Vaccines Against Botulism

 描述（由申请人提供）：肉毒杆菌神经毒素（BoNT）是已知对人类毒性最大的蛋白质，也是肉毒杆菌中毒的病原体。BoNT被组织成三个结构域，涉及催化（LC）、易位（HCT）和受体结合（HCR）。目前存在八种BoNT血清型（A-H），其基于抗每种BoNT血清型的抗-血清的有限交叉血清型保护。目前，没有针对肉毒杆菌中毒的许可疫苗，并且之前从CDC获得的用于高危人群的实验性五血清型类毒素疫苗于2011年停止使用。因此，需要开发针对所有BoNT血清型的强效且有效的BoNT疫苗，以保护处于危险中的人免于暴露，包括处于危险中的平民、第一反应者、军队和研究人员。产生新BoNT疫苗的几种方法尚未产生疫苗产品。通过Barbieri和约翰逊实验室之间的合作开发的两种已发表的针对肉毒杆菌中毒的疫苗方法包括保护免受七种BoNT血清型攻击的HCR亚单位疫苗和保护免受BoNT/A攻击的全长无毒性BoNT（M-BoNT）疫苗。HCR是大量生产的稳定产品，无毒，不受Select Agent监管，因此使产品开发简单明了。本研究的目的是优化HCR和M-BoNT疫苗平台，以产生针对食源性和吸入性肉毒杆菌中毒的泛BoNT保护性疫苗。假设是，与类毒素疫苗相比，已经突变以消除细胞结合和催化活性的天然BoNT或HCR衍生物将提高针对所有BoNT血清型的疫苗效力，同时提高安全性并减少疫苗副作用。具体目标将利用Barbieri和约翰逊实验室的互补研究专长。该目标将使用小鼠攻击模型设计针对肉毒杆菌中毒的泛BoNT血清型保护性疫苗。优化的疫苗将在食物传播和吸入肉毒杆菌中毒模型中进行效力测试。这些研究将产生针对肉毒杆菌中毒的下一代疫苗和对BoNT变体释放的快速反应策略。

 DESCRIPTION (provided by applicant): The botulinum neurotoxins (BoNT) are the most toxic proteins known for humans and the causative agent of botulism. BoNTs are organized into three domains that are involved in catalysis (LC), translocation (HCT), and receptor binding (HCR). There are now eight BoNT serotypes (A-H) based upon limited cross serotype protection of -sera against each BoNT serotype. Currently, there is no licensed vaccine against botulism and the experimental penta-serotype toxoid vaccine previously available from the CDC for at-risk populations was discontinued in 2011. Thus, there is a need to develop a potent and effective BoNT vaccine against all BoNT serotypes to protect at-risk humans from exposure, including civilians in harm's way, first responders, the military, and researchers. Several approaches to generate new BoNT vaccines have not yielded a vaccine product. Two published vaccine approaches against botulism developed through collaborations between the Barbieri and Johnson laboratories include an HCR subunit vaccine that protected against challenge by the seven BoNT serotypes, and a full-length, atoxic BoNT (M-BoNT) vaccine that protected against BoNT/A challenge. HCRs are stable products made in large quantity, are nontoxic and not Select Agent regulated, thus making product development straightforward. The goal of this study is to optimize the HCR and M-BoNT vaccine platforms towards the generation of a pan-BoNT protective vaccine against foodborne and inhalation botulism. The hypothesis is that native BoNT or HCR derivatives that have been mutated to eliminate cell binding and catalytic activity will improve vaccine potency against all BoNT serotypes compared to toxoid vaccines, while enhancing safety and reducing vaccine side effects. The specific aims will utilize the complementary research expertise of both the Barbieri and Johnson laboratories. The aims will engineer a pan-BoNT serotype protective vaccine against botulism, using the mouse challenge model. Optimized vaccines will be tested for potency in food borne- and inhalation- models of botulism. These studies will produce the next generation vaccine against botulism and a strategy for rapid response to the release of BoNT variants.