Hantavirus Vaccines Based On Nonreplicating Adenoviruses

描述（由申请人提供）：汉坦病毒通过来自啮齿动物尿液、粪便或唾液的粉尘颗粒从受感染的啮齿动物传播给人类。旧大陆汉坦病毒在朝鲜战争期间首次被发现，感染了数千名美军，死亡率为10%。这些病毒目前估计每年在亚洲造成5万至20万人死亡。新世界汉坦病毒包括1993年在美国西南部爆发的Sin Nombre病毒和在南美洲造成几次严重流行病的安第斯病毒。新世界汉坦病毒引起汉坦病毒肺综合征（HPS），与严重的临床症状和高达50%的死亡率相关。目前还没有针对汉坦病毒病的药物或疗法，也没有安全有效的疫苗。为了保护北美、南美和亚洲农村地区的人们，迫切需要一种疫苗。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。汉坦病毒是非常稳定的，当在野生小鼠尿液中干燥时，没有复杂的稳定剂。这些病毒可以保持数周的传染性。这些病毒进入人体呼吸道，在年轻健康的成年人中引起致命疾病。因此，汉坦病毒极有可能被用于生物恐怖主义或生物战。我们提出构建表达汉坦病毒蛋白的非复制腺病毒（Ad）载体。在包括艾滋病毒、狂犬病和癌症在内的几个领域，广告载体是公认的候选疫苗；并且与其他疫苗策略相比具有主要优势。Ad载体不会复制和传播到其他宿主，也不会像其他病毒载体（如牛痘病毒）那样引起疾病。此外，它们产生强大的细胞介导免疫，我们假设这一特性对产生持续保护性免疫的疫苗很重要。我们将在最近描述的叙利亚金仓鼠汉坦病毒感染模型中测试几种潜在的ad -汉坦病毒疫苗。评估CD8+、CD4+ T淋巴细胞反应和NK细胞反应的质量和数量。这些研究将优化仓鼠疫苗的构建、递送方法和免疫的产生。这将是挑战实验的前奏，在实验中，接种了疫苗的仓鼠将受到安第斯病毒的挑战，这种病毒会导致类似于人类的致命肺部疾病。

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.