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
基本信息
- 批准号:7664027
- 负责人:
- 金额:$ 295.91万
- 依托单位:
- 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:2009-06-18 至 2014-05-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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):疫苗被广泛视为具有成本效益的干预措施,可预防和控制典型的地方性和流行性传染病,以及限制新出现的感染和某些生物恐怖剂的传播和影响。然而,由于缺乏有关自然感染和候选疫苗引起的保护作用的“真实”(即有效)免疫学机制的信息,阻碍了针对其中一些药物的新的和改进的疫苗的开发。对于通过粘膜表面(包括胃肠道(GI))进入宿主的病原体来说尤其如此。因此,该提议的重点是进一步加深我们对可在人类GI微环境中引发的保护性免疫机制的理解。此外,由于正常的胃肠菌群(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微生物群与宿主免疫反应之间的相互作用进行开创性研究。我们将集中精力深入研究 3 种主要的革兰氏阴性细菌人类病原体,包括幽门螺杆菌、伤寒沙门氏菌和志贺氏菌,每种病原体主要影响胃肠道的一个不同主要部分(分别是胃、回肠和结肠)。由于几乎所有有关保护性粘膜免疫决定因素的有限信息均来自成人研究,因此我们还将集中精力探索儿童和老年人对经许可的 Ty21a 伤寒口服免疫的反应。为了解决这项任务的复杂性,我们组建了一个多学科团队,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、高通量技术、微生物学、基因组学、蛋白质化学以及临床胃肠病学和疫苗学领域的知名研究人员组成(在进行内窥镜检查和进行内窥镜检查方面拥有丰富的经验) 疫苗试验)。此外,我们建议开发两项新技术来广泛推进人类免疫学研究,包括基于人类的方法来研究整个伤寒沙门氏菌 ORFeome 以识别 CD8+ T 细胞反应,以及肽构象约束技术和潜在的粘膜佐剂来推进幽门螺杆菌疫苗。我们期望 CCHI 能够在对人类健康非常重要的领域提供急需的信息。
相关性:尽管非常需要针对主要人类病原体(尤其是通过肠粘膜进入人类宿主的病原体)的新的和改进的疫苗,但由于对保护性肠道免疫的决定因素了解不足,这一领域受到阻碍。此外,人们对肠道微生物群在调节口服疫苗免疫原性中的作用知之甚少,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:食蟹猴和人类的痢疾杆菌 1 疫苗的保护性免疫机制(Sztein,M)
项目 1 描述(由申请人提供):志贺氏菌是一种全球性感染,因在某些环境中快速传播而臭名昭著。一种血清型,1 型痢疾志贺氏菌(S.dysenteriae 1),可以引起毁灭性的流行病,病死率很高,因此它被列为 B 类优先病原体,极有可能被用作生物武器。目前尚无针对志贺氏菌的疫苗。由于对志贺氏菌感染的保护性免疫的具体决定因素的信息严重缺乏,有效志贺氏菌疫苗的开发受到阻碍。由于在临床试验中用野生型痢疾杆菌 1 进行挑战研究以推进疫苗开发相关的风险所带来的限制,因此迫切需要非人类灵长类动物模型。我们已经用野生型痢疾杆菌 1 株 1617 建立了攻击模型,迄今为止,其攻击率为 100%(6 只食蟹猴中的 6 只接受了 10e11 cfu 胃内攻击)。此外,我们还加深了对挑战后引发的免疫反应的理解。在本申请中,我们建议通过解决以下具体目标来继续这些研究:(1)评估新型减毒沙门氏菌 1 突变株的胃内免疫可引起免受野生型沙门氏菌 1 胃内攻击的保护这一假设; (2) 评估以下假设:在用痢疾沙门氏菌 1 减毒株免疫和/或用野生型痢疾沙门氏菌 1 攻击的食蟹猴循环中观察到的一组确定的免疫反应与保护相关,并且代表效应部位(即粘膜组织)和次级淋巴器官中存在的免疫反应。这些转化研究对于进一步了解介导对痢疾沙门氏菌 1 的保护和人类对疫苗接种反应的持久性的免疫学机制至关重要。(3) 评估用减毒沙门氏菌 1 菌株免疫猴子对猴子粪便中结肠微生物群的影响,以及现有微生物群对观察到的免疫反应和免受攻击的保护的影响。最后,我们将利用即将进行的减毒痢疾沙门氏菌 1 株 CVD 1256 试验来评估以下假设:在人体中全身和局部观察到的免疫反应与食蟹猴中与保护相关的免疫反应相似(目标 1 和 2)。这些研究将提供宝贵的见解,可能会加速痢疾杆菌减毒疫苗的开发1。
相关性:该项目的总体目标是开发一种安全有效的痢疾杆菌 1 疫苗,这是一种 B 类优先病原体,有可能用作生物武器。目前,尚无针对志贺氏菌的疫苗,针对多种抗生素耐药菌株感染的治疗选择也有限。鉴于成功控制这种感染的现有措施的缺点及其生物恐怖主义的潜力,开发 1 型痢疾沙门氏菌疫苗非常重要。
项目成果
期刊论文数量(0)
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Marcelo B. Sztein其他文献
Thymic physiology and biochemistry.
