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）：肉毒杆菌神经毒素是由肉毒梭菌菌株产生的七种（血清型 A-G）药理学相似但血清学不同的强效神经麻痹蛋白家族。它们被认为是已知毒性最强的毒素，并被 CDC 指定为 A 类生物威胁制剂。疫苗是预防肉毒杆菌中毒的唯一综合手段。然而，目前还没有 FDA 批准的肉毒疫苗，现有的五价肉毒类毒素 (PBT) 疫苗（过去 35 年的 IND 产品）最后一次配制是在 1990 年代，由 20 世纪 70 年代初生产的成分制成。 PBT 的供应极其有限，而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 片段的内在特性对使用 Hc 作为候选疫苗提出了挑战：与疫苗配方、稳定性和针对工程毒素的保护相关的问题。为了解决有效肉毒杆菌疫苗未得到满足的迫切医疗需求，盖瑟斯堡紧急产品开发公司 (Emergent) 在内部资助了基于毒素分子 LHN 片段的重组肉毒杆菌疫苗 (rBot) 的开发。基于 LHN 的候选疫苗具有优于其他重组方法的优势，包括提高稳定性、针对毒素亚型的交叉保护以及易于配制为多价疫苗。拟议工作的总体目标是开发一种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重要的生物威胁血清型。如果美国政府愿意，可以稍后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，这种方法产生强烈的保护性免疫反应，并且对毒素亚型有效。为了开展这项研究计划，Emergent 与健康保护局（英国波顿当）合作。这些组织共同提供了肉毒杆菌疫苗开发方面的丰富经验。先进的工艺开发已经完成，并且已经开发出一致且商业上可行的制造工艺，可生产高度纯化和可溶的 LHN 蛋白。这笔赠款的具体目标包括进入一期临床试验所需的活动： 1. 单价 LHN/A&B 和二价 LHN/AB 疫苗的临床前测试 2. cGMP 临床批次（单价 LHN/A、B 和二价）的生产LHN/AB 最终产品）3. cGMP 临床批次的稳定性测试（LHN/A、B 和 LHN/AB）