Development of a prototype Klebsiella O polysaccharide conjugate vaccine

克雷伯菌 O 多糖结合疫苗原型的开发

基本信息

  • 批准号:
    8841098
  • 负责人:
  • 金额:
    $ 23.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-06-15 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Klebsiella pneumoniae (KP) are increasingly important Gram-negative bacterial pathogens that cause pneumonia, wound and urinary tract infections, bacteremia and meningitis. Like other Enterobacteriaceae, KP have become resistant to extended spectrum of beta lactamases (ESBL) antibiotics, including third generation cephalosporins. KP now comprise an increasing percentage of these ESBL-producing bacteria and alarmingly, in the last decade KP have become increasingly resistant to carbapenem. Carbapenamse-resistant KP (KPC) now represent 8% of all KP and in data reported to the CDC have increased over 6 fold in the last decade, resulting in extended hospitalization, increased costs and mortality. These nightmare bugs necessitate the use of toxic, less effective last resort antibiotics. Based on the dwindling pipeline of antibiotics being developed, there is little likelihood that new antibiotics will be available in the near term. A vaccine against KP could elict antibodies that would provide adjunctive therapy for KP that would not be subject to antibiotic resistance mechanisms. We previously developed a 23-valent KP capsular polysaccharide vaccine that progressed to human trials. Since relatively few KP O serotypes account for >70% of KP infections, we reason that a multivalent COPS-based KP vaccine could provide wide coverage and be less difficult and expensive to produce. We propose to develop a prototype conjugate vaccine against the core/O polysaccharide from the lipopolysaccharide (LPS) of a virulent KP (O1K2) linked to an established carrier protein, CRM197 by two different conjugation chemistries. In Specific Aim 1 we will construct a recombinant attenuated strain of KP that can serve as a reagent strain that can be used to safely purify large amounts of KP COPS. As we have successfully done for other GNB pathogens (Shigella, Salmonella, Francisella) we will generate mutations in the guanosine biosynthesis pathway enzymes, and confirm loss of virulence in murine challenge studies. We will generate a second mutation in the genes encoding the KP capsule which will permit a more efficient purification of the surface COPS antigen. In Specific Aim 2 we will test the hypothesis that conjugation of KP type O1 COPS to an established protein carrier, CRM197 will induce anti-LPS antibodies that mediate opsonophagocytosis of KP by phagocytes and will protect mice from lethal homologous KP challenges in both intraperitoneal and intratracheal mouse challenge models. We will vary the linkage (random coupling versus end-linkage) and use of linkers to assess which construct elicits optimal antibody responses and protection. At the conclusion of these studies, we intend to have a KP COPS conjugate vaccine that may serve as a prototype for a multivalent KP COPS vaccine that can be used in the prevention and/or development of a KP-antibody-enriched IVIG for the treatment of KP infection, even if the strains are highly resistant to antibiotics. We also will have a production strain of KP that will be safe for scale-up and allow for more efficient purification of the KP COPS.
 描述(由申请人提供):肺炎克雷伯菌 (KP) 是日益重要的革兰氏阴性细菌病原体,可引起肺炎、伤口和尿路感染、菌血症和脑膜炎,与其他肠杆菌科细菌一样,KP 已对广谱 β 内酰胺酶 (ESBL) 产生耐药性。 )抗生素,包括第三代头孢菌素 KP,现在在这些产生 ESBL 的细菌中所占的比例越来越大,令人担忧的是,过去十年,KP 对碳青霉烯类抗生素的耐药性日益增强,目前,碳青霉烯酶耐药性 KP (KPC) 占所有 KP 的 8%,并且向 CDC 报告的数据在过去十年中增加了 6 倍以上,导致住院时间延长、费用增加和这些噩梦般的细菌需要使用有毒、效果较差的抗生素,鉴于正在开发的抗生素品种不断减少,短期内出现新的抗生素的可能性很小。针对 KP 的疫苗可以产生抗体,为 KP 提供辅助治疗,而不受抗生素耐药机制的影响,我们之前开发了一种 23 价 KP 荚膜多糖疫苗,该疫苗已进入人体试验阶段,因为 KP O 血清型相对较少,>70。 % 的 KP 感染,我们认为基于 COPS 的多价 KP 疫苗可以提供广泛的覆盖范围,并且生产难度和成本较低,我们建议开发一种针对 KP 感染的原型结合疫苗。来自有毒 KP (O1K2) 脂多糖 (LPS) 的核心/O 多糖通过两种不同的缀合化学与已建立的载体蛋白 CRM197 连接,在具体目标 1 中,我们将构建可用作试剂的重组 KP 减毒菌株。正如我们对其他 GNB 病原体所做的成功一样,该菌株可用于安全纯化大量 KP COPS。 (志贺氏菌、沙门氏菌、弗朗西斯氏菌)我们将在鸟苷生物合成途径酶中产生突变,并在小鼠攻击研究中确认毒力丧失。我们将在编码 KP 胶囊的基因中产生第二个突变,这将允许更有效地纯化。在特定目标 2 中,我们将测试 KP O1 型 COPS 与已建立的蛋白质载体 CRM197 缀合将诱导介导抗 LPS 抗体的假设。吞噬细胞对 KP 的调理吞噬作用,将保护小鼠在腹膜内和气管内小鼠攻击模型中免受致命的同源 KP 攻击。我们将改变连接(随机偶联与末端连接)和连接体的使用,以评估哪种构建体引发最佳抗体反应和保护。在这些研究结束时,我们打算开发出一种 KP COPS 结合疫苗,它可以作为多价 KP COPS 疫苗的原型,用于预防和/或开发富含 KP 抗体的 IVIG 来治疗 KP 感染,即使菌株对抗生素具有高度耐药性,我们也将拥有可安全扩大规模并允许更多的 KP 生产菌株。 KP COPS 的高效纯化。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Alan S. Cross其他文献

