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: 8662687
• 负责人: Marcela F Pasetti
• 金额: $ 64.1万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662687
• 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Biodefense食物和水传播病原体的广谱小儿疫苗：Shigella，Salmonella和Yersinia肠结肠镜。新生儿，婴儿和幼儿是可能不容忍的最脆弱的群体之一，也不对在人类成年人中起作用的疫苗做出充分的反应。我们将探索一种新型的平台技术，该技术由非生存的非生物修饰的乳酸乳酸乳球颗粒，指定的革兰氏阳性增强子基质（GEM）组成，该技术将设计为从粒子表面上的每种病原体中展示III型分泌抗原。这些抗原脱落的颗粒将合并以产生宽光谱疫苗。乳酸乳乳杆菌的宝石颗粒（益生菌衍生物）具有出色的安全性，可以用粘液施用，具有强大的辅助特性（肽聚糖包膜刺激先天免疫力），非常稳定（消除了对冷链的需求），易于制造和廉价。评估显示耶尔森氏菌鼠疫LCRV的宝石颗粒的初步研究表明，它们具有高度的免疫原性，并赋予了对新生儿免疫的小鼠的致命细菌感染的全面保护。抗原携带颗粒会诱导健壮的粘膜以及全身性TH1型免疫。可以预防食物和水传播疾病的小儿宝石疫苗将成为重要的公共卫生工具，以实现生物化的目的，也可以防止在学校和日托环境中以及旅行者中的肠胃感染。这项工作将以四个目标进行。在AIM 1中，我们将构建显示shigella iPad和ipab，Symmanella sipb和sipd和Yersinia lcrv和Yopb保护抗原的L.乳酸颗粒颗粒。每个粒子将显示每个靶病原体的两种抗原，并且可以根据需要单独使用或组合（以多价格式）使用。在AIM 2中，我们将在不同动物模型中进行研究，以证明候选疫苗的免疫原性。在AIM 3中，我们将使用优化的免疫计划和不同的挑战模型检查其保护效果。在AIM 4中，我们将以稳定性和整体安全性来表征最终产品，以满足调查新药（IND）应用的要求。在此阶段，我们将开始制定临床发展计划，并将寻求资金来源来测试人类的这些疫苗。提出的工作非常重要，因为它解决了需要安全有效的小儿疫苗，以造成毁灭性食物和水传播疾病，而该疾病没有可用的疫苗。我们是研究使用乳酸乳杆菌颗粒颗粒作为小儿肠疫苗的唯一组。如果成功，这项工作将揭示新的疫苗范式，以防止婴儿感染性疾病。该项目的目的是开发一种新型的非生存的，非遗传修饰的基于乳酸乳杆菌的多价疫苗，以保护婴儿和幼儿免受沙门氏菌，志贺氏菌和耶尔西尼亚小肠结肠炎（B类病原体）引起的疾病。这些病原体的保守保护性III型分泌蛋白将显示在粒子表面上。免疫原性和保护功效将在被免疫的新生儿的小鼠中进行测试。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，易于分娩（粘膜疫苗）以及简单且廉价的生产。 相关性：该项目的目的是开发一种新型的非生存，非遗传修饰的基于乳酸乳杆菌的多价疫苗，以保护婴儿和幼儿免受沙门氏菌，志贺氏菌和耶尔森氏菌（B类病原体）引起的疾病。这些病原体的保守保护性III型分泌蛋白将显示在粒子表面上。免疫原性和保护功效将在被免疫的新生儿的小鼠中进行测试。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，易于分娩（粘膜疫苗）以及简单且廉价的生产。

项目成果

Intradermal delivery of Shigella IpaB and IpaD type III secretion proteins: kinetics of cell recruitment and antigen uptake, mucosal and systemic immunity, and protection across serotypes.

• DOI: 10.4049/jimmunol.1302743
• 发表时间: 2014-02-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Heine SJ;Diaz-McNair J;Andar AU;Drachenberg CB;van de Verg L;Walker R;Picking WL;Pasetti MF
• 通讯作者: Pasetti MF

Live Attenuated Human Salmonella Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity.

• DOI: 10.1128/ecosalplus.esp-0010-2016
• 发表时间: 2016-11
• 期刊: EcoSal Plus
• 作者: Galen JE;Buskirk AD;Tennant SM;Pasetti MF
• 通讯作者: Pasetti MF