Bivalent Recombinant LHn Botulinum Vaccine (Serotypes A and B)

描述（由申请人提供）：肉毒神经毒素是由肉毒梭菌菌株产生的一个7种（血清型A-G）相似但血清学上不同的强效神经麻痹蛋白家族。它们被认为是已知的毒性最大的毒素，并被CDC指定为A类生物威胁剂。疫苗是预防肉毒杆菌中毒的唯一综合性手段。然而，目前没有FDA批准的肉毒杆菌疫苗，现有的五价肉毒杆菌类毒素（PBT）疫苗（过去35年的IND产品）最后一次配制是在20世纪90年代，由20世纪70年代初生产的组分制成。PBT的供应极其有限，并且该产品的效力似乎正在下降。还有其他重组肉毒杆菌疫苗正在开发中，它们大多基于毒素分子的重链（Hc）片段。Hc片段的固有特性对Hc作为候选疫苗的使用提出了挑战：与疫苗制剂、稳定性和针对工程毒素的保护相关的问题。为了解决对有效肉毒杆菌疫苗的紧急未满足的医疗需求，紧急产品开发盖瑟斯堡（紧急）已经内部资助了基于毒素分子的LHN片段的重组肉毒杆菌疫苗（rBot）的开发。基于LHN的候选疫苗提供优于其他重组方法的优势，包括改善的稳定性、针对毒素亚型的交叉保护以及易于配制成多价疫苗。拟议工作的总体目标是开发针对肉毒杆菌神经毒素血清型A和B的安全有效的疫苗，这两种血清型被视为最突出的生物威胁血清型。如果美国政府希望，可以在以后将其他血清型添加到疫苗制剂中。在豚鼠和小鼠中的免疫原性和效力测试表明，这种方法产生强烈的保护性免疫应答，并且对毒素亚型有效。为了开展这项研究计划，Emergent与英国健康保护局（Porton Down）合作。这些组织在肉毒杆菌疫苗开发方面提供了丰富的经验。已经完成了先进的工艺开发，并且已经开发了一致的和商业上可行的生产工艺，该工艺生产高度纯化和可溶的LHN蛋白。该补助金的具体目的包括进入1期临床试验所需的活动：1。单价LHN/A & B和二价LHN/AB疫苗的临床前试验2. cGMP临床批次（单价LHN/A、B和二价LHN/AB成品）的生产3. cGMP临床批次（LHN/A、B和LHN/AB）的稳定性试验

DESCRIPTION (provided by applicant): Botulinum neurotoxins are a family of seven (serotypes A-G) pharmacologically similar but serologically distinct potent neuroparalytic proteins produced by strains of Clostridium botulinum. They are recognized as the most poisonous toxins known and are designated by CDC as Category A biothreat agents. Vaccines provide the only comprehensive means of protection against botulinum intoxication. However, there are currently no FDA-approved botulinum vaccines, and the existing pentavalent botulinum toxoid (PBT) vaccine (an IND product for the last 35 years) was last formulated in 1990s from components manufactured in the early 1970s. The supply of PBT is extremely limited, and the product appears to be decreasing in potency. There are other recombinant botulinum vaccines under development, and they are mostly based on the heavy chain (Hc) fragment of the toxin molecule. Intrinsic properties of the Hc fragment present challenges to the use of Hc as a vaccine candidate: issues associated with vaccine formulation, stability and protection against engineered toxins. To address the urgent unmet medical need for an effective botulinum vaccine, Emergent Product Development Gaithersburg (Emergent) has internally funded the development of a recombinant botulinum vaccine (rBot) based on the LHN fragment of the toxin molecule. The LHN-based vaccine candidate offers advantages over other recombinant approaches, including improved stability, cross- protection against toxin subtypes and ease of formulation into a multivalent vaccine. The overall objective of the proposed work is to develop a safe and efficacious vaccine against botulinum neurotoxin serotypes A and B, which are viewed as the most prominent biothreat serotypes. Additional serotypes can be added to the vaccine formulation later if the U.S. Government so desires. Immunogenicity and efficacy testing in guinea pigs and mice has shown that this approach produces a strong and protective immune response and is effective against toxin subtypes. To undertake this research program, Emergent has partnered with the Health Protection Agency (Porton Down, UK). Together, these organizations offer a wealth of experience in botulinum vaccine development. Advanced process development has been completed, and a consistent and commercially viable manufacturing process has been developed that produces highly purified and soluble LHN proteins. The specific aims of this grant include activities required for entrance into Phase 1 clinical trial: 1. Pre-clinical Testing of Monovalent LHN/A&B and Bivalent LHN/AB Vaccine 2. Manufacture of cGMP Clinical Lots (Monovalent LHN/A, B and Bivalent LHN/AB Final Product) 3. Stability Testing of cGMP Clinical Lots (LHN/A, B and LHN/AB)