胸腺生理学和生物化学。
- DOI:
- 发表时间:
1987 - 期刊:
- 影响因子:0
- 作者:
R. Schulof;Paul H. Naylor;Marcelo B. Sztein;Allan L. Goldstein - 通讯作者:
Allan L. Goldstein
Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road
志贺菌疫苗的临床试验:在漫长而艰难的道路上前进两步后退一步
- DOI:
10.1038/nrmicro1662 - 发表时间:
2007-07-01 - 期刊:
- 影响因子:103.300
- 作者:
Myron M. Levine;Karen L. Kotloff;Eileen M. Barry;Marcela F. Pasetti;Marcelo B. Sztein - 通讯作者:
Marcelo B. Sztein
The two-faced T cell epitope
双面T细胞表位
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:4.8
- 作者:
L. Moise;Andres H. Gutierrez;C. Bailey;Frances E Terry;Qibin Leng;Karim M. Abdel Hady;Nathan c. VerBerkmoes;Marcelo B. Sztein;P. Losikoff;William D. Martin;Alan Rothman;Anne Searls De Groot - 通讯作者:
Anne Searls De Groot
Tu1886 – Commensal Derived Bioproducts Contribute to Modulate <em>S.</em> Typhi-Host Interaction
- DOI:
10.1016/s0016-5085(19)39869-5 - 发表时间:
2019-05-01 - 期刊:
- 影响因子:
- 作者:
Stefania Senger;Laura Ingano;Kourtney Nickerson;Marcelo B. Sztein;Alessio Fasano - 通讯作者:
Alessio Fasano
Safety and immunogenicity in humans of enterotoxigenic Escherichia coli double mutant heat-labile toxin administered intradermally
皮内注射产肠毒素大肠埃希氏菌双突变不耐热肠毒素在人体中的安全性和免疫原性
- DOI:
10.1038/s41541-025-01071-7 - 发表时间:
2025-02-01 - 期刊:
- 影响因子:6.500
- 作者:
Marcela F. Pasetti;Patricia L. Milletich;Jessica A. White;Jessica Butts;Rebecca C. Brady;Michelle D. Dickey;Cassandra Ballou;Nicole Maier;Marcelo B. Sztein;Shahida Baqar;A. Louis Bourgeois;David I. Bernstein - 通讯作者:
David I. Bernstein
Marcelo B. Sztein的其他文献
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{{ truncateString('Marcelo B. Sztein', 18)}}的其他基金
Defining immunological mechanisms of serovar cross-reactivity to develop broad spectrum protective vaccines for typhoidal and non-typhoidal Salmonella infections in humans
定义血清型交叉反应的免疫学机制,以开发针对人类伤寒和非伤寒沙门氏菌感染的广谱保护性疫苗
- 批准号:
10584484 - 财政年份:2019
- 资助金额:
$ 295.91万 - 项目类别:
Defining immunological mechanisms of serovar cross-reactivity to develop broad spectrum protective vaccines for typhoidal and non-typhoidal Salmonella infections in humans
定义血清型交叉反应的免疫学机制,以开发针对人类伤寒和非伤寒沙门氏菌感染的广谱保护性疫苗
- 批准号:
10364714 - 财政年份:2019
- 资助金额:
$ 295.91万 - 项目类别:
Broad spectrum vaccines to enteric fevers in humans: cross protective immunity
人类肠热病广谱疫苗:交叉保护性免疫
- 批准号:
8233359 - 财政年份:2011
- 资助金额:
$ 295.91万 - 项目类别:
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:
8282922 - 财政年份:2009
- 资助金额:
$ 295.91万 - 项目类别:
Mucusal and Systemic Immunity, Vaccines and Microbiota Interplay in Humans
人类粘膜和系统免疫、疫苗和微生物群的相互作用
- 批准号:
8835015 - 财政年份:2009
- 资助金额:
$ 295.91万 - 项目类别:
Mucusal and Systemic Immunity, Vaccines and Microbiota Interplay in Humans
人类粘膜和系统免疫、疫苗和微生物群的相互作用
- 批准号:
8707660 - 财政年份:2009
- 资助金额:
$ 295.91万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 295.91万 - 项目类别:
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:
8485521 - 财政年份:2009
- 资助金额:
$ 295.91万 - 项目类别:
A novel whole ORFeome approach to identify CD8+ T cell responses to S. Typhi prot
一种新颖的全 ORFeome 方法来识别 CD8 T 细胞对伤寒沙门氏菌 prot 的反应
- 批准号:
7701566 - 财政年份:2009
- 资助金额:
$ 295.91万 - 项目类别:
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