Development of a Next Generation Anthrax Vaccine, AV7909

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，支持启动临床试验，以确定下一代炭疽疫苗AV 7909的最佳剂量和时间表。AV 7909是由紧急生物解决方案的FDA批准的BioThrax（25）炭疽疫苗和免疫刺激寡核苷酸化合物CPG 7909（VaxImmuneTM）由科利制药集团开发。在之前的一项评估第一代AV 7909疫苗安全性和免疫原性的1/2期临床试验中，与BioThrax单独使用相比，AV 7909将峰值抗保护性抗原（PA）升数增加了6倍，并将达到峰值滴度的时间缩短了21天。此外，仅需要2个剂量的AV 7909来引发与单独三个剂量的BioThrax所达到的相同的血清抗PA IgG水平。迄今为止，还没有任何一种炭疽疫苗能如此迅速地表现出如此显著的免疫原性。本提案的具体目的包括：1）AV 7909的cGMP生产; 2）非临床GLP安全性和毒性评价; 3）开发适用于AV 7909的豚鼠暴露后预防（PEP）气雾剂激发模型。下一代炭疽疫苗所需的一个关键组成部分是它能够在接触后的情况下与抗生素一起使用。为了在治疗性施用时有效，疫苗必须以最小剂量快速诱导高抗保护性抗原（PA）滴度。此外，疫苗必须易于在大规模暴露后接种疫苗的情况下接种。尽管第一代AV 7909在之前的1/2期试验中表现出优异的免疫应答，但疫苗是在两个单独的小瓶中生产的，并在给药前混合。为了使疫苗更加用户友好，紧急正在开发一种在一个单一的小瓶共配制方法。本提案的所有特定目标将使用通过新方法生产的新cGMP AV 7909疫苗批次进行。此外，尽管兔子和非人灵长类动物（NHP）通常被认为是炭疽感染的两种首选动物模型，并已广泛用于炭疽疫苗功效研究，但兔子模型可能不适合评估AV 7909。由于研究表明兔子对CpG分子的反应很差，我们需要开发一种替代的小动物模型（例如，豚鼠模型）以满足FDA的“动物规则”，该规则要求两种相关的动物模型用于评估生物防御疫苗。

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.