Bivalent Recombinant LHn Botulinum Vaccine (Serotypes A and B)

二价重组 LHn 肉毒杆菌疫苗（血清型 A 和 B）

• 批准号: 7897868
• 负责人: Sukjoon Park
• 金额: $ 39.94万
• 依托单位: EMERGENT PRODUCT DEVELOPMENT GAITHERSBUR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-25 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897868
• 关键词: Achievement; Address; Affect; Animal Model; Animal Testing; Animals; Antibodies; Antigens; Applications Grants; Binding; Biological Assay; Bontoxilysin; Botulinum Toxins; Botulism; Breathing; Categories; Cavia; Centers for Disease Control and Prevention (U.S.); Clinical Research; Clostridium botulinum; Commit; Cyclic GMP; Development; Diphtheria; Dose; Drug Formulations; Endopeptidases; Engineering; Excision; FDA approved; Family; Foundations; Funding; Future; Gills; Goals; Government; Grant; Guidelines; Health protection; Human; Human Resources; Immune response; Immunization; Intensive Care; Intoxication; Isoelectric Point; Licensing; Licensure; Manufacturer Name; Medical; Mus; N-terminal; Neurons; Neurotoxins; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physiological; Preparation; Prevention; Principal Investigator; Process; Production; Property; Proteins; Recombinant Vaccines; Recombinants; Research; Research Personnel; Risk; Safety; Seeds; Serotyping; Serum; Site-Directed Mutagenesis; Solid; Technology; Testing; Tetanus Toxoid; Toxicity Tests; Toxin; Toxoids; Vaccine Research; Vaccine Therapy; Vaccines; Work; animal efficacy; animal rule; base; biodefense; biothreat; botulinum; botulism immune globulin; clinical lot; clinical material; efficacy testing; experience; immunogenicity; improved; killings; manufacturing process; meetings; mouse model; neutralizing antibody; operation; pre-clinical; prevent; product development; programs; receptor; research clinical testing; response; scale up; stability testing; treatment program; vaccine candidate; vaccine development

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)

描述（由申请人提供）：肉毒神经毒素是七个（血清型A-G）药理学上相似但在血清学上不同的有效神经分析蛋白的家族，该蛋白质由肉毒梭菌菌株产生。它们被认为是已知的最有毒毒素，被CDC指定为A类生物治疗剂。疫苗提供了防止肉毒杆菌中毒的唯一全面方法。但是，目前尚无FDA批准的肉毒杆菌疫苗，现有的五体肉毒纤维毒素（PBT）疫苗（过去35年的IND产品）于1990年代由1970年代初制造的组件制定。 PBT的供应极为有限，产品的效力似乎正在降低。还有其他正在开发的重组肉毒纤维疫苗，它们主要基于毒素分子的重链（HC）片段。 HC片段的内在特性对使用HC作为疫苗候选者面临着挑战：与疫苗配方，稳定性和针对工程毒素的保护相关的问题。为了满足对有效肉毒杆菌疫苗的紧急医疗需求，新兴产品开发盖瑟斯堡（Empry）基于毒素分子的LHN片段，内部资助了重组肉毒纤维疫苗（RBOT）的发展。基于LHN的疫苗候选者比其他重组方法具有优势，包括提高稳定性，针对毒素亚型的交叉保护以及易于制剂到多价疫苗中。拟议工作的总体目的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，这些疫苗被视为最突出的生物治疗血清型。如果美国政府渴望，则可以将其他血清型添加到疫苗配方中。豚鼠和小鼠的免疫原性和功效测试表明，这种方法会产生强烈而保护的免疫反应，并且有效地抗毒素亚型。为了实施这项研究计划，Emperent与健康保护局（英国Porton Down）合作。这些组织共同提供了丰富的肉毒杆菌疫苗开发经验。先进的过程开发已经完成，并且已经开发出一致且商业上可行的制造工艺，可产生高度纯化和可溶性的LHN蛋白质。该赠款的具体目的包括进入第1阶段临床试验所需的活动：1。单价LHN/A＆A＆A＆A＆a＆a＆a＆a＆a ab疫苗的临床前测试2。cGMP临床批次的生产（单价LHN/A，A，B和双重LHN/AB最终产品）3。