A. L. lactis-based vaccine for children with broad spectrum for enteric pathogens

基于乳酸乳球菌的儿童疫苗，具有广谱肠道病原体

• 批准号: 8277397
• 负责人: Marcela F Pasetti
• 金额: $ 64.89万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-07 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277397
• 关键词: Achyrocline; Address; Adjuvant; Adult; Adverse effects; Affect; Animal Model; Animals; Anthrax Attack; Antibiotics; Antigen Targeting; Antigens; Area; Attention; Attenuated Live Virus Vaccine; Bacillus anthracis spore; Bacterial Infections; Biological; Bioterrorism; Categories; Cells; Child; Childhood; Clinical; Clinical Research; Cold Chains; Communicable Diseases; Day Care; Dendritic Cells; Development; Development Plans; Disease; Distress; Drug Formulations; Engineering; Enhancers; Enteral; Exhibits; Food; Funding Agency; Home environment; Human; Immune response; Immune system; Immunity; Immunization Schedule; In Vitro; Infant; Infection; Injection of therapeutic agent; Investigational New Drug Application; Lactococcus lactis; Licensing; Life; Maryland; Mass Vaccinations; Modeling; Mus; Names; Natural Immunity; Newborn Infant; Oklahoma; Organism; Peptidoglycan; Phenotype; Plague; Plasmids; Play; Population; Probiotics; Production; Property; Protein Secretion; Proteins; Public Health; Readiness; Relative (related person); Request for Applications; Role; Route; Safety; Salmonella; Schedule; Schools; Shigella; Staging; Subunit Vaccines; Surface; System; T-Lymphocyte; Technology; Temperature; Testing; Therapeutic Intervention; Universities; Vaccinated; Vaccines; Virulent; Vulnerable Populations; Water; Work; Yersinia; Yersinia enterocolitica; Yersinia pestis; abstracting; age group; aluminum sulfate; base; biodefense; cost; enteric pathogen; high risk; immunogenic; immunogenicity; in vivo; manufacturing process; mucosal vaccination; mucosal vaccine; neonatal human; novel; novel vaccines; particle; pathogen; prevent; protective efficacy; protein expression; research clinical testing; response; tool; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vector vaccine; weapons

DESCRIPTION (provided by applicant): The purpose of this application is the development of a broad-spectrum pediatric vaccine against Category B Biodefense food and water borne pathogens: Shigella, Salmonella and Yersinia enterocolitica. Newborns, infants and young children are among the most vulnerable groups of the population who may not tolerate, neither respond adequately to vaccines that work in human adults. We will explore a novel platform technology consisting of nonliving, non-genetically modified, Lactococcus lactis particles, designated Gram-positive Enhancer Matrix (GEM) that will be engineered to display Type III secretion antigens from each of these pathogens on the particle surface. These antigen-displaying particles will be combined to produce a broad spectrum vaccine. The L. lactis GEM particles (probiotic derivatives) have an outstanding safety profile, can be administered mucosally, have strong adjuvant properties (the peptidoglycan envelope stimulates innate immunity), are highly stable (eliminating the need for cold chain), easy to manufacture and inexpensive. Preliminary studies evaluating GEM particles displaying Yersinia pestis LcrV showed that they are highly immunogenic and confer full protection against lethal bacterial infection in mice immunized as newborns. The antigen-carrying particles induced robust mucosal as well as systemic Th1 type immunity. A pediatric GEM-based vaccine that can protect against food and water borne diseases would be an important public health tool for purposes of biodefense but also to prevent enteric infection in school and day care settings, as well as for travelers. The work will be conducted in 4 Aims. In Aim 1 we will construct the L. lactis GEM particles displaying Shigella IpaD and IpaB, Salmonella SipB and SipD and Yersinia LcrV and YopB protective antigens. Each particle will display two antigens from each of the target pathogens and the particles can be used alone or combined (in a multivalent format) as needed. In Aim 2 we will perform studies in different animal models to demonstrate immunogenicity of the vaccine candidates. In Aim 3 we will examine their protective efficacy using optimized immunization schedules and different challenge models. In Aim 4 we will characterize the final product in terms of stability and overall safety to satisfy requirements for an Investigational New Drug (IND) application. At this stage we will start developing a clinical development plan and will seek funding sources to test these vaccines in humans. The work proposed is highly significant, as it addresses the need for a safe and effective pediatric vaccine for devastating food and water borne diseases for which no vaccines are available. We are the only group investigating the use of L. lactis GEM particles as pediatric enteric vaccines. If successful, this work will unravel a new vaccine paradigm to prevent infectious diseases in infants. The purpose of this project is to develop a novel non-living, non-genetically modified L. lactis-based multivalent vaccine to protect infants and young children against disease caused by Salmonella, Shigella and Yersinia enterocolitica (Category B pathogens). Conserved protective type III secretion proteins from these pathogens will be displayed on the particle surface. Immunogenicity and protective efficacy will be tested in mice immunized as newborns. Advantages of this vaccine technology include: an outstanding safety profile, broad protection against multiple pathogens, ease of delivery (mucosal vaccination) and simple and inexpensive production. Relevance: The purpose of this project is to develop a novel non-living, non-genetically modified L. lactis-based multivalent vaccine to protect infants and young children against disease caused by Salmonella, Shigella and Yersinia enterocolitica (Category B pathogens). Conserved protective type III secretion proteins from these pathogens will be displayed on the particle surface. Immunogenicity and protective efficacy will be tested in mice immunized as newborns. Advantages of this vaccine technology include: an outstanding safety profile, broad protection against multiple pathogens, ease of delivery (mucosal vaccination) and simple and inexpensive production.

