Second Generation Dengue Vaccine

描述(申请人提供)：登革热(登革热)是最重要的节肢动物传播的人类病毒感染，每年约有1亿例和25,000人死亡，威胁着全球超过35亿人。登革热病毒引起登革热(DF)、登革出血热(DHF)和登革休克综合征(DSS)，在世界亚热带和热带地区流行。到目前为止，还没有预防DF的有效疫苗，也没有针对这种疾病的药物治疗。登革热感染是由四种不同的RNA病毒之一引起的：登革1型(DEN-1)、DEN-2、DEN-3和DEN-4。要使登革热疫苗安全有效，它必须能够中和所有四种登革热病毒。Inviragen的四价DEN疫苗(DENVax)由减毒活的DEN-2 PDK-53病毒和表达DEN-1、DEN-3和DEN-4结构基因(PrM和E)的三个嵌合体组成，并保留了导致原始DEN-2疫苗安全性的基因改变。我们已经在AG129小鼠和猴子身上证明了DENVax的安全性和有效性。在这些研究中，我们已经确定了诱导针对所有四种DENV血清型的中和抗体的四价配方。然而，对DENVax-4的反应受到来自其他更强大嵌合体的干扰的限制。在这项建议中，我们将检验这样一个假设，即通过对DENVax-4感染性克隆的遗传操作，可以进一步优化对DENVax-4疫苗构建的免疫反应。我们建议设计和鉴定一种新的嵌合DEN2/4疫苗，并在小鼠和猴子身上测试这种疫苗的安全性和有效性。这项建议独特地利用了Inviragen Inc.、CDC和威斯康星大学麦迪逊分校可用的资源、设施和试剂。开发有效的登革热疫苗是预防和控制这一全球新出现疾病的重要途径。因维拉根公司的长期目标是开发一种安全有效的登革热疫苗。公共卫生意义：登革病毒(DEN)是一种由蚊子传播的RNA病毒，是人类最重要的节肢动物传播病毒感染，每年约有1亿例病例和2.5万人死亡。我们正在开发一种安全有效的四价登革热疫苗，该疫苗将预防所有四种登革热血清型。这种疫苗将保护美国游客免受登革热感染，并显著改善全球公共健康，因为全球有超过35亿人受到登革热的威胁。

DESCRIPTION (provided by applicant): Dengue (DEN) is the most important arthropod-borne viral infection of humans with about 100 million cases and 25,000 deaths annually, threatening over 3.5 billion people worldwide. The dengue viruses cause dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), and are endemic throughout the world's subtropical and tropical regions. To date, there is no effective vaccine to prevent against DF and no drug treatment for the disease. Dengue infection is caused by one of four different RNA viruses: dengue type 1 (DEN-1), DEN-2, DEN-3 and DEN-4. For a dengue vaccine to be safe and effective, it must be capable of neutralizing all four of the dengue viruses. Inviragen's tetravalent DEN vaccine (DENVax) consists of the live attenuated DEN-2 PDK-53 virus and three chimeras expressing the structural genes (prM and E) from DEN-1, DEN-3 and DEN-4, and retaining the genetic alterations responsible for the safety of the original DEN-2 vaccine. We have demonstrated the safety and efficacy of DENVax in AG129 mice and monkeys. In these studies we have identified tetravalent formulations that induce neutralizing antibodies to all four DENV serotypes. However, the responses to DENVax-4 were limited by interference from the other, more robust chimeras. In this proposal, we will test the hypothesis that the immune responses to the DENVax-4 vaccine construct can be further optimized through genetic manipulation of the DENVax-4 infectious clone. We propose to design and characterize a new chimeric DEN2/4 vaccine, and test the safety and efficacy of this vaccine in mice and monkeys. This proposal uniquely utilizes resources, facilities and reagents available at Inviragen Inc, CDC, and the University of Wisconsin-Madison. The development of an effective dengue vaccine represents an important approach to the prevention and control of this global emerging disease. Inviragen's long term goal is to develop a safe and effective dengue vaccine. PUBLIC HEALTH RELEVANCE: Dengue virus (DEN), a mosquito-borne RNA virus, is the most important arthropod-borne viral infection of humans with about 100 million cases and 25,000 deaths annually. We are developing a safe and effective tetravalent dengue vaccine that will protect against all four dengue serotypes. Such a vaccine would protect U.S. travelers from dengue infection, and significantly improve global public health as dengue threatens over 3.5 billion people worldwide.