Recombinant Attenuated Bacterial Vaccines Against Biodefense Agents

描述（由申请人提供）：我们建议开展实验，以确定所有的安全性、有效性和免疫原性特征，并提供数据，以获得FDA的I期临床试验IND许可，分别测试重组减毒鼠伤寒沙门菌、甲型副伤寒沙门菌和伤寒沙门菌疫苗，以预防沙门氏菌引起的胃肠炎、肠热和伤寒，并使用这些减毒载体提供额外的保护性抗原，以保护所有致病性耶尔森氏菌。所有志贺氏菌种和血清型以及大多数大肠埃希菌EPEC和ExPEC病原体。我们还建议进行相同系列的研究，以利用最近开发的沙门氏菌疫苗递送流感抗原，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，以及针对新构建的有效DNA疫苗递送系统递送的HA抗原的类型特异性免疫。衰减和抗原递送的手段基于许多新发现/开发的创新策略，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，目前正在一项比较I期临床试验中进行评估。在这项双盲试验中，在高达109 CGU的剂量后，没有出现不良事件，没有血液培养阳性，也没有在粪便中脱落疫苗。这些沙门氏菌载体构成了一种最有效的佐剂，因为它可以将工程配体展示和递送到各种先天免疫的外部和内部受体上，并刺激所有分泌腺和所有粘膜表面的粘膜免疫。这些疫苗结构可以快速改变和验证，在两到三周内提供或合成新的保护性抗原，并且可以经济有效地以数百万或数十亿剂量快速生产，作为可储存以在任何紧急情况下快速部署的耐热疫苗。我们将制作所有候选疫苗的主种子，验证其效力、安全性、遗传纯度和稳定性，并向FDA修改我们的主文件，以包括有关这些新疫苗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.