Alphavirus Vaccines for Biodefense

甲型病毒包括发展良好的生物武器和剧毒的新兴病原体。 有可能在美国建立地方病。东部(EEEV)和西部(WeEV) 马脑炎已经是美国本土的疾病，会在蚊子或气雾剂之后导致致命疾病 变速箱。委内瑞拉马脑炎病毒(VEEV)导致人类周期性大规模流行 这种疾病也可能是致命的，包括1971年德克萨斯州的疫情，也是一种高度具有气溶胶传染性的疾病 武器。基孔肯雅病毒(CHIKV)几十年来一直是严重、 非洲和亚洲的慢性关节炎，最近出现的流行病涉及数百万人在 非洲东海岸和印度次大陆附近的岛屿。成百上千的超标 在这些暴发期间涉及神经系统疾病的死亡表明，CHIKV可能最近已经成为 毒力更强。通过病毒旅行者进口到美洲，结合2007年的意大利Chik 一名来自印度的旅行者发起的疫情，突显了CHIKV对美洲构成的严重威胁； 流行风险包括埃及伊蚊栖息的新热带/亚热带地区， 和美国的温带地区，由另一种有效的媒介Ae.白纹伊蚊。 所有这些甲型病毒都需要疫苗，以防止它们作为生物学上的潜在影响 武器，特别是对VEEV和CHIKV来说，控制流行地区的传播，使 美国面临进口和地方病流行的风险。我们将利用我们最新的嵌合甲型病毒 设计优化这4种病毒的候选疫苗，并在啮齿动物和非人类身上进行测试 灵长类动物的衰减性、免疫原性和有效性。具体目标是：1)生成和优化 通过结合旨在调节宿主转录的减毒突变来引领候选疫苗 关闭毒力机制，以及消除蚊子感染性的新遗传策略；2)开发 食蟹猴作为CHIKV的非人灵长类动物模型，并描述了 这些动物，以及；3)在小鼠和非人类灵长类动物模型中测试最终疫苗的减毒效果， 免疫原性、有效性和毒力稳定性，并通过测试潜力评价其环境安全性 蚊子媒介和水库宿主，或其模型。由此产生的疫苗将准备好进入最终的 产品开发和临床试验。

The alphaviruses include well developed biological weapons and highly virulent, emerging pathogens with the potential for endemic establishment in the United States. Eastern (EEEV) and western (WEEV) equine encephalitis are already native to the US, and cause fatal disease following mosquito or aerosol transmission. Venezuelan equine encephalitis virus (VEEV) causes periodic, massive epidemics of human disease that can also be fatal, including a 1971 Texas outbreak, and is also a highly aerosol-infectious weapon. Chikungunya virus (CHIKV) has for decades been an important but neglected cause of severe, chronic arthritis in Africa and Asia, and recently emerged to cause epidemics involving millions of people on islands off the eastern coast of Africa, and in the Indian subcontinent. Hundreds to thousands of excess deaths involving neurologic disease during these outbreaks suggest that CHIKV may have recently become more virulent. Importations into the Americas via viremic travelers, combined with a 2007 Italian CHIK epidemic initiated by a traveler from India, underscore the severe threat that CHIKV poses to the Americas; the risk for endemic establishment includes both neotropical/subtropical regions inhabited by Aedes aegypti, and temperate areas of the U.S. that are populated by the other efficient vector, Ae. albopictus. Vaccines are needed for all of these alphaviruses, both to prevent their potential impact as biological weapons and, especially for VEEV and CHIKV, to control transmission in endemic locations that puts the U.S. at risk for importation and endemic establishment. We will capitalize on our recent chimeric alphavirus design to optimize vaccine candidates for these 4 viruses, and to test them in rodents and nonhuman primates for attenuation, immunogenicity and efficacy. The specific aims are to: 1) Generate and optimize lead vaccine candidates by combining attenuating mutations designed to modulate the host transcriptional shutoff virulence mechanism, and a novel genetic strategy to eliminate mosquito infectivity; 2) Develop cynomolgus macaques as a nonhuman primate model for CHIKV, and characterize the course of infection in these animals, and; 3) Test the final vaccines in murine and nonhuman primate models for attenuation, immunogenicity, efficacy and virulence stability, and evaluate their environmental safety by testing potential mosquito vectors and reservoir hosts, or models thereof. The resulting vaccines will be ready for final product development and clinical trials.