Recombinant Attenuated Bacterial Vaccines Against Biodefense Agents

针对生物防御剂的重组减毒细菌疫苗

• 批准号: 8463108
• 负责人: ROY CURTISS III
• 金额: $ 96.41万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463108
• 关键词: Adjuvant; Adverse event; Antibodies; Antibody Formation; Antigens; Apoptosis; Attenuated; Bacteremia; Bacterial Vaccines; Biological Containment; Blood; Categories; Cell Nucleus; Cellular Immunity; Clinical Trials; Cytolysis; Cytosol; DNA Vaccines; Data; Dose; Double-Blind Method; Emergency Situation; Endosomes; Engineering; Enteral; Equilibrium; Escherichia coli; Exhibits; Feces; Flagellin; Fluids and Secretions; Gastroenteritis; Gene Expression; Genetic; Gland; Government; Hemagglutinin; Human; Human Volunteers; Immunity; Immunization; Immunocompromised Host; Infection; Influenza; Intestines; Intravenous; Legal patent; Licensing; Ligands; Lipid A; Lymphoid Tissue; Mucosal Immunity; Mucous Membrane; Mus; Natural Immunity; Newborn Infant; Oral; Outcome; Pasteurella pseudotuberculosis; Phase I Clinical Trials; Production; Property; Recombinants; Research; Route; Safety; Salmonella; Salmonella Vaccines; Salmonella typhi; Salmonella typhimurium; Secretory Immunoglobulin A; Secure; Seeds; Series; Serotyping; Shigella; Surface; Surface Antigens; System; Testing; Typhoid Fever; Vaccine Design; Vaccines; Vagina; Validation; Viral; Yersinia; Yersinia enterocolitica; Yersinia pestis; attenuation; base; biodefense; comparative; coping; cost; design; design and construction; enteropathogenic Escherichia coli; immunogenicity; improved; in vivo; influenza virus vaccine; influenzavirus; innovation; intraperitoneal; novel; novel vaccines; pathogen; pre-clinical research; preclinical study; pregnant; prevent; receptor; rectal; research clinical testing; research study; vaccine candidate; vaccine delivery; vaccine efficacy; vector; vector vaccine

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.

描述（由申请人提供）：我们建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 I 期临床试验 IND 许可，以测试重组减毒鼠伤寒沙门氏菌、甲型副伤寒疫苗和伤寒疫苗，分别预防沙门氏菌引起的胃肠炎、肠热病和伤寒病，并使用这些减毒疫苗 载体可传递额外的保护性抗原，以预防所有致病性耶尔森菌属、所有志贺氏菌属和血清型以及大多数大肠杆菌 EPEC 和 ExPEC 致病变种。我们还建议进行同一系列的研究，以便能够使用最近开发的沙门氏菌疫苗来传递流感抗原，以诱导针对所有流感病毒类型的长期保护性细胞免疫和抗体反应，以及由新构建的有效DNA疫苗传递系统传递的针对HA抗原的类型特异性免疫。减毒和抗原递送方法基于许多新发现/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，目前正在比较性 I 期临床试验中进行评估。在这项双盲试验中，在剂量高达 109 CGU 后，没有出现任何不良事件，没有出现血培养阳性，也没有疫苗在粪便中脱落。这些沙门氏菌载体构成了最有效的佐剂，因为将工程配体展示和递送到各种先天免疫外部和内部受体，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，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量的热稳定疫苗，并可以储存以便在任何紧急情况下快速部署。我们将为所有候选疫苗制作主种子，验证其效力、安全性、遗传纯度和稳定性，并修改我们与 FDA 的主文件，以包含有关这些新疫苗结构的结构和特性的所有信息。