Hantavirus Vaccines Based On Nonreplicating Adenoviruses

描述(申请人提供)：汉坦病毒在受感染的啮齿动物之间以来自啮齿动物尿液、粪便或唾液的粉尘颗粒传播给人类。旧世界汉坦病毒是在朝鲜战争期间首次发现的，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50,000-200,000人死亡。新世界汉坦病毒包括1993年在美国西南部造成疫情的辛诺布雷病毒和在南美洲造成几次严重疫情的安第斯病毒。新世界汉坦病毒导致汉坦病毒肺综合征(HPS)，并与严重的临床症状和高达50%的死亡率有关。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，以保护北美、南美洲和亚洲农村地区的人民。此外，汉坦病毒疫苗对于防范潜在的生物恐怖袭击或军事用途非常重要。汉坦病毒在没有复杂的稳定剂的情况下，在野外用小鼠尿液干燥后非常稳定。这些病毒可以在几周内保持传染性。这些病毒进入人类呼吸道，并在年轻、健康的成年人中引起致命疾病。因此，汉坦病毒有很大的潜力用于生物恐怖主义或生物武器。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。在包括艾滋病毒、狂犬病和癌症在内的几个领域，腺病毒载体是公认的候选疫苗；与其他疫苗策略相比，它具有重大优势。与痘苗病毒等其他病毒载体不同，腺病毒载体不会复制和传播到其他宿主或引起疾病。此外，它们还能产生强大的细胞免疫，我们推测，这一特性在产生持续、保护性免疫的疫苗中将是重要的。我们将在最近描述的一种感染汉坦病毒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。这些研究将优化疫苗的结构、输送方式和金黄地鼠的免疫生产。这将是挑战实验的前奏，在这些实验中，接种疫苗的仓鼠将受到安第斯病毒的挑战，安第斯病毒会导致一种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.