Development of a mucosally administered trivalent serotype A,B, E botulinum va

描述（由申请人提供）：由于其高效力和用作生物武器的潜力，肉毒杆菌毒素被列为A类生物威胁。由于没有FDA批准的疫苗，因此快速开发可用于攻击事件的疫苗是一个高度优先事项。我们的I期项目的总体目标是开发口服给药的多价血清型A、B和E肉毒杆菌疫苗。我们已经发现，当口服给药时，血清型A和B的HC 50分别诱导针对高水平攻击的免疫。口服疫苗接种的基础是每种毒素血清型（Hc50或片段C）重链羧基末端50%结合并穿过肠上皮细胞并进入血液和淋巴循环的固有性质。 具体而言，在目标1中，我们将确定HC 50血清型E作为粘膜免疫原的能力。在具体目标2中，我们将制备三价A、B和E疫苗，并在小鼠中测试当通过鼻内途径粘膜给予疫苗时疫苗诱导的保护性免疫。在具体目标3中，我们计划对大鼠进行口服免疫，并确定三价疫苗是否可以诱导保护性免疫，以确定免疫持续时间以及与佐剂注射疫苗相比免疫应答的稳健性。还将讨论通过鼻内或口服途径接种疫苗预期产生的粘膜免疫的其他成分。以多聚分泌伊加形式存在的粘液免疫可通过在毒素进入全身循环之前灭活一部分毒素来提供额外水平的保护以对抗毒素暴露。可以通过粘膜施用，特别是通过口服途径施用的肉毒杆菌毒素的疫苗预期具有优于注射对应物的几个优点。由于疫苗可以在没有受过训练的人员的情况下接种，它将避免使用侵入性针头和相关的疼痛。预期这将为最终用户带来更大的依从性和便利性，并有可能在传统诊所或医生办公室之外传播疫苗进行接种，从而有可能快速实施预防性疫苗接种计划。I期工作的最终结果将是鉴定血清型A、B、E的有效粘膜组合疫苗。 在II期，该项目将涉及1）提高性能的配方研究，2）在其他动物模型中研究疫苗，3）更好地表征三价疫苗的生产工艺。在第二阶段结束时，我们预计已经确定了一种疫苗，以推进临床研究。

DESCRIPTION (provided by applicant): Botulinum toxin is classified as a category A biothreat due to its high potency and the potential to be used as a bioweapon. Because there is no FDA-approved vaccine, there is a high priority in rapid development of a vaccine that can be used in the event of an attack. The overall goal of our Phase I project is to develop an orally administered multivalent serotype A, B, and E botulinum vaccine. We have discovered that Hc50 of serotypes A and B individually induce immunity against high level challenge when administered orally. The basis for oral vaccination is the inherent property of the carboxyl terminal 50% of the heavy chain of each of the serotypes of the toxin (Hc50 or fragment C) to bind and to cross intestinal epithelial cells and enter blood and lymphatic circulation. Specifically, in aim 1, we will determine the capacity of Hc50 serotype E to act as a mucosal immunogen. In specific aim 2, we will make the trivalent A, B, and E vaccine and test the vaccine in mice for induction of protective immunity when the vaccine is given mucosally by the intranasal route. In specific aim 3, we plan to immunize rats orally and determine whether the trivalent vaccine can induce protective immunity, to determine the duration of immunity, and the robustness of the immune response in comparison to injected vaccine given with an adjuvant. The additional component of mucosal immunity, which is expected from the application of the vaccine by the intranasal or oral route will also be addressed. Mucosal immunity in the form of polymeric secretory IgA may provide an additional level of protection against toxin exposure by inactivating a portion of it before it crosses into general circulation. A vaccine for botulinum toxin that can be administered mucosally, especially by the oral route, is expected to have several advantages over an injected counterpart. As the vaccine can be given without trained personnel, it will avoid the use of invasive needles and the associated pain. This is expected to result in greater compliance and convenience for the end user and the possibility of disseminating the vaccine outside of the traditional clinic or doctor's office setting for vaccination, resulting in the possibility of rapid implementation of a preventive vaccination program. The end result of Phase I work will be the identification of an effective mucosal combination vaccine for serotypes A, B, E. In Phase II, the project will involve 1) formulation studies to improve performance, 2) study of the vaccine in additional animal models, and 3) greater characterization of processes for making the trivalent vaccine. At the end of Phase II, we expect to have identified a vaccine to advance to clinical studies.