Development of a Next Generation Anthrax Vaccine, AV7909

描述(由申请人提供)：项目概要-本申请的重点是完成支持启动临床试验的临床前工作，以确定下一代炭疽疫苗AV7909的最佳剂量和时间表。AV7909由Emerent BioSolutions公司批准的BioThrax(25)炭疽疫苗和Coley制药集团开发的免疫刺激寡核苷酸化合物CPG7909(VaxImmuneTM)组成。在评估第一代AV7909疫苗的安全性和免疫原性的前1/2期临床试验中，与单独使用BioThrax相比，AV7909的抗保护性抗原(PA)峰值滴度增加了6倍，达到峰值滴度的时间减少了21天。此外，只需要两剂AV7909就能产生与三剂BioThrax单独使用相同的血清抗PA IgG水平。到目前为止，还没有以任何方式交付的炭疽疫苗如此迅速地展示出如此戏剧性的免疫原性。这项建议的具体目标包括：1)生产AV7909的cGMP；2)非临床GLP安全性和毒性评估；以及3)开发适用于AV7909的豚鼠暴露后预防(PEP)气雾剂挑战模型。下一代炭疽疫苗所需的一个关键组成部分是它能够在暴露后情况下与抗生素一起使用。为了在治疗时有效，疫苗必须以最小的剂量快速诱导高滴度的抗保护性抗原(PA)。此外，在大规模暴露后接种疫苗的情况下，疫苗必须易于管理。尽管第一代AV7909在之前的1/2阶段试验中表现出良好的免疫反应，但疫苗是在两个单独的瓶子中生产的，并在注射前混合。为了使疫苗更易于使用，Emerent正在开发一种单一瓶装的联合配方方法。这项提议的所有具体目标将与新方法生产的新cGMP AV7909疫苗批次一起进行。此外，尽管兔子和非人灵长类动物(NHP)通常被认为是炭疽病感染的两个首选动物模型，并已被广泛用于炭疽疫苗效力研究，但兔模型可能不适合评估AV7909。由于研究表明兔对CpG分子的反应很差，我们需要开发一个替代的小动物模型(例如，豚鼠模型)来满足FDA的“动物规则”，该规则要求评估生物防御疫苗的两个相关动物模型。

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.