Advancing a Lead Candidate Hantavirus Pulmonary Syndrome DNA Vaccine

描述（由申请人提供）：最致命的汉坦病毒，包括安第斯病毒（ANDV）和Sin Nombre病毒（SNV），是那些引起汉坦病毒肺综合征（HPS）的病毒。HPS对任何年龄的男性和女性都具有高致病性，即使在现代重症监护病房，病死率也高达30-40%。从最初症状到呼吸窘迫和休克的病程进展可能很快。在ANDV感染期间报告的人际传播使这种病毒特别危险。引人注目的是，世界上任何地方都没有批准用于治疗或预防HPS的药物或疫苗。此外，世界上任何地方都没有处于后期开发阶段的HPS疫苗。我们已经开发了一种候选的HPS疫苗。该疫苗是一种DNA疫苗，由编码ANDV和SNV表面糖蛋白的两个质粒组成。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，可引发高滴度中和抗体，并在动物中提供保护。我们的大部分初步数据都涉及到使用基因枪或肌肉电穿孔来传递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。高滴度的中和抗体在兔单次刺激后被激发。

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.'