Live Attenuated Oral Anthrax Vaccine

口服炭疽减毒活疫苗

• 批准号: 8101247
• 负责人: B. KIM LEE SIM
• 金额: $ 30万
• 依托单位: PROTEIN POTENTIAL, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101247
• 关键词: Address; Adverse effects; Aerosols; Anthrax Vaccines; Anthrax disease; Antibiotic Resistance; Antibodies; Attenuated; Bacillus anthracis spore; Bacteria; Biological Assay; Bioterrorism; Categories; Collaborations; Cysteine; DNA Sequence Analysis; Development; Dose; Enzyme-Linked Immunosorbent Assay; Excision; Foundations; Freeze Drying; Genes; Genetic; Glycerol; Goals; Health; Health Professional; Individual; Infectious Agent; Injection of therapeutic agent; Licensing; Life; Mass Vaccinations; Methods; Mus; National Institute of Allergy and Infectious Disease; Needles; O Antigens; Oral; Organism; Phase; Phenotype; Plasmid Cloning Vector; Plasmids; Population; Preparation; Process; Production; Proteins; Recombinant DNA; Refrigeration; Reproduction spores; Route; Safety; Salmonella typhi; Seeds; Self-Administered; Sequence Analysis; Serum; Small Business Innovation Research Grant; Staging; Technology; Tryptophan; Typhoid Fever; Vaccines; Valine; Vial device; anthrax lethal factor; design; immunogenic; immunogenicity; microbial alkaline proteinase inhibitor; mouse model; oral vaccine; plasmid DNA; pressure; protective efficacy; rat Ran 2 protein; respiratory; response; stability testing; vaccination schedule; vaccine candidate; vector; weapons

DESCRIPTION (provided by applicant): Vaccines are a proven and effective approach for assuring widespread protection of large populations prior to or immediately following a bioterrorism attack. Our goal is to address two significant problems currently raised by bioterrorism threats: 1) the need for an easy method of mass vaccination and 2) the shortcomings of the current anthrax vaccine (NIAID "category A" agent) which requires needles and health professionals for administration, an extended vaccination schedule for protection (6 doses over 18 months) and the concern over adverse effects. To address this challenge, we have exploited the extensive safety record of the existing live, oral Salmonella Typhi Ty21a vaccine by utilizing it as a vector to develop a live oral vaccine carrier stably expressing rPA. We hypothesize that Ty21a is a suitable vaccine carrier for the stable expression of the rPA gene harbored on a low copy number plasmid. Further, we hypothesize that this vaccine can be formulated so that it will be safe, stable, and highly immunogenic and can be easily administered orally. The current proposal is aimed at completing the necessary final development steps (e.g. removal of antibiotic resistance gene from vector plasmid) and full characterization (genetic and microbiological) of the candidate prior to constructing a genetic seed bank and small-scale (5-10 liter) manufacture and lyophilization. Finally, the candidate will be studied for genetic stability, safety, immunogenicity and efficacy in a mouse model of anthrax disease. Successful completion of this Phase I SBIR will provide the foundation for development of an oral anthrax vaccine in a Phase II proposal, and for a platform technology for oral vaccines against multiple other infectious agents. PUBLIC HEALTH RELEVANCE: Anthrax bacteria produce spores that can be processed to become easily airborne. Vaccines are a proven and effective approach for assuring widespread protection of large populations prior to or immediately following a bioterrorism attack. Our goal is to address two significant problems currently raised by bioterrorism threats: 1) the need for an easy method of mass vaccination and 2) the shortcomings of the current anthrax vaccine (NIAID "category A" agent) which requires needles and health professionals for administration, an extended vaccination schedule for protection (6 doses over 18 months) and the concern over adverse effects. Further, we hypothesize that this vaccine can be formulated so that it will be safe, stable, and highly immunogenic and ultimately can be easily administered orally.

描述（由申请人提供）：疫苗是一种经过验证的有效方法，可确保在生物恐怖袭击之前或之后对大量人群进行广泛保护。我们的目标是解决目前生物恐怖主义威胁引发的两个重大问题：1）需要一种简单的大规模疫苗接种方法；2）当前炭疽疫苗（NIAID“A 类”制剂）的缺点，需要针头和卫生专业人员来接种。管理、延长疫苗接种计划以提供保护（18 个月内接种 6 剂）以及对不良反应的担忧。为了应对这一挑战，我们利用现有口服伤寒沙门氏菌 Ty21a 活疫苗的广泛安全记录，将其用作载体，开发出稳定表达 rPA 的口服活疫苗载体。我们假设 Ty21a 是一种合适的疫苗载体，可稳定表达低拷贝数质粒上的 rPA 基因。此外，我们假设这种疫苗可以被配制得安全、稳定、具有高免疫原性，并且可以很容易地口服给药。目前的提案旨在完成必要的最终开发步骤（例如从载体质粒中去除抗生素抗性基因）和候选者的全面表征（遗传和微生物），然后再构建遗传种子库和小规模（5-10升） ）制造和冻干。最后，将在炭疽病小鼠模型中研究候选药物的遗传稳定性、安全性、免疫原性和功效。第一阶段 SBIR 的成功完成将为第二阶段提案中口服炭疽疫苗的开发以及针对多种其他传染原的口服疫苗的平台技术奠定基础。 公共卫生相关性：炭疽细菌产生的孢子经过处理后很容易在空气中传播。疫苗是一种经过验证的有效方法，可确保在生物恐怖主义袭击之前或之后对大量人口提供广泛保护。我们的目标是解决目前生物恐怖主义威胁引发的两个重大问题：1）需要一种简单的大规模疫苗接种方法；2）当前炭疽疫苗（NIAID“A 类”制剂）的缺点，需要针头和卫生专业人员来接种。管理、延长疫苗接种计划以提供保护（18 个月内接种 6 剂）以及对不良反应的担忧。此外，我们假设这种疫苗可以被配制得安全、稳定、具有高免疫原性，并且最终可以很容易地口服给药。

项目成果

Protection against inhalation anthrax by immunization with Salmonella enterica serovar Typhi Ty21a stably producing protective antigen of Bacillus anthracis.

通过免疫沙门氏菌伤寒杆菌 Ty21a 稳定产生炭疽杆菌保护性抗原来预防吸入性炭疽。

• 发表时间: 2017
• 影响因子: 9.2
• 作者: Sim, B Kim Lee;Li, Minglin;Osorio, Manuel;Wu, Yun;Wai, Tint T;Peterson, Johnny W;James, Eric R;Chakravarty, Sumana;Gao, Lixin;Xu, Rui;Kc, Natasha;Stafford, Richard E;Lawrence, William S;Yeager, Linsey A;Peel, Jennifer E;Sivasubramani, Sathe
• 通讯作者: Sivasubramani, Sathe