Toward the development of a stable, freeze-dried formulation of Helicobacter pylori killed whole cell vaccine adjuvanted with a novel mutant of Escherichia coli heat-labile toxin.
Toward the development of a stable, freeze-dried formulation of Helicobacter pylori killed whole cell vaccine adjuvanted with a novel mutant of Escherichia coli heat-labile toxin.
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开发一种稳定的冻干幽门螺杆菌灭活全细胞疫苗制剂，辅以大肠杆菌不耐热毒素的新型突变体。
DOI：
10.1016/j.vaccine.2009.10.147
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发表时间：
2010
期刊：
影响因子：
5.5
通讯作者：
Nabors,GaryS
中科院分区：
文献类型：
--
作者：
Summerton,NancyA;Welch,RichardW;Bondoc,Laureano;Yang,Huei-Hsiung;Pleune,Brett;Ramachandran,Naryaswamy;Harris,AndreaM;Bland,Desiree;Jackson,WJames;Park,Sukjoon;Clements,JohnD;Nabors,GaryS
目前还没有预防幽门螺杆菌感染的疫苗，这种感染的药物治疗复杂，患者依从性差，治疗成本高，对耐药菌株无效。需要一项新的医学进步来减少消化性溃疡疾病和胃癌的发生率，这两种疾病是由幽门螺杆菌感染引起的。临床试验是用福尔马林灭活的幽门螺杆菌全细胞(HWC)疫苗与粘膜佐剂MLT(R192G)联合给予的，MLT是大肠杆菌不耐热毒素的突变体。在该疫苗的初始剂量之后，一些受试者出现了胃肠道副作用。为了减少副作用并潜在地进一步增加HWC疫苗可以安全注射的佐剂数量，我们对一种携带A亚单位两个突变的LT进行了实验，在第192位用G替换R，在第211位用A替换L。双突变体LT(DmLT)佐剂与单突变体LT一样有效地刺激小鼠的免疫反应。此外，在挑战感染后，dmLT佐剂疫苗在降低胃尿素酶水平(对幽门螺杆菌感染的诊断)和通过胃匀浆定量分析评估幽门螺杆菌在胃中的定植方面与单一突变体LT同样有效。开发了一种HWC的冷冻干燥配方，以提高稳定性并潜在地减少对冷链维护的依赖。通过胃尿素酶分析和胃匀浆对幽门螺杆菌活菌的分析，观察到dmLT佐剂冻干疫苗在小鼠模型中与液体制剂具有同样的保护作用。在评估的配方限度内，没有观察到冻干疫苗的紧张性或水分含量的容易检测的效果。在37℃下进行的加速稳定性研究中，冻干疫苗仍然与在2-8℃下储存的疫苗具有同等的保护作用。临床开发所选的配方由每毫升2.5×1010个福尔马林灭活细胞在6.5%海藻糖、0.5%甘露醇和10 mM柠檬酸缓冲液(pH 6.8)中组成。
No vaccine exists for the prevention of infection with the ubiquitous gastric pathogen Helicobacter pylori, and drug therapy for the infection is complicated by poor patient compliance, the high cost of treatment, and ineffectiveness against drug-resistant strains. A new medical advancement is required to reduce the incidence of peptic ulcer disease and stomach cancer, two conditions caused by infection with H. pylori. Clinical trials have been performed with a formalin-inactivated H. pylori whole cell (HWC) vaccine, given orally in combination with the mucosal adjuvant mLT(R192G), a mutant of Escherichia coli heat-labile toxin. Following the initial dose of this vaccine, some subjects experienced gastrointestinal side effects. To reduce side effects and potentially further increase the amount of adjuvant that can safely be administered with the HWC vaccine, experiments were performed with a form of LT that carried two mutations in the A subunit, a substitution of G for R at position 192, and A for L at position 211. The double mutant LT (dmLT) adjuvant stimulated immune responses as effectively as the single mutant LT in mice. Additionally, following a challenge infection, the dmLT-adjuvanted vaccine was as effective as single mutant LT in reducing gastric urease levels (diagnostic for H. pylori infection), and H. pylori colonization in the stomach as assessed by quantitative analysis of stomach homogenates. A lyophilized formulation of HWC was developed to improve stability and to potentially reduce reliance on cold chain maintenance. It was observed that a dmLT-adjuvanted lyophilized vaccine was equally as protective in the mouse model as the liquid formulation as assessed by gastric urease analysis and analysis of stomach homogenates for viable H. pylori. No readily detectable effect of tonicity or moisture content was observed for the lyophilized vaccine within the formulation limits evaluated. In an accelerated stability study performed at 37°C the lyophilized vaccine remained equally as protective as vaccine stored at 2–8°C. The formulation selected for clinical development consisted of 2.5×1010formalin-inactivated cells per ml in 6.5% trehalose, 0.5% mannitol, and 10mM citrate buffer at pH 6.8.
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成功免疫螺杆菌属胃部感染：使用霍乱毒素 B 亚基全细胞疫苗
影响因子：
3.1
作者：
Adrian K. C. Lee;Minhui Chen
通讯作者：
Minhui Chen
DOI：
10.1086/513791
发表时间：
1997
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Daniel A. Scott
通讯作者：
Daniel A. Scott
影响因子：
5.5
作者：
BAQAR, S;BOURGEOIS, AL;PAVLOVSKIS, OR
通讯作者：
PAVLOVSKIS, OR
影响因子：
5.5
作者：
G. Losonsky;K. Kotloff;R. Walker
通讯作者：
G. Losonsky;K. Kotloff;R. Walker
幽门螺杆菌的患病率/疾病相关性
影响因子：
7.6
作者：
J. Lambert;S. K. Lin
通讯作者：
S. K. Lin