Live Attenuated Bacterial Vaccines Against Plaque

描述（由申请人提供）：虽然新的治疗干预和被动免疫将在生物防御中发挥重要作用，但对于主要威胁的预先存在的免疫力没有替代品。不幸的是，对于大多数传染性病原体，目前不可行提供引起足够保护的疫苗的快速施用。此外，任何免疫接种计划都应该具有高水平的安全性和公众接受度。我们设想了一种包括减毒活肠道细菌疫苗的应对策略。这些疫苗将是非常安全的，并会引起粘膜和全身反应。单靠它们就可以保护许多暴露于生物攻击的人，也许在免疫后一周内。那些受到充分保护的人可能是那些经历小的自然暴露水平的人，例如处理受污染邮件的邮政工人。然而，预计一些受害者可能会接触到超正常的接种物，可能是通过气溶胶或胃肠道途径。对于这些个体，保护性疫苗接种方案可以包括用粘膜剂引发，然后用胃肠外施用的亚单位疫苗按需加强。在加强免疫后，预期接受者将产生快速、有力、平衡的免疫应答，这将在粘膜水平上并通过Th 1和Th 2系统组分保护它们。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针对炭疽和鼠疫的保护，并结合载体本身提供的针对伤寒的保护。炭疽/鼠疫产品开发计划的这一部分侧重于鼠疫组分的开发。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有效的候选疫苗。这项工作将分四个阶段进行：第一阶段。最终研制出人类可用的疫苗。这将包括在不存在抗生素选择（目前被FDA禁止）的情况下稳定异源抗原表达质粒。第二阶段。证明在第1阶段构建的候选疫苗的免疫原性。将在我们的标准化小鼠模型中测试构建体以诱导血清IgG。第三阶段在鼠疫气溶胶激发模型中证明最终的人用候选疫苗的有效性。这些研究将由Battelle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前数据包的准备、IND前会议、临床申办者的正式支持以及FDA在IND前会议中要求的所有研究的执行。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.