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NIAID A类制剂，已被武器化，因此迫切需要一种安全有效的疫苗，可以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，快速开发（在一到两年内）安全有效的神经毒素五价疫苗，提供针对毒素血清型A、B、C、E和F的免疫保护;第二，在五年内开发包括血清型D和G的完全保护性七价疫苗。该项目的合作伙伴包括来自行业（DynPort Vaccine Company LLC：DVC）、内布拉斯加大学林肯分校（University of Nebraska-Lincoln：UNL）和科罗拉多大学健康科学中心（University of Colorado：UC-HSC）以及军方（美国陆军传染病医学研究所（U.S. Army Medical Research Institute of Infectious Diseases：USAMRIID）的代表。我们将采取的实现这些目标的方法是基于成功的开发和表达的酵母，巴斯德毕赤酵母，肉毒杆菌型特异性毒素的重链蛋白片段，当纯化和管理的实验动物，提供保护性免疫攻击与致死剂量的肉毒杆菌神经毒素。针对血清型A和B的单价候选疫苗已经在UNL进行了药品生产质量管理规范的试点生产，针对血清型C、E和F的候选疫苗也处于工艺开发的后期阶段，从而提高了第一个特定目标成功的可能性。为开发抗血清型A、B、C、E和F的候选疫苗而建立的方法学提供了丰富的知识体系，其余两种血清型（D和G）的等效候选疫苗的开发将基于这些知识体系，从而促进第二个具体目标的实现。UC-HSC将在液体和冻干疫苗的配制和稳定方面提供专业知识，这对实现这两个具体目标至关重要。拟议的研究将有很高的成功概率，部分原因是采用了高度创新的方法，让行业伙伴DVC作为牵头机构，其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范围内预防肉毒杆菌神经毒素的免疫防御，并消除肉毒杆菌毒素作为大规模杀伤性武器。

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.