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Multivalent Oral Vaccine against Enterotoxigenic Escherichia coli and Enteric Fevers

Multivalent Oral Vaccine against Enterotoxigenic Escherichia coli and Enteric Fevers
抗产肠毒素大肠杆菌和肠热病的多价口服疫苗
批准号:
9202738
负责人:
B. KIM LEE SIM
金额:
$29.75万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-18 至 2018-07-31

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中文摘要
翻译
产肠毒素E.大肠杆菌(ETEC)菌株、志贺氏菌属和伤寒沙门氏菌, 它们是NIAID B类优先因子,每年在全世界范围内总共影响超过4亿人。 目前,没有针对ETEC或志贺氏菌病的疫苗。有伤寒疫苗。一个负担得起的,有效的, 针对所有3种微生物的口服多价疫苗将具有巨大的公共卫生重要性, 在旅行者和军事人员中有很大的商业市场。我们的长期目标是创造一个 抗ETEC、志贺氏菌病和伤寒的稳定口服疫苗。开始实现 为此目标,我们使用已获得许可的Ty 21 a伤寒疫苗来表达宋内志贺氏菌的O抗原, 生产一种名为TyOraSs的候选疫苗,该疫苗正在开发中。主要毒力决定因素 ETEC的主要致病因子是定植因子抗原(CFA或粘附素)和两种肠毒素,即不耐热(LT)和 热稳定毒素(STa)。一种有效的ETEC疫苗应诱导抗体阻断细菌附着 和/或中和毒素在动物模型中,CFA和毒素的抗体具有协同保护作用。它 我们团队的成员已经证明,代表7个独立表位的多表位融合抗原(MEFA) CFA ETEC粘附素和两种毒素可以融合为单一蛋白质(此处指定为MEFA+T),以诱导 阻断异质性ETEC菌株与人结肠癌细胞粘附的交叉保护性抗体 在体外,中和所有ETEC菌株中的两种毒素。在这个项目中,我们将稳定地表达这些多个 粘附素和两种毒素的类毒素形式稳定地作为全毒素结构的CFA-类毒素融合盒抗原 在Ty 21 a中,使用哺乳动物评估Ty 21 a-ETEC疫苗的免疫原性和保护效力。 仔猪和兔攻击模型。具体而言,我们将:1)生成并表征 基因优化的Ty 21 a表达染色体整合的ETEC多表位融合抗原(MEFA) + 细胞内或分泌形式的类毒素LT-STa(命名为Ty 21 a-ETEC MEFA-T),2)证明 对ETEC和S.伤寒,通过粘膜免疫小鼠,和3)建立保护性 在兔定植模型和哺乳仔猪致死感染模型中对ETEC的有效性。我们的建议 是独一无二的,因为我们在构建多价ETEC融合抗原方面的专业知识, Ty 21 a作为表达异源抗原的平台,以及用动物模型表达 明确评估疫苗的保护效力。一种独立的ETEC伤寒疫苗 实质性的影响,但是我们的目标是利用这个项目的成功作为发展的基础, 针对ETEC、伤寒和志贺氏菌病的多价疫苗。在第二阶段,我们将生成一个三元组 病原体疫苗、TyOraSs-ETEC疫苗或两种二价疫苗; 用于按照cGMP生产和作为泡沫干燥疫苗的疫苗候选菌株 产品;进行所需的临床前研究;设计临床方案;并准备IND。
英文摘要
Enteric diseases caused by enterotoxigenic E. coli (ETEC) strains, Shigella spp, and Salmonella Typhi, all of which are NIAID Category B priority agents, collectively affect > 400 million people annually worldwide. Currently, there is no vaccine against ETEC or shigellosis. A typhoid vaccine exists. An affordable, effective, oral multivalent vaccine against all 3 organisms would have enormous public health importance, and a substantial commercial market among travelers and military personnel. Our long-term goal is to create a stable, orally administered vaccine against ETEC, shigellosis and typhoid. To begin the process of achieving this goal we have used the licensed Ty21a typhoid vaccine to express the O-antigen of Shigella sonnei to produce a vaccine candidate called TyOraSs, which is under development. The major virulence determinants of ETEC are the colonization factor antigens (CFAs or adhesins) and two enterotoxins, the heat-labile (LT) and heat-stable toxin (STa). An effective ETEC vaccine should induce antibodies that block bacterial attachment and/or to neutralize the toxins. In animal models antibodies to CFA and toxin are synergistically protective. It has been shown by members of our team that a multi-epitope fusion antigen (MEFA) representing 7 separate CFA ETEC adhesins and two toxins can be fused as a single protein (designated here as MEFA+T) to induce cross-protective antibodies that blocks adherence of heterogeneous ETEC strains to human colon cancer cells in vitro, and neutralizes two toxins in all ETEC strains. In this project we will stably express these multiple adhesins and the toxoid form of both toxins stably as a holotoxin structured CFA-toxoid fusion cassette antigen in Ty21a, and assess immunogenicity and protective efficacy of our Ty21a-ETEC vaccine using the suckling piglet and rabbit challenge models. Specifically we will, 1) Generate and characterize vaccine strain(s) of genetically optimized Ty21a expressing chromosomally integrated, ETEC multi-epitope fusion antigen (MEFA) + toxoid LT-STa (designated Ty21a-ETEC MEFA-T) either intra-cellularly or in secreted form, 2) Demonstrate immunogenicity against ETEC and S. Typhi, by mucosal immunization of mice, and 3) Establish protective efficacy against ETEC in the rabbit colonization model and suckling piglet lethal infection model. Our proposal is unique because of our expertise at construction of multivalent ETEC fusion antigens, experience with using Ty21a as a platform for expressing heterologous antigens, and capabilities with animal models to unambiguously assess vaccine protective efficacy. A stand-alone ETEC-typhoid vaccine would have substantial impact, however our aim to use success in this project as a foundation for the development of a multivalent vaccine against ETEC, typhoid, and shigellosis. In Phase II we will generate a single triple pathogen vaccine, TyOraSs-ETEC vaccine, or two bivalent vaccines; generate a master cell bank of the vaccine candidate strain(s) for manufacturing in compliance with cGMPs and as a foam-dried vaccine product(s); conduct required pre-clinical studies; design a clinical protocol; and prepare an IND.
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In vitro bioreactor production of a genetically modified late liver stage-arresting replication competent Plasmodium falciparum sporozoite vaccine
  • 批准号:
    10547414
  • 项目类别:
  • 资助金额:
    $30.0万
  • 财政年份:
    2022
  • 负责人:
    B. KIM LEE SIM
  • 依托单位:
In vitro bioreactor production of a genetically modified late liver stage-arresting replication competent Plasmodium falciparum sporozoite vaccine
  • 批准号:
    10634703
  • 项目类别:
  • 资助金额:
    $30.0万
  • 财政年份:
    2022
  • 负责人:
    B. KIM LEE SIM
  • 依托单位:
海外基金