Recombinant Attenuated Bacterial Vaccines Against Biodefense Agents

描述(由申请人提供)：我们提议进行实验，以确定所有安全性、有效性和免疫原性特征，并提供数据以获得FDA的IND许可证，用于第一阶段临床试验，测试重组减毒鼠伤寒沙门氏菌、副伤寒A和伤寒疫苗分别预防沙门氏菌诱导的胃肠炎、肠热病和伤寒，并使用这些相同的减毒载体传递额外的保护性抗原，以对抗所有致病耶尔森菌种、所有志贺氏菌属和血清型以及大多数大肠杆菌EPEC和ExPEC病毒型。我们亦建议进行同一系列的研究，以便使用最近发展的沙门氏菌疫苗传递流感抗原，以诱导对所有流感病毒类型的长期保护性细胞免疫和抗体反应，以及通过新构建的有效DNA疫苗传递系统传递的针对HA抗原的特定类型免疫。减毒和抗原传递手段基于许多创新的新发现/开发的策略，这些策略存在于三种不同的重组减毒伤寒沙门氏菌疫苗载体中，目前正在进行一项比较的I期临床试验。在这项双盲试验中，没有不良反应，没有阳性血培养，也没有疫苗在剂量高达109CGU后在粪便中脱落。这些沙门氏菌载体是一种最有效的佐剂，因为它们可以展示和运送工程配体到各种天然免疫的外部和内部受体，并在所有分泌腺和所有粘膜表面刺激粘膜免疫。这些疫苗的结构可以被迅速改变和验证，以在两到三周内提供或导致新的保护性抗原的合成，并且可以经济高效地快速生产数百万或数十亿剂，作为一种耐热疫苗，可以储存起来，以便在任何紧急情况下快速部署。我们将制作所有候选疫苗的主种子，验证它们的效力、安全性、遗传纯度和稳定性，并修改我们与FDA的主文件，以包括这些新疫苗构建的结构和特性的所有信息。

DESCRIPTION (provided by applicant): We propose to conduct experiments to establish all safety, efficacy and immunogenicity features and provide data to secure IND licenses from FDA for Phase I clinical trials to test recombinant attenuated Salmonella Typhimurium, Paratyphi A and Typhi vaccines to prevent Salmonella-induced gastroenteritis, enteric fever and typhoid fever, respectively, and using these same attenuated vectors to deliver additional protective antigens to protect against all pathogenic Yersinia species, all Shigella species and serotypes and most Escherichia coli EPEC and ExPEC pathovars. We also propose to conduct the same series of studies to enable use of a recently developed Salmonella vaccine to deliver influenza antigens to induce long-term protective cellular immunity and antibody responses to all influenza virus types and type-specific immunity against HA antigens delivered by a newly constructed efficacious DNA vaccine delivery system. The means of attenuation and antigen delivery are based on many innovative newly discovered/developed strategies that are present in three different recombinant attenuated S. Typhi vaccine vectors currently being evaluated in a comparative Phase I clinical trial. In this double-blinded trial, there have been no adverse events, no positive blood cultures and no shedding of vaccine in stools after doses of up to 109 CGU. These Salmonella vectors constitute a most effective adjuvant due to display and delivery of engineered ligands to various innate immunity external and internal receptors and stimulate mucosal immunity in all secretory glands and on all mucosal surfaces. These vaccine constructions can be rapidly altered and verified to deliver or cause synthesis of new protective antigens in two to three weeks and can be cost effectively rapidly manufactured in millions or billions of doses as a thermostable vaccine that can be stockpiled for rapid deployment in any emergency. We will make Master Seeds of all candidate vaccines, validate their potency, safety, genetic purity and stability and amend our Master File with FDA to include all information on the construction and properties of these new vaccine constructions.