O antigen seroepidemiology of Klebsiella clinical isolates and implications for immunoprophylaxis of Klebsiella infections.
克雷伯氏菌临床分离株的 O 抗原血清流行病学及其对克雷伯氏菌感染免疫预防的影响。
  • DOI:
    10.1016/j.vaccine.2003.11.026
  • 发表时间:
    2004-02-17
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Matthias Trautmann;Markus Ruhnke;T. Rukavina;T. Held;Alan S. Cross;Reinhard Marre;Chris Whitfield
  • 通讯作者:
    Chris Whitfield
NEU1 Sialidase Regulates the Sialylation State of CD31 and Disrupts CD31-driven Capillary-like Tube Formation in Human Lung Microvascular Endothelia*
NEU1 唾液酸酶调节 CD31 的唾液酸化状态并破坏人肺微血管内皮细胞中 CD31 驱动的毛细血管样管形成*
  • DOI:
    10.1074/jbc.m114.555888
  • 发表时间:
    2014-02-18
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Chunsik Lee;Anguo Liu;A. Mir;a;a;S. Hyun;Erik P. Lillehoj;Alan S. Cross;A. Passaniti;P. Richard Grimm;Bo;P. Welling;Joseph A. Madri;H. DeLisser;S. Goldblum
  • 通讯作者:
    S. Goldblum
The O-glycan is essential for the induction of protective antibodies against lethal infection by flagella A-bearing Pseudomonas aeruginosa
O-聚糖对于诱导针对带有鞭毛 A 的铜绿假单胞菌致命感染的保护性抗体至关重要
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Myeongjin Choi;S. Shridhar;Heather Fox;Kun Luo;M. Amin;S. Tennant;R. Simon;Alan S. Cross
  • 通讯作者:
    Alan S. Cross
Inflammatory cytokines produced in response to experimental human gonorrhea.
针对实验性人类淋病而产生的炎症细胞因子。
  • DOI:
    10.1093/infdis/172.1.186
  • 发表时间:
    1995-07-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kyle H. Ramsey;Herman Schneider;Alan S. Cross;John W. Boslego;David L. Hoover;Terri L. Staley;Robert A. Kuschner;Carolyn D. Deal
  • 通讯作者:
    Carolyn D. Deal
A combination of burn wound injury and Pseudomonas infection elicits unique gene expression that enhances bacterial pathogenicity
  • DOI:
    10.1128/mbio.02454-23
  • 发表时间:
    2023-12-19
  • 期刊:
  • 影响因子:
    6.4
  • 作者:
    Adrienne R Kambouris;Jerod Brammer;Holly Roussey;Chixiang Chen;Alan S. Cross
  • 通讯作者:
    Alan S. Cross

Alan S. Cross的其他文献

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{{ truncateString('Alan S. Cross', 18)}}的其他基金

Development of a prototype Klebsiella O polysaccharide conjugate vaccine
克雷伯菌 O 多糖结合疫苗原型的开发
  • 批准号:
    9089850
  • 财政年份:
    2015
  • 资助金额:
    $ 23.03万
  • 项目类别:
Novel peptide antagonist theraphy for superantigen- induced lethal shock
用于超抗原诱导致死性休克的新型肽拮抗剂疗法
  • 批准号:
    8233382
  • 财政年份:
    2011
  • 资助金额:
    $ 23.03万
  • 项目类别:
Novel peptide antagonist theraphy for superantigen- induced lethal shock
用于超抗原诱导致死性休克的新型肽拮抗剂疗法
  • 批准号:
    7670085
  • 财政年份:
    2009
  • 资助金额:
    $ 23.03万
  • 项目类别:
Tularemia
兔热病
  • 批准号:
    7678793
  • 财政年份:
    2008
  • 资助金额:
    $ 23.03万
  • 项目类别:
Role of Sialidase in Pulmonary Host Defenses and Acute Lung Injury
唾液酸酶在肺宿主防御和急性肺损伤中的作用
  • 批准号:
    7866681
  • 财政年份:
    2007
  • 资助金额:
    $ 23.03万
  • 项目类别:
Role of Sialidase in Pulmonary Host Defenses and Acute Lung Injury
唾液酸酶在肺宿主防御和急性肺损伤中的作用
  • 批准号:
    7318032
  • 财政年份:
    2007
  • 资助金额:
    $ 23.03万
  • 项目类别:
Role of Sialidase in Pulmonary Host Defenses and Acute Lung Injury
唾液酸酶在肺宿主防御和急性肺损伤中的作用
  • 批准号:
    7637431
  • 财政年份:
    2007
  • 资助金额:
    $ 23.03万
  • 项目类别:
Role of Sialidase in Pulmonary Host Defenses and Acute Lung Injury
唾液酸酶在肺宿主防御和急性肺损伤中的作用
  • 批准号:
    7477660
  • 财政年份:
    2007
  • 资助金额:
    $ 23.03万
  • 项目类别:
Early events during infection with anthrax
炭疽感染期间的早期事件
  • 批准号:
    7028848
  • 财政年份:
    2005
  • 资助金额:
    $ 23.03万
  • 项目类别:
Early events during infection with anthrax
炭疽感染期间的早期事件
  • 批准号:
    6873824
  • 财政年份:
    2005
  • 资助金额:
    $ 23.03万
  • 项目类别:

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金黄色葡萄球菌VraSR及VraSR调控基因表达分析
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