Hantavirus Vaccines Based On Nonreplicating Adenoviruses

描述（由申请方提供）：汉坦病毒通过啮齿动物尿液、粪便或唾液中的粉尘颗粒从受感染的啮齿动物传播给人类。旧世界汉坦病毒在朝鲜战争期间首次被发现，感染了数千名美国士兵，死亡率为10%。据估计，这些病毒目前每年在亚洲造成5万至20万人死亡。新世界汉他病毒包括1993年在美国西南部引起暴发的辛农布尔病毒和在南美洲引起几次严重流行的安第斯山脉病毒。新世界汉他病毒引起汉他病毒肺综合征（HPS），并与严重的临床症状和高达50%的死亡率相关。目前还没有治疗汉坦病毒病的药物或疗法，也没有安全有效的疫苗。 迫切需要一种疫苗来保护南北美洲和亚洲农村地区的人们。此外，汉坦病毒疫苗对于防止潜在的生物恐怖袭击或军事用途非常重要。汉坦病毒在野外的老鼠尿中干燥后非常稳定，不需要复杂的稳定剂。这些病毒的传染性可持续数周。这些病毒进入人类呼吸道，在年轻健康的成年人中引起致命的疾病。因此，汉坦病毒有很大的可能被用于生物恐怖主义或生物战。我们建议构建表达汉坦病毒蛋白的非复制型腺病毒（Ad）载体。Ad载体在包括HIV、狂犬病和癌症在内的几个领域中是成熟的疫苗候选物;并且相对于其他疫苗策略具有主要优势。Ad载体不会像其他病毒载体（例如牛痘病毒）那样复制和传播到其他宿主或引起疾病。此外，它们产生强大的细胞介导的免疫力，我们假设这一特性在产生持续保护性免疫力的疫苗中很重要。我们将在最近描述的汉坦病毒感染的叙利亚金黄仓鼠模型中测试几种潜在的Ad-汉坦病毒疫苗。 将评价CD 8+、CD 4 + T淋巴细胞应答和NK细胞应答的质量和数量。 这些研究将优化疫苗构建、递送方法和在仓鼠中产生免疫力。 这将是激发实验的前奏，在该实验中，接种疫苗的仓鼠将被安第斯山脉病毒激发，该病毒引起与人类相似的致命肺部疾病。

DESCRIPTION (provided by applicant): Hantaviruses are spread from infected rodents to man in dust particles derived from rodent urine, feces or saliva. Old World hantaviruses were first recognized during the Korean war, infecting thousands of U.S. troops with 10% mortality. These viruses currently are estimated to cause 50,000-200,000 deaths each year in Asia. New World hantaviruses include the Sin Nombre virus that caused an outbreak in the southwestern U.S. in 1993 and Andes virus which has caused several severe epidemics in South America. New World hantaviruses cause hantavirus pulmonary syndrome (HPS) and are associated with severe clinical symptoms and up to 50% mortality. There are no drugs or therapies for hantavirus disease, or safe, effective vaccines. A vaccine is urgently needed in order to protect people in rural areas of the North and South America and Asia. Moreover, a hantavirus vaccine is very important to protect against potential bioterrorist attacks or military use. Hantaviruses are extremely stable, when dried in mouse urine in the wild, and without sophisticated stabilizing agents. These viruses can remain infectious for weeks. The viruses enter the human respiratory tract and cause lethal disease in young, healthy adults. Therefore, there is substantial potential for hantaviruses to be used in bioterrorism or biowarfare. We propose to construct non-replicating adenovirus (Ad) vectors expressing hantavirus proteins. Ad vectors are well established vaccine candidates in several areas including HIV, rabies and in cancer; and have major advantages over other vaccine strategies. Ad vectors do not replicate and spread to other hosts or cause disease as with other virus vectors such as vaccinia virus. Moreover, they produce robust cell-mediated immunity, a property which we hypothesize will be important in a vaccine that produces sustained, protective immunity. We will test several potential Ad-hantavirus vaccines in a recently described Syrian golden hamster model of hantavirus infection. The quality and quantity of CD8+, CD4+ T lymphocyte responses and NK cell responses will be evaluated. These studies will optimize the vaccine construct, delivery methods and production of immunity in hamsters. This will be a prelude to challenge experiments in which vaccinated hamsters will be challenged with Andes virus that causes a lethal pulmonary disease similar to that in humans.