Alphavirus Vaccines for Biodefense

甲病毒包括发达的生物武器和高毒性的新兴病原体 有可能在美国流行。东部（EEEV）和西部（WEEV） 马脑炎已经在美国本土流行，并在蚊子或气雾剂后引起致命疾病 传输委内瑞拉马脑炎病毒（VEEV）引起人类周期性大规模流行病， 这种疾病也可能是致命的，包括1971年德克萨斯州的爆发，也是一种高度气溶胶传染性的疾病。 武器基孔肯雅病毒（CHIKV）几十年来一直是一个重要的，但被忽视的原因严重， 在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， 非洲东海岸的岛屿和印度次大陆。数百到数千个多余的 在这些爆发期间涉及神经系统疾病的死亡表明，CHIKV最近可能已经成为 更致命。通过病毒携带者进入美洲的进口，加上2007年意大利的CHIK 由印度旅行者发起的流行病，强调了CHIKV对美洲构成的严重威胁; 地方病建立的风险包括埃及伊蚊居住的新热带/亚热带地区， 以及美国的温带地区，这些地区由另一种有效的载体Ae居住。白纹伊蚊 所有这些甲病毒都需要疫苗，以防止它们作为生物病毒的潜在影响。 武器，特别是VEEV和CHIKV，以控制流行地区的传播， 美国面临输入和流行的风险。我们将利用我们最近的嵌合甲病毒 设计优化这4种病毒的候选疫苗，并在啮齿动物和非人类中进行测试 用于减毒、免疫原性和功效。具体目标是：1）生成和优化 通过组合旨在调节宿主转录的减毒突变来引导候选疫苗 关闭毒力机制，以及消除蚊子传染性的新遗传策略; 2）开发 食蟹猴作为CHIKV的非人灵长类动物模型，并表征了 这些动物，和; 3）在鼠和非人灵长类动物模型中测试最终疫苗的减毒， 免疫原性、效力和毒力稳定性，并通过测试其潜在的环境安全性， 蚊媒和贮存宿主或其模型。由此产生的疫苗将准备好进行最后的 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.