Live Attenuated Bacterial Vaccines Against Plaque

描述（由申请人提供）：尽管新的治疗干预和被动免疫将在生物防御中发挥至关重要的作用，但对主要威胁的预先免疫是不可替代的。不幸的是，对于大多数传染性病原体，目前还无法提供快速接种疫苗以获得充分保护。此外，任何免疫规划都应具有高度的安全性和公众接受度。我们设想一种应对策略，包括减毒肠道细菌活疫苗。这些疫苗将是非常安全的，并且会引起粘膜和全身反应。单独使用它们，可能在接种疫苗的一周内，就能保护许多遭受生物攻击的人。那些受到充分保护的人可能是那些接触到少量自然辐射的人，比如处理受污染邮件的邮政工人。然而，预计一些受害者将暴露于超正常的接种，可能是通过气溶胶或胃肠道途径。对于这些个体，保护性的疫苗接种方案可以包括用粘膜剂启动，然后按需注射注射亚单位疫苗。在增强后，接受者将有望产生快速，有力，平衡的免疫反应，这将在粘膜水平上通过Th1和Th2系统成分保护他们。该申请要求支持基于沙门氏菌的平台技术的最终临床前开发，其最终目的是在单一疫苗中提供对炭疽和鼠疫的保护，并结合媒介本身提供的对伤寒的保护。炭疽/鼠疫产品开发计划的这一部分侧重于鼠疫成分的开发。在该奖项结束时，我们将准备进行临床试验，预计将产生临床和经济上有效的候选疫苗。这项工作将分四个阶段进行：第一阶段。人类疫苗的最终构建。这将包括在没有抗生素选择的情况下稳定外源抗原表达质粒（目前被FDA禁止）。阶段2。在第一阶段构建的候选疫苗的免疫原性证明。构建体将在我们的标准化小鼠模型中进行诱导血清IgG的测试。阶段3。在鼠疫气溶胶攻毒模型中证明最终的人用候选疫苗的有效性。这些研究将在巴特尔通过分包合同进行。第四阶段。进行临床前研究并制定临床计划。这将包括ind前包的准备，ind前会议，临床申办者的正式支持，以及FDA在ind前会议中授权的所有研究的表现。在该奖项结束时，我们将准备启动一种或多种候选疫苗的临床试验。

DESCRIPTION (provided by applicant): Though novel therapeutic interventions and passive immunization will have vital, roles to play in biodefense, there is no substitute for pre-existing immunity to the major threats. Unfortunately, for most infectious agents it is not currently feasible to provide rapid administration of vaccines that elicit adequate protection. Moreover, any immunization program should have both a high level of safety and public acceptance. We envision a response strategy that includes live attenuated enteric bacterial vaccines. These vaccines would be very safe, and would elicit both mucosal and systemic responses. Alone, they would protect many exposed to bioattack, perhaps within one week of immunization. Those adequately protected would likely be those experiencing small, natural levels of exposure, such as postal workers handling contaminated mail. However, it is anticipated that some victims would be exposed to a supra-normal inoculum, presumably by the aerosol or gastrointestinal route. For these individuals, a protective vaccination regimen could include priming with the mucosal agent, followed by on-demand boosting with a parenterally administered subunit vaccine. After boosting, the recipients would be expected to generate fast, vigorous, balanced immune responses, which would protect them at the level of the mucosa and via both Th1 and Th2 systemic components. This application requests support for final pre-clinical development of a Salmonella-based platform technology, the ultimate intent of which is to provide protection against anthrax and plague in a single vaccine, combined with protection against typhoid fever provided by the vector itself. This portion of the anthrax/plague product development plan focuses on development of the plague component. By the conclusion of this award, we will be ready for clinical trials which are expected to result in clinically and economically effective vaccine candidates. This work will be pursued in four phases: Phase 1. Final construction of a human-ready vaccine. This will include stabilization of the heterologous antigen expression plasmid in the absence of antibiotic selection (currently forbidden by the FDA). Phase 2. Demonstration of immunogenicity of the vaccine candidates constructed under Phase 1. Constructs will be tested in our standardized mouse model for induction of serum IgG. Phase 3. Demonstration of efficacy of the final human-ready vaccine candidate in aerosol challenge models of plague. These studies will be performed by subcontract at Battelle. Phase 4. Perform preclinical studies and develop a clinical plan. This will include preparation of the pre-IND packet, the pre-IND meeting, formalizing support from the clinical sponsor, and performance of all studies mandated by the FDA in the pre-IND meeting. By the conclusion of this award, we will be prepared to initiate clinical trials of one or more vaccine candidates.