Live Attenuated Oral Anthrax Vaccine

描述（由申请人提供）：疫苗是一种经证明有效的方法，可确保在生物恐怖主义袭击之前或之后立即对大量人群进行广泛保护。我们的目标是解决目前由生物恐怖主义威胁引起的两个重大问题：（1）需要一种简单的大规模疫苗接种方法;（2）目前的炭疽疫苗（NIAID“A类”制剂）的缺点，它需要针头和卫生专业人员进行接种，延长疫苗接种时间表以提供保护（18个月内接种6剂），以及对不良反应的关注。为了应对这一挑战，我们利用现有活的口服伤寒沙门氏菌Ty 21 a疫苗的广泛安全性记录，将其用作载体来开发稳定表达rPA的活的口服疫苗载体。我们假设Ty 21 a是一种合适的疫苗载体，用于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配制成安全、稳定和高度免疫原性的疫苗，并且可以容易地口服给药。当前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耐药基因），并在构建遗传种子库和小规模（5-10 L）生产和冻干之前对候选物进行全面表征（遗传学和微生物学）。最后，将在炭疽病小鼠模型中研究候选物的遗传稳定性、安全性、免疫原性和有效性。第一阶段SBIR的成功完成将为第二阶段建议中的口服炭疽疫苗的开发提供基础，并为针对多种其他传染性病原体的口服疫苗的平台技术提供基础。 公共卫生相关性：炭疽细菌产生孢子，可以被加工成容易通过空气传播。疫苗是确保在生物恐怖主义袭击之前或之后立即为大量人口提供广泛保护的经证明有效的方法。我们的目标是解决目前由生物恐怖主义威胁引起的两个重大问题：（1）需要一种简单的大规模疫苗接种方法;（2）目前的炭疽疫苗（NIAID“A类”制剂）的缺点，它需要针头和卫生专业人员进行接种，延长疫苗接种时间表以提供保护（18个月内接种6剂），以及对不良反应的关注。此外，我们假设这种疫苗可以配制成安全、稳定和高度免疫原性的疫苗，最终可以很容易地口服给药。

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.