Developing an inactivated whole cell H. pylori vaccine

开发灭活的全细胞幽门螺杆菌疫苗

• 批准号: 7110186
• 负责人: GARY S NABORS
• 金额: $ 10.55万
• 依托单位: EMERGENT PRODUCT DEVELOPMENT GAITHERSBUR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110186
• 关键词: Helicobacter; T lymphocyte; adult human (21+); bacterial vaccines; cancer prevention; clinical trial phase I; cooperative study; dosage; flow cytometry; gastric mucosa; gastrointestinal infection; genetically modified animals; human subject; immunologic assay /test; immunomodulators; infection related neoplasm /cancer; laboratory mouse; lyophilization; patient oriented research; peptic ulcer; pharmacokinetics; stomach neoplasms; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): Currently there exists no vaccine 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. Clearly 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. Pre-clinical studies have suggested that vaccination could not only prevent infection, but could also be used to resolve active infections. An effective vaccine may also protect against re-infection as well as be an impediment to transmission in at-risk populations. Antex Biologics is an industry leader in H. pylori vaccine development, and is committed to bringing an H. pylori vaccine to the market. The company has performed two Phase 1 clinical trials with a formalin-inactivated Helicobacter pylori Whole Cell (HWC) vaccine, which was given orally in combination with the adjuvant mLT(R192G), a mutant of E. coli heat-labile toxin. Pre-clinical results suggest that the use of an adjuvant with HWC is required for vaccine efficacy. In an effort to bring to market an optimally safe, stable, and potent vaccine, we propose in this application to evaluate clinically two new aspects of the vaccine formulation, namely 1) a lyophilized rather than liquid active ingredient (HWC), and 2) a novel double mutant form of LT (dmLT) that has reduced enterotoxic activity compared to the single mutant mLT(R192G), yet retains full adjuvant activity. The lyophilization process for HWC will be selected based upon in vitro testing of the product for characteristics such as moisture content and reconstitution behavior, and in vivo based upon animal immunization and challenge experiments. The final formulation selected will be used to advance understanding of the vaccine mechanism of action through the use of CD4, antibody, and IFN-gamma knockout mouse studies, and flow cytometric studies examining the nature of the gastric T cell infiltrate in vaccinated and challenged mice. cGMP lots of lyophilized HWC and dmLT will be produced and a Phase 1 dose escalation safety trial in uninfected and infected, asymptomatic subjects will be performed. Because dmLT has yet to be evaluated clinically, the maximum tolerable dose of dmLT alone will be determined first in both populations. Following dmLT dose selection, the maximum tolerable dose of lyophilized and reconstituted HWC in the context of a fixed dose of dmLT will then be determined, again in both populations. Diarrhea is the most likely adverse event that will define tolerance limits. A panel of immunological tests will be performed on subjects receiving the full vaccination series with HWC + dmLT, including serum and mucosal antibodies to HWC and dmLT, and PBMC proliferation and cytokine production in response to restimulation with H. pylori lysate. Diagnostic testing will also be performed on infected subjects post-vaccination to assess changes in their colonization state. This trial will position the vaccine for more highly powered Phase 1 or early Phase 2 trials, and thus will move H. pylori vaccination one step closer to being a reality.

描述（由申请人提供）： 目前，尚无疫苗可预防普遍存在的胃部病原体幽门螺杆菌感染，且该感染的药物治疗由于患者依从性差、治疗费用高且对耐药菌株无效而变得复杂。显然，需要新的医学进步来降低消化性溃疡病和胃癌的发病率，这两种疾病都是由幽门螺杆菌感染引起的。临床前研究表明，疫苗接种不仅可以预防感染，还可以用于解决活动性感染。有效的疫苗还可以防止再次感染，并阻止高危人群中的传播。 Antex Biologics 是幽门螺杆菌疫苗开发的行业领导者，致力于将幽门螺杆菌疫苗推向市场。该公司已使用福尔马林灭活幽门螺杆菌全细胞 (HWC) 疫苗进行了两项 1 期临床试验，该疫苗与佐剂 MLT(R192G)（一种大肠杆菌不耐热毒素突变体）口服组合。临床前结果表明，需要使用 HWC 佐剂才能发挥疫苗功效。为了将最安全、稳定和有效的疫苗推向市场，我们建议在本申请中对疫苗配方的两个新方面进行临床评估，即 1) 冻干而非液体活性成分 (HWC)，以及 2) 新型双突变形式 LT (dmLT)，与单突变 mLT(R192G) 相比，其肠毒性活性降低，但保留了完整的活性成分。 辅助活性。 HWC 的冻干工艺将根据产品的水分含量和重构行为等特性的体外测试以及基于动物免疫和攻击实验的体内测试来选择。最终选定的配方将用于通过使用 CD4、抗体和 IFN-γ 敲除小鼠研究以及检查接种疫苗和受攻击小鼠胃 T 细胞浸润性质的流式细胞术研究来加深对疫苗作用机制的了解。将生产 cGMP 批次的冻干 HWC 和 dmLT，并将在未感染和感染、无症状受试者中进行一期剂量递增安全试验。由于 dmLT 尚未进行临床评估，因此将首先确定两个人群中单独使用 dmLT 的最大耐受剂量。选择 dmLT 剂量后，将再次在两个群体中确定固定剂量 dmLT 背景下冻干和重构 HWC 的最大耐受剂量。腹泻是最有可能定义耐受限度的不良事件。将对接受 HWC + dmLT 全面疫苗接种系列的受试者进行一组免疫学测试，包括针对 HWC 和 dmLT 的血清和粘膜抗体，以及响应幽门螺杆菌裂解物再刺激的 PBMC 增殖和细胞因子产生。疫苗接种后还将对受感染的受试者进行诊断测试，以评估其定植状态的变化。该试验将使该疫苗能够进行更高效的第一阶段或早期第二阶段试验，从而使幽门螺杆菌疫苗接种更接近现实。

项目成果

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.

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
• 发表时间: 2010
• 期刊: Vaccine
• 影响因子: 5.5
• 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
• 通讯作者: Nabors,GaryS