestinal (Gl) tract. Thus, this proposal is focused on furthering our understanding of the protective immunological mechanisms that can be elicited in the Gl microenvironment of humans. Moreover, because the normal Gl flora (microbiota) is certain to influence the host immune response, we propose to conduct pioneering studies on the interactions between the local intestinal microbiota and the host immune response in humans. We will focus our efforts on in-depth studies of 3 major gram negative bacterial human pathogens including Helicobacter pylori, Salmonella enterica serovar Typhi and Shigella, each primarily affecting a distinct major segment of the Gl tract (i.e., the stomach, ileum and colon, respectively). Because virtually all of the limited information available concerning the determinants of protective mucosal immunity comes from studies in adults, we will also focus some efforts in exploring the responses to oral immunization with the licensed Ty21a typhoid in children and, for the first time, the elderly. To address the complexity of this undertaking, we have assembled a multidisciplinary team consisting of renowned investigators in the fields of innate and adaptive immunity, molecular biology, mucosal biology and physiology, biochemistry, high-throughput technology, microbiology, genomics, protein chemistry and clinical gastroenterology and vaccinology (with extensive experience in performing endoscopies and in conducting vaccine trials). In addition, we propose to develop two novel technologies to broadly advance the study of human immunology, including a human-based approach to study the entire S. Typhi ORFeome to identify CD8+ T cell responses and a peptide conformation constrainment technology and potential mucosal adjuvants to advance H. pylori vaccines. We expect this CCHI to yield much needed information in an area of great importance to human health. RELEVANCE: In spite of the great need for new and improved vaccines against major human pathogens, particularly those that enter the human host through the intestinal mucosa, this field is impeded by insufficient knowledge of the determinants of protective gut immunity. Moreover, little is known concerning the role of the gut microbiota in modulating the immunogenicity of oral vaccines and vice versa. The wealth of data generated by these studies is likely to lead to major advances in mucosal vaccine development in humans. PROJECT 1: PROTECTIVE IMMUNE MECHANISMS TO S. DYSENTERIAE 1 VACCINES IN CYNOMOLGUS MACAQUES AND HUMANS (Sztein, M) PROJECT 1 DESCRIPTION (provided by applicant): Shigella is a global infection that is notorious for disseminating rapidly in certain settings. One serotype, Shigella dysenteriae type 1 (S. dysenteriae 1), can cause devastating pandemics with high case fatality rates and thus it has been classified as a Category B priority pathogen with high potential to be used as a biological weapon. There is no available vaccine for Shigella. The development of effective Shigella vaccines has been hampered by a considerable lack of information of the specific determinants of protective immunity to Shigella infection. Because of the limitations imposed by the risks associated with performing challenge studies with wild type S. dysenteriae 1 in clinical trials to advance vaccine development, a nonhuman primate model is urgently needed. We have already established a challenge model with wild-type S. dysenteriae 1 strain 1617 which, to date, exhibited an attack rate of 100% (6 of 6 cynomolgus macaques challenged with 10e11 cfu intragastrically). Furthermore, we have advanced our understanding of the immune responses elicited following challenge. In this application we propose to continue these studies by addressing the following Specific Aims: (1) evaluate the hypothesis that intragastric immunization with novel attenuated S. dysenteriae 1 mutant strains elicits protection from intragastric challenge with wild type S. dysenteriae 1; (2) evaluate the hypotheses that a defined set of immune responses observed in circulation in cynomolgus immunized with attenuated strains of S. dysenteriae 1 and/or challenged with wild type S. dysenteriae 1 correlate with protection and are representative of those present at effector sites (i.e., mucosal tissues) and secondary lymphoid organs. These translational studies are central to further our understanding of the immunological mechanisms that mediate protection to S. dysenteriae 1 and longevity of the responses to vaccination in humans, (3) To evaluate the effects of immunization of monkeys with attenuated S. dysenteriae 1 strains on the colonic microbiota in stools of monkeys and the impact of the existing microbiota on the observed immune responses and protection from challenge. Finally, we will take advantage of an upcoming trial with the attenuated S. dysenteriae 1 strain CVD 1256 to evaluate the hypothesis that the immune responses observed systemically and locally in humans are similar to those that correlate with protection in cynomolgus macaques (Aims 1 and 2). These studies will provide valuable insights that might accelerate the development of attenuated vaccines for S. dysenteriae 1. RELEVANCE: The overall objective of this project is to develop a safe and effective vaccine for S. dysenteriae 1, a Category B priority pathogen with potential to be used as a biological weapon. Currently, there is no available vaccine for Shigella and limited treatment options for infections with multiple antibiotic resistant strains. Given the shortcomings of available measures to successfully control this infection, and its bioterrorism potential, to develop a S. dysenteriae type 1 vaccine is of great importance.

