Preclinical Assessment of a Multi-Head Electroporation Device for Delivery of Bio

描述（由申请人提供）：基于DNA的疫苗具有良好的安全记录，具有内在稳定性，易于创建，可以快速生产，不需要冷链储存，使该技术在对抗生物恐怖主义威胁，新兴传染病或基因工程病原体方面具有吸引力。尽管有这些属性，但DNA疫苗在很大程度上由于与无效递送方法相关的不良免疫原性而没有实现常规使用。我们之前开发并测试了A类生物威胁拉沙病毒（LASV）的DNA疫苗。这种沙粒病毒在西非流行，每年感染数十万人，并可引起高度致命的出血热。我们发现，通过皮内电穿孔（ID-EP）递送的LASV密码子优化的DNA疫苗在豚鼠和非人灵长类动物疾病模型中对LASV攻击具有完全保护作用。尽管这些结果非常令人鼓舞，并且从患者的角度来看，ID-EP技术是一种非常可耐受的递送方法，但仍需要改进以使该技术适用于大规模疫苗接种。 在本申请中，我们描述了技术改进，与我们现有的递送平台相比，我们预计这些技术改进将导致更好的疫苗效力和易用性。我们建议开发具有双深度和/或多个EP阵列的新型设备，其可以针对空间分离的皮肤区域。我们将使用LASV DNA疫苗本身或与细胞因子佐剂或与另外两种沙粒病毒的DNA疫苗组合来测试这些装置。我们的主要目标是：1）开发自动化的多头ID/EP装置，其能够将多种产品同时递送至离散位点和/或靶向皮肤的不同隔室; 2）确定LASV DNA疫苗与编码用新型ID-EP装置递送的分子佐剂的质粒共同施用的影响;以及3）评估多阵列ID-EP装置有效递送多剂沙粒病毒疫苗的能力。这些目标的实现不仅将填补一个关键的生物防御和公共卫生方面的差距，对LASV的医疗对策，但也将推进DNA疫苗领域一般提供一个高度耐受的大规模接种方法，适合多剂疫苗输送。

DESCRIPTION (provided by applicant): DNA-based vaccines have an excellent safety record, are inherently stable, are simple to create, can be manufactured rapidly and do not require cold-chain storage, making this technology attractive for use against bioterrorism threats, emerging infectious diseases or genetically engineered pathogens. Despite these attributes, DNA vaccines have not achieved routine usage in large part due to poor immunogenicity related to ineffective delivery methods. We previously developed and tested a DNA vaccine for the Category A biothreat Lassa virus (LASV). This arenavirus is endemic in West Africa where it infects hundreds of thousands of people each year and can cause a highly lethal hemorrhagic fever. We showed that a codon optimized DNA vaccine for LASV delivered by intradermal electroporation (ID-EP) is completely protective against LASV challenge in both guinea pig and nonhuman primate disease models. Although these results are highly encouraging and the ID-EP technology is a very tolerable delivery method from a patient perspective, improvements are still needed to make the technology suitable for mass vaccination. In this application, we describe technological improvements that we expect will result in better vaccine efficacy and ease of use as compared to our existing delivery platform. We propose to develop novel devices with dual depth and/or multiple EP arrays that can target spatially separated skin areas. We will test the devices using the LASV DNA vaccine by itself or delivered in combination with cytokine adjuvants or with DNA vaccines for two additional arenaviruses. Our main goals are: 1) Develop automated, multi-head ID/EP devices able to deliver multiple products to discreet sites simultaneously and/or target different compartments of the skin; 2) Determine the affect of co-administering the LASV DNA vaccine with plasmids encoding molecular adjuvants delivered with the novel ID-EP devices; and, 3) Assess the ability of the multi-array ID-EP devices to effectively deliver multiagent arenavirus vaccines. Accomplishment of these goals will not only fill a critical biodefense and public health gap with respect to medical countermeasures against LASV, but will also advance the DNA vaccine field in general by providing a highly tolerable mass vaccination method amenable to multiagent vaccine delivery.