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: 8259119
• 负责人: ROY CURTISS III
• 金额: $ 102.57万
• 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/8259119
• 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（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IND许可，用于I期临床试验，以测试重组减毒鼠伤寒沙门氏菌、甲型副伤寒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来递送另外的保护性抗原，以保护抵抗所有致病性耶尔森氏菌属物种、所有志贺氏菌属物种和血清型以及大多数大肠杆菌EPEC和ExPEC致病变种。我们亦建议进行同一系列的研究，以使最近开发的沙门氏菌疫苗能够输送流感抗原，从而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，以及针对HA抗原的类型特异性免疫，这些免疫是由新构建的有效DNA疫苗输送系统输送的。减毒和抗原递送的手段是基于存在于三种不同的重组减毒链球菌中的许多创新的新发现/开发的策略。伤寒疫苗载体目前正在比较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，没有不良事件，没有阳性血培养，也没有粪便中的疫苗脱落。这些沙门氏菌载体构成了最有效的佐剂，这是由于工程化配体对各种先天免疫外部和内部受体的展示和递送，并刺激所有分泌腺和所有粘膜表面上的粘膜免疫。这些疫苗结构可以快速改变并验证以在两到三周内递送或引起新的保护性抗原的合成，并且可以成本有效地快速制造数百万或数十亿剂量的热稳定疫苗，其可以储存用于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，验证其效力、安全性、遗传纯度和稳定性，并与FDA一起修改我们的主文件，以包括有关这些新疫苗结构和特性的所有信息。