描述（由申请人提供）：疫苗被广泛视为预防和控制经典流行和流行传染病的经济有效干预措施，并限制了新兴感染和某些生物疾病药物的传播和影响。但是，由于缺乏有关自然感染和候选疫苗所引起的保护的“真实”（即手术性的）免疫机制的信息，对这些药物中的某些药物的开发和改进的疫苗的开发受到了阻碍。对于通过粘膜表面进入宿主（包括胃肠道（GL）道）进入宿主的病原体尤其如此。因此，该提议的重点是进一步了解我们对人类的GL微环境中可以引起的保护性免疫机制的理解。此外，由于正常的GL菌群（微生物群）肯定会影响宿主免疫反应，因此我们建议对人类局部肠道菌群与宿主免疫反应之间的相互作用进行开创性研究。我们将精力集中在对3个主要革兰氏阴性细菌人体病原体（包括幽门螺杆菌，沙门氏菌肠道血清Typhi和Shigella）中的深入研究上，每个病原体分别影响了GL区域的主要主要部分（即胃，鸡肠和结肠）。由于几乎所有有关保护性粘膜免疫决定因素的有限信息来自成人研究，因此我们还将集中精力探索儿童中的持牌Ty21a伤寒的口服免疫反应，以及第一次，老年人。为了解决这项事业的复杂性，我们组建了一个多学科团队，该团队由著名的研究人员组成，该团队由先天性和适应性免疫，分子生物学，粘膜生物学和生理学，生物化学，高直体技术，微生物学，微生物学，基因组学，蛋白质化学和临床式（涉及杂种学）（涉及经验）（涉及促进型，蛋白质化学，蛋白质化学，蛋白质化学，蛋白质化学，蛋白质化学，蛋白质化学，蛋白质化学，粘膜生物学和生理学（疫苗试验）。此外，我们建议开发两种新型技术，以广泛推进人类免疫学的研究，包括一种基于人类的Typhi Orfeome的方法，以鉴定CD8+ T细胞反应以及肽构象的限制技术和潜在的粘膜辅助剂，以推动幽门螺杆菌疫苗。我们希望这种CCHI能够在对人类健康非常重要的领域中产生急需的信息。 相关性：尽管非常需要针对主要的人类病原体的新疫苗和改进的疫苗，尤其是那些通过肠道粘膜进入人类宿主的病原体，但该领域受到对保护性肠道免疫决定因素的了解不足的阻碍。此外，关于肠道微生物群在调节口服疫苗的免疫原性中的作用，反之亦然，反之亦然。这些研究产生的大量数据可能会导致人类粘膜疫苗开发的重大进展。 项目1：囊肿猕猴和人类中的s。dysenteriae1疫苗的保护性免疫机制（Sztein，M） 项目1描述（由申请人提供）：Shigella是一种全球感染，在某些情况下迅速传播臭名昭著。一种血清型，志贺氏菌头脑1型（S. s. dysenteriae 1），可能会引起具有高病例死亡率的毁灭性大流行病，因此已被归类为具有高潜力的B类优先病原体，可以用作生物武器。志贺氏菌没有可用的疫苗。由于缺乏对志贺氏菌感染的保护性免疫的特定决定因素的信息，有效的志贺氏菌疫苗的发展受到了阻碍。由于在临床试验中使用野生型S. dendenteriae 1进行挑战研究的风险施加的局限性，以推动疫苗开发，因此迫切需要一种非人类灵长类动物模型。我们已经建立了一个野生型S. dysenteriae 1菌株1617的挑战模型，迄今为止，该模型的攻击率为100％（6个cynomolgus猕猴中的6个在胃内受到10E11 CFU的质疑）。此外，我们已经提出了对挑战后引起的免疫反应的理解。在此应用中，我们建议通过解决以下具体目的来继续这些研究：（1）评估以下假设：胃内免疫，新型减毒s。dysenteriae1突变菌株1突变菌株对胃内挑战产生了抗胃内挑战的保护。 (2) evaluate the hypotheses that a defined set of immune responses observed in circulation in cynomolgus immunized with attenuated strains of S. dysenteriae 1 and/or challenged with wild type S. dysenteriae 1 correlate with protection and are representative of those present at effector sites (i.e., mucosal tissues) and secondary lymphoid organs.这些翻译研究对于进一步的理解至关重要，我们对介导对人类疾病的葡萄球菌的保护和对人类疫苗接种的反应的寿命的寿命，（3）以评估猴子对依然菌群1链球菌对猴子的影响的影响对猴子的影响和对现有的微microbeys的影响和反应的影响，以评估猴子对猴子的免疫接种的影响。最后，我们将利用即将进行的试验，即减毒的S. dysenteriae 1菌株CVD 1256，以评估以下假设：人类系统地和局部观察到的免疫反应与与cynomolgus猕猴保护的人相似（AIM 1和2）。这些研究将提供有价值的见解，这些见解可能会加速降低疫苗的疫苗1。 相关性：该项目的总体目的是为S. dyensenteriae 1开发安全有效的疫苗，这是B类优先病原体，其潜力被用作生物武器。当前，尚无用于志贺氏菌的可用疫苗和有限的治疗选择，用于具有多种抗生素抗菌菌株的感染。考虑到成功控制这种感染的可用措施的缺点及其生物恐怖的潜力，开发了鼻梭菌1型疫苗非常重要。