Live Vector Vaccines Against Agents of Bioterror

描述（由申请人提供）：美国正处于生物攻击的真实威胁之下。虽然人们早就知道我们的敌人有能力进行生物攻击，但直到2001年9月以后，人们才清楚地认识到这种威胁是真实的。不幸的是，美国在应对生物攻击方面毫无准备。虽然快速识别释放剂、新的治疗干预措施和被动免疫将在生物防御中发挥重要作用，但对主要威胁的预先免疫是不可替代的。这种免疫既可以在这些剂释放之前提供，也可以在发现释放后不久提供。不幸的是，对于大多数传染因子，目前无法提供同样快速保护的疫苗的快速施用。此外，至关重要的是要确保任何免疫规划都具有高水平的安全性和公众接受度。因此，我们设想一种应对策略，其中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。只需注射一剂，就能保护许多受到生物攻击的人，并在一周内进行免疫接种。受保护的可能是那些接触到少量或自然水平辐射的人，比如处理受污染邮件的邮政工人。然而，预计一些受害者将接触到超正常的疫苗，通常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包括用粘膜剂启动，然后按需加强注射亚单位疫苗。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。这个U19将结合马里兰大学学校疫苗开发中心和化学和生物防御中心在开发针对炭疽、鼠疫和肉毒杆菌中毒的肠道疫苗方面的丰富经验。开发的产品将在动物身上进行测试，并确定初始增强反应的特征。在合同期限内，我们将生产一系列候选疫苗，立即进行1期人体试验。

DESCRIPTION (provided by applicant): The United States is under a genuine threat of biological attack. Whereas it has long been known that our enemies were capable of biological assault, only since September 2001 has it become clear that this threat is real. Unfortunately, the US is woefully unprepared to respond to biological attack. While rapid identification of released agents, 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. This immunity can either be provided before such agents are released, or can be provided soon after release has been detected. Unfortunately, for most infectious agents it is not currently feasible to provide rapid administration of vaccines that provide equally rapid protection. Moreover, it will be vital to ensure that any immunization program have both a high level of safety as well as public acceptance. We therefore envision a response strategy which includes live attenuated enteric bacterial vaccines. These vaccines would be very safe, and would elicit both mucosal and systemic responses. After just a single dose, they would protect many exposed to bioattack, and within one week of immunization. The protected would likely be those exposed to small or natural levels of exposure, such as postal workers handling contaminated mail. However, it is anticipated that some victims would be exposed to supra-normal inocula, typically by the aerosol or gastrointestinal routes. For these individuals, a protective vaccination regimen could include priming with the mucosal agent, followed by on-demand boosting with 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 U19 will combine the vast experience of the University of Maryland School Center for Vaccine Development and the Chemical and Biological Defence Center, Porton Down in the development of enteric vaccines against anthrax, plague and botulism. The products developed will be tested in animals and the characteristics of prime-boost responses determined. During the term of the award, we will generate a series of vaccine candidates for immediate Phase 1 human trials.