Fast-Track Production of a Heptavalent Botulinum Vaccine

描述(由申请人提供)： 肉毒杆菌神经毒素是一种NIAID A类毒剂，已被武器化，因此迫切需要一种安全、有效的疫苗来预防所有七种已知的毒素血清型。该项目的两个具体目标是：第一，(在一至两年内)快速开发一种安全有效的神经毒素五价疫苗，该疫苗将对A、B、C、E和F型毒素提供免疫保护；第二，在五年内开发一种完全保护性的七价疫苗，包括D型和G型。该项目的合作伙伴包括工业界(dyport Vaccine Company LLC：DVC)、学术界(内布拉斯加州大学林肯分校：UNL和科罗拉多大学健康科学中心：UC-HSC)和军方(美国陆军传染病医学研究所：USAMRIID)的代表。我们将采取的实现这些目标的方法是基于在巴斯德毕赤酵母中成功开发和表达血清特异性毒素重链蛋白片段，当对实验动物进行纯化和应用时，该片段可提供保护性免疫，以抵御致命剂量的肉毒杆菌神经毒素的攻击。针对A型和B型的单价候选疫苗已经在目前的良好制造规范中试生产，而针对C型、E型和F型的候选疫苗正处于UNL工艺开发的后期阶段，从而促进了第一个特定目标成功的可能性。为开发针对A、B、C、E和F血清型的候选疫苗而建立的方法提供了丰富的知识体系，为开发针对其余两个血清型(D和G)的等效候选疫苗提供了基础，从而促进了第二个具体目标的实现。UC-HSC将在液体疫苗和冻干疫苗的配制和稳定方面贡献专业知识，这对实现这两个特定目标至关重要。拟议的研究将有很高的成功几率，部分原因是由行业合作伙伴DVC担任牵头机构的高度创新的方法，DVC的商业模式是通过管理和协调科学分包商进行疫苗开发。该项目成功完成的影响将是一种有效的七价疫苗，用于在快速但现实的时间框架内对肉毒神经毒素进行预防性免疫防御，并消除作为大规模杀伤性武器的肉毒毒素。

DESCRIPTION (provided by applicant): Botulinum neurotoxin, an NIAID class A agent, has been weaponized, thus dictating an urgent need for a safe, efficacious vaccine that will protect against all seven known serotypes of the toxin. The two specific aims of this project are first, the fast-track development (within one-to-two years) of a safe and efficacious pentavalent vaccine for the neurotoxin that will provide immunologic protection against toxin serotypes A, B, C, E and F; and second, development of a fully protective heptavalent vaccine to include serotypes D and G within five years. The partners for this project include representatives from industry (DynPort Vaccine Company LLC:DVC), academe (University of Nebraska-Lincoln: UNL and the University of Colorado Health Sciences Center: UC-HSC) and the military (U.S. Army Medical Research Institute of Infectious Diseases: USAMRIID). The approach we will take to achieve these aims is based upon the successful development and expression in the yeast, P. pastoris, of serotype-specific toxin heavy-chain protein fragments, that, when purified and administered to experimental animals, provide protective immunity against challenge with lethal doses of the botulinum neurotoxins. Monovalent vaccine candidates against serotypes A and B are already in current Good Manufacturing Practices pilot production, and vaccine candidates for serotypes C, E and F are in advanced stages of process development at UNL, thus facilitating the likelihood of success of the first specific aim. The methodologies established for development of vaccine candidates against serotypes A, B, C, E and F provide a rich body of knowledge on which the development of equivalent vaccine candidates for the remaining two serotypes (D and G) will be based, thus facilitating accomplishment of the second specific aim. UC-HSC will contribute expertise in formulating and stabilizing both liquid and lyophilized vaccines, essential for the achievement of both specific aims. The proposed research will have a high probability of success, in part, because of the highly innovative approach of having the industry partner, DVC, whose business model is vaccine development through management and coordination of scientific subcontractors, serve as the lead institution. The impact of the successful completion of the project will be an effective heptavalent vaccine for prophylactic immune defense against botulinum neurotoxin within an expedited, but realistic, timeframe and elimination of botulinum toxin as a weapon of mass destruction.