Pushko P, Geisbert J, Parker M, Jahrling P, Smith J
Virology Division, United States Army Medical Research Institute for Infectious Diseases, Fort Detrick, Frederick, Maryland 21702, USA.
J Virol. 2001 Dec;75(23):11677-85. doi: 10.1128/JVI.75.23.11677-11685.2001.
Lassa and Ebola viruses cause acute, often fatal, hemorrhagic fever diseases, for which no effective vaccines are currently available. Although lethal human disease outbreaks have been confined so far to sub-Saharan Africa, they also pose significant epidemiological concern worldwide as demonstrated by several instances of accidental importation of the viruses into North America and Europe. In the present study, we developed experimental individual vaccines for Lassa virus and bivalent vaccines for Lassa and Ebola viruses that are based on an RNA replicon vector derived from an attenuated strain of Venezuelan equine encephalitis virus. The Lassa and Ebola virus genes were expressed from recombinant replicon RNAs that also encoded the replicase function and were capable of efficient intracellular self-amplification. For vaccinations, the recombinant replicons were incorporated into virus-like replicon particles. Guinea pigs vaccinated with particles expressing Lassa virus nucleoprotein or glycoprotein genes were protected from lethal challenge with Lassa virus. Vaccination with particles expressing Ebola virus glycoprotein gene also protected the animals from lethal challenge with Ebola virus. In order to evaluate a single vaccine protecting against both Lassa and Ebola viruses, we developed dual-expression particles that expressed glycoprotein genes of both Ebola and Lassa viruses. Vaccination of guinea pigs with either dual-expression particles or with a mixture of particles expressing Ebola and Lassa virus glycoprotein genes protected the animals against challenges with Ebola and Lassa viruses. The results showed that immune responses can be induced against multiple vaccine antigens coexpressed from an alphavirus replicon and suggested the possibility of engineering multivalent vaccines based upon alphavirus vectors for arenaviruses, filoviruses, and possibly other emerging pathogens.
拉沙病毒和埃博拉病毒会引发急性、通常致命的出血热疾病，目前尚无有效的疫苗。尽管迄今为止致命的人类疾病疫情仅限于撒哈拉以南非洲地区，但病毒意外传入北美和欧洲的几起事件表明，它们在全球范围内也构成了重大的流行病学担忧。在本研究中，我们基于源自委内瑞拉马脑炎病毒减毒株的RNA复制子载体，开发了针对拉沙病毒的实验性单价疫苗以及针对拉沙病毒和埃博拉病毒的二价疫苗。拉沙病毒和埃博拉病毒基因由重组复制子RNA表达，这些RNA还编码复制酶功能，并能够在细胞内高效自我扩增。用于疫苗接种时，重组复制子被整合到病毒样复制子颗粒中。用表达拉沙病毒核蛋白或糖蛋白基因的颗粒对豚鼠进行疫苗接种，可使其免受拉沙病毒的致死性攻击。用表达埃博拉病毒糖蛋白基因的颗粒进行疫苗接种也可保护动物免受埃博拉病毒的致死性攻击。为了评估一种能同时预防拉沙病毒和埃博拉病毒的单一疫苗，我们开发了表达埃博拉病毒和拉沙病毒糖蛋白基因的双表达颗粒。用双表达颗粒或表达埃博拉病毒和拉沙病毒糖蛋白基因的颗粒混合物对豚鼠进行疫苗接种，可保护动物免受埃博拉病毒和拉沙病毒的攻击。结果表明，可以诱导针对从甲病毒复制子共表达的多种疫苗抗原的免疫反应，并提示了基于甲病毒载体设计针对沙粒病毒、丝状病毒以及可能其他新兴病原体的多价疫苗的可能性。