描述（由申请人提供）： 该应用的目的是开发针对 B 类生物防御食品和水源病原体的广谱儿科疫苗：志贺氏菌、沙门氏菌和小肠结肠炎耶尔森氏菌。新生儿、婴儿和幼儿是人口中最脆弱的群体，他们可能无法耐受对成人有效的疫苗，也不会产生充分的反应。我们将探索一种新颖的平台技术，该技术由非生命、非转基因乳酸乳球菌颗粒组成，称为革兰氏阳性增强子基质（GEM），该技术将被设计为在颗粒表面展示来自每种病原体的 III 型分泌抗原。这些抗原展示颗粒将被组合起来生产广谱疫苗。乳酸乳球菌 GEM 颗粒（益生菌衍生物）具有出色的安全性，可以粘膜给药，具有很强的佐剂特性（肽聚糖包膜刺激先天免疫），高度稳定（无需冷链），易于制造和便宜。评估展示鼠疫耶尔森氏菌 LcrV 的 GEM 颗粒的初步研究表明，它们具有高度免疫原性，可为新生儿免疫的小鼠提供全面的保护，防止致命细菌感染。携带抗原的颗粒诱导了强大的粘膜和全身 Th1 型免疫。基于 GEM 的儿科疫苗可以预防食物和水传播疾病，这将是一种重要的公共卫生工具，不仅用于生物防御，还可以预防学校和日托机构以及旅行者的肠道感染。这项工作将按照 4 个目标进行。在目标 1 中，我们将构建展示志贺氏菌 IpaD 和 IpaB、沙门氏菌 SipB 和 SipD 以及耶尔森氏菌 LcrV 和 YopB 保护性抗原的乳酸乳球菌 GEM 颗粒。每个颗粒将展示来自每种目标病原体的两种抗原，并且颗粒可以根据需要单独使用或组合使用（以多价形式）。在目标 2 中，我们将在不同的动物模型中进行研究，以证明候选疫苗的免疫原性。在目标 3 中，我们将使用优化的免疫计划和不同的挑战模型来检查它们的保护功效。在目标 4 中，我们将描述最终产品的稳定性和整体安全性，以满足研究性新药 (IND) 申请的要求。在此阶段，我们将开始制定临床开发计划，并寻求资金来源以在人体中测试这些疫苗。拟议的工作非常重要，因为它解决了对安全有效的儿科疫苗的需求，用于治疗尚无疫苗的破坏性食物和水传播疾病。我们是唯一研究使用乳酸乳球菌 GEM 颗粒作为儿科肠道疫苗的小组。如果成功，这项工作将揭示一种新的疫苗范例来预防婴儿传染病。该项目的目的是开发一种新型非活体、非转基因乳酸乳球菌多价疫苗，以保护婴幼儿免受沙门氏菌、志贺氏菌和小肠结肠炎耶尔森氏菌（B 类病原体）引起的疾病。来自这些病原体的保守保护性 III 型分泌蛋白将展示在颗粒表面。将在新生儿免疫的小鼠中测试免疫原性和保护功效。该疫苗技术的优点包括：出色的安全性、针对多种病原体的广泛保护、易于递送（粘膜疫苗接种）以及生产简单且廉价。 相关性：该项目的目的是开发一种新型非活体、非转基因乳酸乳球菌多价疫苗，以保护婴幼儿免受沙门氏菌、志贺氏菌和小肠结肠炎耶尔森氏菌（B 类病原体）引起的疾病。来自这些病原体的保守保护性 III 型分泌蛋白将展示在颗粒表面。将在新生儿免疫的小鼠中测试免疫原性和保护功效。该疫苗技术的优点包括：出色的安全性、针对多种病原体的广泛保护、易于递送（粘膜疫苗接种）以及生产简单且廉价。