Advancing a Lead Candidate Hantavirus Pulmonary Syndrome DNA Vaccine

推进主要候选汉坦病毒肺综合征 DNA 疫苗

基本信息

批准号：
9057440
负责人：
Jay Williams Hooper
金额：
$ 57.88万
依托单位：
GENEVA FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-16 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057440
关键词：
Acute Adult Advanced Development Age Andes Virus Animal Model Animals Biological Products Case Fatality Rates Categories Containment Country Cyclic GMP DNA DNA Vaccines Data Development Devices Disease Disease Progression Disease model Drug Delivery Systems Electroporation Endothelium Future Genes Hamsters Hantavirus Hantavirus Pulmonary Syndrome Human Injection of therapeutic agent Intensive Care Units Jet Injections Lead Licensing Licensure Membrane Glycoproteins Mesocricetus auratus Modeling Muscle National Institute of Allergy and Infectious Disease Needles Oryctolagus cuniculus Persons Pharmaceutical Preparations Phase Plasmids Pleural effusion disorder Prevention Pulmonary Edema Reporting Research Respiratory distress Shock Sin Nombre virus Symptoms Technology Testing Therapeutic Time Tissues Toxicology United States Vaccines Virus Virus Diseases Woman animal rule base efficacy testing gene gun human disease immunogenicity innovation interest men neutralizing antibody nonhuman primate pathogen plasmid DNA pre-clinical prevent product development research and development research clinical testing therapy development time use transmission process vaccine development viral DNA

项目摘要

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.'

描述（由申请人提供）：包括安第斯山脉病毒（ANDV）和Sin nombre病毒（SNV）在内的最致命的汉坦病毒是引起汉坦病毒肺综合征（HPS）的最致命的汉坦病毒。 HPS在任何年龄的男性和女性中都具有高度致病性，即使在现代重症监护病房中也是30-40％。疾病从第一次症状到呼吸窘迫的发展可能很快。报道的在ANDV感染期间的人向人传播使该病毒特别危险。引人注目的是，没有许可用于治疗或预防世界任何地方HPS的药物或疫苗。此外，世界上任何地方的高级开发中都没有HPS疫苗。我们已经开发了一种候选HPS疫苗。该疫苗是一种由两种编码ANDV和SNV表面糖蛋白的质粒组成的DNA疫苗。在概念证明的研究中，我们证明了这些DNA疫苗单独或结合使用，引起了中和抗体并赋予动物保护的保护。我们的许多初步数据都涉及使用基因枪或肌肉电穿孔输送DNA疫苗。最近，我们使用无针头喷射装置测试了SNV DNA疫苗的输送。单一提升后，在兔子中引起了中和抗体。这一发现很重要，因为药物装置相对便宜，并且已经被FDA用于注射疫苗的510（k）。在这里，我们提出1）使用无针头装置传递的HPS DNA疫苗在非人类灵长类动物中进行免疫原性（中和抗体），2）生产HPS DNA疫苗质粒作为CGMP DNA，3）进行GLP临床毒性测试，以hPS DNA液体的模型和4）进行了模型'和4）Frution'和4）Futeruine'和4）。 CFR 601.90]功效测试。我们的HPS动物模型涉及感染ANDV的成年叙利亚仓鼠。 ANDV感染的仓鼠中的HP与人类中的HP相似，包括：孵育时间，快速发作/进展，靶组织（内皮），肺水肿，胸膜积液和休克。完成后，这项研究将推进通过无针技术传递的铅候选HPS疫苗，以便将其准备好进行1期临床测试。同时，现有的HP动物模型将被改进并标准化，以用于涉及“动物规则”的许可策略。