Advancing a Lead Candidate Hantavirus Pulmonary Syndrome DNA Vaccine

描述（由申请方提供）：最致命的汉他病毒，包括安第斯山脉病毒（ANDV）和辛诺布尔病毒（SNV），是引起汉他病毒肺综合征（HPS）的病毒。HPS在任何年龄的男性和女性中都是高致病性的，即使在现代重症监护病房中，病死率也高达30-40%。从最初症状到呼吸窘迫和休克的疾病进展可能很快。在ANDV感染期间报告的人与人之间的传播使得这种病毒特别危险。引人注目的是，世界上任何地方都没有获得许可用于治疗或预防HPS的药物或疫苗。此外，世界上任何地方都没有处于高级开发阶段的HPS疫苗。我们已经开发出一种候选HPS疫苗。该疫苗是由编码ANDV和SNV表面糖蛋白的两个质粒组成的DNA疫苗。在概念验证研究中，我们证明了这些DNA疫苗，单独或联合使用，可以引发高滴度的中和抗体，并在动物中提供保护。我们的大部分初步数据都涉及使用基因枪或肌肉电穿孔来递送DNA疫苗。最近，我们使用PharmaJet无针喷射注射装置测试了SNV DNA疫苗的递送。在单次加强免疫后，在兔中引起高滴度中和抗体。 这一发现很重要，因为PharmaJet设备相对便宜，并且已经被FDA批准用于注射疫苗。在此，我们建议1）在非人灵长类动物中测试使用PharmaJet无针装置递送的HPS DNA疫苗的免疫原性（中和抗体），2）将HPS DNA疫苗质粒制造为cGMP DNA，3）对HPS DNA疫苗进行GLP临床前毒理学测试，以及4）完善我们的HPS动物模型，以供将来用于“动物规则”[21 CFR 601.90]有效性测试。我们的HPS动物模型涉及感染ANDV的成年叙利亚仓鼠。ANDV感染仓鼠中的HPS与人类中的HPS非常相似，包括：孵育时间、快速发作/进展、靶组织（内皮）、肺水肿、胸腔积液和休克。完成后，这项研究将推进一个领先的候选人HPS疫苗，通过无针技术提供，到一个点，它将准备进行第一阶段临床试验。与此同时，现有的HPS动物模型将被改进和标准化，以用于涉及“动物规则”的许可策略。'

DESCRIPTION (provided by applicant): The most lethal hantaviruses, including Andes virus (ANDV) and Sin Nombre virus (SNV), are those that cause hantavirus pulmonary syndrome (HPS). HPS is highly pathogenic in men and women of any age with a case-fatality rate of 30-40% even in modern intensive care units. Progression of the disease from first symptoms to respiratory distress and shock can be rapid. Reported person-to-person transmission during ANDV infection makes this virus especially dangerous. Strikingly, there are no drugs or vaccines licensed for the treatment or prevention of HPS anywhere in the world. Moreover, there are no HPS vaccines in advanced development anywhere in the world. We have developed a candidate HPS vaccine. The vaccine is a DNA vaccine consisting of two plasmids that encode the surface glycoproteins of ANDV and SNV. In proof-of-concept studies, we demonstrated that these DNA vaccines, delivered alone or in combination, elicit high-titer neutralizing antibodies and confer protection in animals. Much of our preliminary data has involved delivering the DNA vaccines using either a gene gun, or muscle electroporation. Recently, we tested delivery of the SNV DNA vaccine using the PharmaJet needle-free jet injection device. High-titer neutralizing antibodies were elicited in rabbits after a single boost. This finding is important because the PharmaJet device is relatively inexpensive and already is 510(k)-cleared by the FDA for injection of vaccines. Here, we propose to 1) test the HPS DNA vaccine delivered using the PharmaJet needle-free device for immunogenicity (neutralizing antibodies) in nonhuman primates, 2) manufacture HPS DNA vaccine plasmids as cGMP DNA, 3) conduct GLP preclinical toxicology testing of the HPS DNA vaccine, and 4) refine our HPS animal model for future use in 'Animal Rule' [21 CFR 601.90] efficacy testing. Our HPS animal model involves adult Syrian hamsters infected with ANDV. HPS in ANDV-infected hamsters closely resembles HPS in humans including: incubation time, rapid onset/progression, target tissue (endothelium), pulmonary edema, pleural effusion, and shock. When completed, this research will have advanced a lead-candidate HPS vaccine, delivered by needle-free technology, to a point where it will be ready for Phase 1 clinical testing. At the same time, an existing animal model of HPS would be refined and standardized for use in licensure strategies involving the 'Animal Rule.'