Development of a Next Generation Anthrax Vaccine, AV7909

下一代炭疽疫苗 AV7909 的开发

• 批准号: 7645826
• 负责人: Sukjoon Park
• 金额: $ 46.22万
• 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: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645826
• 关键词: Address; Adjuvant; Aerosols; Agreement; Animal Model; Animals; Anthrax Vaccines; Anthrax disease; Antibiotics; Antibodies; Antigens; Bacillus anthracis; Biothrax; Breathing; Cavia; Characteristics; Ciprofloxacin; Clinical; Clinical Trials; CpG 7909; Cyclic GMP; Development; Dose; Drug Formulations; Drug Kinetics; Evaluation; FDA approved; Generations; Immune response; Immunization; Immunoglobulin G; Infection; Lethal Dose 50; Licensing; Licensure; Methods; Modeling; Oligonucleotides; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prophylactic treatment; Rattus; Reproduction spores; Research Personnel; Safety; Schedule; Serum; Testing; Time; Toxic effect; Toxicology; Treatment Protocols; Vaccination; Vaccines; Vial device; Work; animal model development; animal rule; biodefense; immunogenicity; next generation; nonhuman primate; pre-clinical; programs; response; user-friendly; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): Project Summary-This application focuses on completion of preclinical work supporting initiation of a clinical trial to identify the optimum dose and schedule of a next generation anthrax vaccine, AV7909. AV7909 is composed of Emergent BioSolutions' FDA-approved BioThrax (25) anthrax vaccine and the immunostimulatory oligonucleotide compound CPG7909 (VaxImmuneTM) developed by Coley Pharmaceutical Group. In a previous Phase 1/2 clinical trial evaluating safety and immunogenicity of a first generation AV7909 vaccine, AV7909 increased peak anti-protective antigen (PA) liters 6-fold and reduced the time to peak titer by 21 days compared to BioThrax alone. Also, only 2 doses of AV7909 were required to elicit the same serum anti-PA IgG levels achieved by three doses of BioThrax alone. No anthrax vaccine developed to date, delivered by any means, has demonstrated such dramatic immunogenicity so rapidly. The specific aims for this proposal include: 1) cGMP manufacture of AV7909; 2) nonclinical GLP safety and toxicity evaluation; and 3) development of a guinea pig post-exposure prophylaxis (PEP) aerosol challenge model appropriate for AV7909. A key component required of the next generation anthrax vaccine is its ability to be used in conjunction with antibiotics in a post-exposure situation. To be effective when administered therapeutically, the vaccine must induce high anti-protective antigen (PA) titers quickly and with a minimum number of doses. Additionally, the vaccine must be easy to administer in a massive post-exposure vaccination scenario. Even though the first generation AV7909 showed excellent immune responses in a previous Phase 1/2 trial, the vaccine was manufactured in two separate vials and mixed just before administration. To make the vaccine more user- friendly, Emergent is developing a co-formulation method in a single vial. All specific aims for this proposal will be conducted with the new cGMP AV7909 vaccine lots manufactured by the new method. Also, even though rabbits and non-human primates (NHP) are generally considered the two preferred animal models for anthrax infection and have been widely used in anthrax vaccine efficacy studies, the rabbit model may not be suitable for evaluation of AV7909. Since studies indicate rabbits respond poorly to CpG molecules, we need to develop an alternative small animal model (e.g., guinea pig model) to satisfy the FDA's "Animal Rule" which requires two relevant animal models for evaluation of biodefense vaccines.

描述（由申请人提供）：项目摘要 - 本申请的重点是完成临床前工作，支持临床试验的启动，以确定下一代炭疽疫苗AV7909的最佳剂量和时间表。 AV7909由Coley Pharmaceutical Group开发的AV7909由新兴生物溶液（25）炭疽疫苗和免疫刺激寡核苷酸化合物CPG7909（Vaximmunetm）组成。在先前的1/2阶段临床试验中，评估第一代AV7909疫苗的安全性和免疫原性，AV7909增加了峰值抗保护抗原（PA）升高6倍6倍，并减少了与单独使用Biothrax相比，将峰值滴度的时间降低了21天。此外，仅需要2剂AV7909才能单独通过三剂Biothrax获得相同的血清抗PA IgG水平。迄今为止，迄今为止，没有开发任何炭疽疫苗，以任何方式传递，都如此迅速地证明了这种戏剧性的免疫原性。该提案的具体目的包括：1）CGMP AV7909的CGMP制造； 2）非临床GLP安全性和毒性评估； 3）适用于AV7909的豚鼠预防后预防（PEP）气溶胶挑战模型。下一代炭疽疫苗所需的关键组成部分是在暴露后情况下与抗生素结合使用的能力。为了在治疗时施用有效，疫苗必须迅速诱导高抗保护抗原（PA）滴度，并以最少的剂量诱导。此外，在大规模暴露后疫苗接种情况下，疫苗必须易于施用。尽管第一代AV7909在上一期的1/2阶段试验中表现出极好的免疫反应，但该疫苗还是在两个单独的小瓶中生产，并在给药前混合。为了使疫苗更加用户友好，Emprent正在单个小瓶中开发一种共制造方法。该提案的所有具体目的将使用新方法生产的新CGMP AV7909疫苗批次进行。同样，即使兔子和非人类灵长类动物（NHP）通常被认为是炭疽感染的两个首选动物模型，并且已被广泛用于炭疽疫苗疗效研究中，但兔模型可能不适合评估AV7909。由于研究表明兔子对CpG分子的反应较差，因此我们需要开发一种替代小动物模型（例如豚鼠模型），以满足FDA的“动物规则”，该模型需要两个相关的动物模型来评估生物粘固疫苗。