Development of a Next Generation Anthrax Vaccine, AV7909

下一代炭疽疫苗 AV7909 的开发

基本信息

批准号：
7454548
负责人：
Sukjoon Park
金额：
$ 147.14万
依托单位：
EMERGENT PRODUCT DEVELOPMENT GAITHERSBUR
依托单位国家：
美国
项目类别：
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/7454548
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 Generations Immune response Immunization Immunoglobulin G Infection Lethal Dose 50 Licensing Licensure Methods Modeling Numbers Oligonucleotides Oryctolagus cuniculus Pharmaceutical Preparations Pharmacologic Substance Phase Prophylactic treatment Range Rattus Reproduction spores Research Personnel Safety Schedule Serum Testing Time Toxic effect Toxicology Treatment Protocols United States Food and Drug Administration Vaccination Vaccines Vial device Work biodefense day immunogenicity model development next generation nonhuman primate pre-clinical programs response user-friendly vaccine development vaccine efficacy

项目摘要

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，支持启动临床试验，以确定下一代炭疽疫苗 AV7909 的最佳剂量和时间表。 AV7909由Emergent BioSolutions经FDA批准的BioThrax（25）炭疽疫苗和Coley Pharmaceutical Group开发的免疫刺激寡核苷酸化合物CPG7909（VaxImmuneTM）组成。在之前评估第一代 AV7909 疫苗的安全性和免疫原性的 1/2 期临床试验中，与单独使用 BioThrax 相比，AV7909 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 剂 AV7909 即可引发与单独使用 3 剂 BioThrax 所达到的相同血清抗 PA IgG 水平。迄今为止，还没有开发出任何炭疽疫苗，无论通过何种方式，都能如此迅速地表现出如此显着的免疫原性。该提案的具体目标包括：1）AV7909的cGMP生产； 2）非临床GLP安全性和毒性评价； 3) 开发适合 AV7909 的豚鼠暴露后预防 (PEP) 气溶胶激发模型。下一代炭疽疫苗所需的一个关键组成部分是它能够在暴露后情况下与抗生素结合使用。为了在治疗上有效，疫苗必须以最少的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疫苗接种场景中接种。尽管第一代 AV7909 在之前的 1/2 期试验中表现出出色的免疫反应，但该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，Emergent 正在开发一种单瓶复合配方方法。该提案的所有具体目标将通过新方法生产的新 cGMP AV7909 疫苗批次来实现。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的小动物模型（例如豚鼠模型）来满足FDA的“动物规则”，该规则需要两种相关的动物模型来评估生物防御疫苗。