Potentiating an Anthrax DNA Vaccine with Electroporation

描述（由申请人提供）：炭疽是一种由炭疽杆菌引起的传染病，由于其潜在的生物战用途而成为一个紧迫的问题，最有可能通过雾化炭疽孢子传播，导致致命的吸入性炭疽。目前的疫苗通过诱导针对炭疽毒素亚单位保护性抗原（PA）的抗体来提供保护，具有显著的缺点，包括制造问题、缺乏标准化和质量控制、需要重复注射以及经常发生副作用，使得其不足以用于大人群。 迫切需要一种新的疫苗。针对炭疽毒素的DNA疫苗将是经济的，相对容易制备，储存和标准化，应该引起很少的副作用，如果有的话。DNA疫苗的应用方法对效力至关重要。疫苗将通过电穿孔递送，因为该方法提供一致的、高水平的、可扩展的免疫原表达，其与高强度的、持久的抗体应答相关。Ichor已经开发出一种适合临床研究的疫苗施用器。 在SBIR I期可行性研究中，Ichor使用研究质粒证明，在小型啮齿动物中进行三次或更少次免疫接种后，基于电穿孔的抗PA免疫接种可诱导强大的抗PA抗体应答和长期免疫记忆。该程序是剂量有效的，可扩展到更大的物种，并诱导保护性抗体的形成。在完成第一阶段目标后，Ichor已开始设计候选疫苗，并正在小鼠免疫学研究中对其进行验证。 根据SBIR第二阶段，Ichor的目标是开发一种有效、简单和可靠的炭疽疫苗，在最低数量的免疫接种后提供长期保护。根据具体目标#1，将在小鼠中进行探索性毒理学研究，以消除具有不可接受毒副作用的候选构建体。然后将在兔免疫学研究中测试两个或三个选定的构建体。根据结果，将选择一个单一结构，并在家兔GLP有效性研究中进行试验。这些研究将评估接种兔对活B吸入激发的保护作用。炭疽孢子如果候选疫苗提供了足够的保护，研究将进入第2年。根据具体目标#2，将在恒河猴中进行正式的GLP免疫研究，包括免疫学、安全性和有效性终点。这将有助于选择拟定的人体剂量。基于该剂量，将在特定目标#3中进行正式的安全性研究。这些研究将包括在大鼠中进行的生物分布和整合研究以及在家兔中进行的毒理学评价。研究完成后，Ichor将与FDA展开IND前讨论。

DESCRIPTION (provided by applicant): Anthrax, an infectious disease caused by Bacillus anthracis, became a pressing concern because of its potential biowarfare use, most likely via aerosolized anthrax spore dissemination, resulting in deadly inhalation anthrax. The current vaccine, which confers protection by inducing antibodies against anthrax toxin subunit Protective Antigen (PA), has significant drawbacks including manufacturing issues, lack of standardization and quality control, the need for repeated injections, and frequent occurrence of side effects, making it inadequate for use in large populations. A new vaccine is urgently needed. A DNA vaccine directed against anthrax toxin would be economical, relatively easy to prepare, store and standardize, should induce few, if any, side effects. The method of application of a DNA vaccine is critical for efficacy. Vaccine will be delivered by electroporation because this method provides consistent, high level, scalable immunogen expression, which correlates with high magnitude, durable antibody responses. Ichor has already developed a vaccine applicator suitable for clinical studies. Under SBIR Phase I feasibility studies, Ichor has demonstrated, using a research plasmid, that electroporation-based immunization against-PA, induced robust anti-PA antibody response and long term immunological memory after three or fewer immunizations in small rodents. The procedure was dose efficient, scalable to larger species and induced the formation of protective antibodies. Following completion of the Phase I objectives, Ichor has started designing vaccine candidates and is in the process of validating them in mouse immunological studies. Under SBIR Phase II, Ichor's goal is to develop an effective, simple and reliable anthrax vaccine that provide long-term protection after a minimum number of immunizations. Under Specific Aim #1, exploratory toxicological studies will be conducted in mice to eliminate construct candidates with unacceptable toxic side effects. Two or three selected constructs will then be tested in immunological studies in rabbits. Based on the results, one single construct will be selected and tested in GLP efficacy studies in rabbits. These studies will assess protection of vaccinated rabbits against inhalation challenge with live B. anthracis spores. If adequate protection is provided by the vaccine candidate, studies will progress into Year 2. Under Specific Aim #2, formal GLP immunization studies will be conducted in rhesus monkeys with immunological, safety and efficacy endpoints. This will help select a proposed human dose. Based on that dose, formal safety studies will be conducted in Specific Aim #3. These will include biodistribution and integration studies in rats and a toxicological evaluation in rabbits. Following the completion of the studies, Ichor will initiate pre- IND discussions with the FDA.