New genetic vaccine to protect aganist botulism

描述（由申请人提供）：肉毒中毒是由七种肉毒杆菌神经毒素（BoNTs）之一引起的严重神经麻痹疾病，由厌氧芽孢形成细菌肉毒梭菌产生。这些蛋白质神经毒素是人类已知的最有效的毒素。目前有BoNT类毒素疫苗作为研究新药。然而，由于与类毒素疫苗相关的许多缺点（即生产危险、制造成本高、高反应原性），迫切需要开发新一代预防肉毒杆菌中毒的疫苗。本研究的目的是利用bont重链的羧基末端50 kDa c片段（Hc）作为抗原，开发一种新的肉毒杆菌中毒疫苗，并研究利用复制缺陷腺病毒载体通过鼻内和经皮途径给药。这些非侵入性的疫苗递送方法无疑将提高疫苗接种计划的依从性，这对于应对使用bont的潜在生物恐怖袭击尤其重要。在构建了复制缺陷腺病毒载体，编码bont重链的免疫原性c片段后，将研究小鼠的疫苗接种方案，比较鼻内和经皮递送方式与皮下注射目前可用的五价肉毒杆菌类毒素疫苗（PBT）。该项目的具体目标是：

DESCRIPTION (provided by applicant): Botulism is a severe neuroparalytic disease caused by one of seven botulinum neurotoxins (BoNTs), produced by the anaerobic, spore-forming bacterium Clostridium botulinum. These protein neurotoxins are the most potent toxins known to man. There are BoNT toxoid vaccines available currently as Investigational New Drugs. However, due to the numerous shortcomings associated with the toxoid vaccines (i.e., dangerous to produce, high cost of manufacturing, high reactogenicity), there is an urgent need to develop new generation vaccines for the prevention of botulism. The goals of this research are to develop a new botulism vaccine using the carboxyl-terminal 50 kDa C-fragments (Hc) of the heavy chains in BoNTs as antigens and to study the delivery of the vaccine utilizing a replication-defective adenoviral vector via the intranasal and transcutaneous routes. These non-invasive vaccine delivery methods will undoubtedly enhance the compliance of a vaccination program, which is especially critical in response to a potential bioterrorist attack using BoNTs. After construction of replication-defective adenoviral vectors encoding the immunogenic C-fragments of the heavy chains in BoNTs, vaccination protocols in mice comparing the intranasal and transcutaneous delivery modes with the subcutaneous injection of the currently available pentavalent botulinum toxoid vaccine (PBT) will be studied. The specific aims of this project are: Specific Aim #1: To construct replication-defective adenoviral vectors encoding the C-fragments of the heavy chains in BoNTs. Specific Aim #2: To study the mucosal and systemic immunity elicited by the vectored vaccine developed in aim #1 through intranasal and transcutaneous immunization in a mouse model.