Individual and bivalent vaccines based on alphavirus replicons protect guinea pigs against infection with Lassa and Ebola viruses
Individual and bivalent vaccines based on alphavirus replicons protect guinea pigs against infection with Lassa and Ebola viruses
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DOI：
10.1128/jvi.75.23.11677-11685.2001
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发表时间：
2001-12-01
影响因子：
5.4
通讯作者：
Smith, J
中科院分区：
文献类型：
--
作者：
Pushko, P;Geisbert, J;Smith, J
拉沙病毒和埃博拉病毒引起急性、往往致命的出血热疾病，目前没有有效的疫苗。虽然致命的人类疾病爆发迄今仅限于撒哈拉以南非洲，但它们也在全世界引起严重的流行病学问题，几起病毒意外输入北美和欧洲的事件就证明了这一点。在本研究中，我们开发了拉沙病毒的实验性个体疫苗和拉沙病毒和埃博拉病毒的二价疫苗，这些疫苗基于来自委内瑞拉马脑炎病毒减毒株的RNA复制子载体。拉沙和埃博拉病毒基因由重组复制子RNA表达，所述重组复制子RNA也编码复制酶功能并且能够进行有效的细胞内自我扩增。对于疫苗接种，将重组复制子掺入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接种豚鼠，可保护豚鼠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接种疫苗也保护动物免受埃博拉病毒的致命攻击。为了评估针对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的糖蛋白基因的双表达颗粒。用双表达颗粒或表达埃博拉和拉沙病毒糖蛋白基因的颗粒混合物接种豚鼠，保护动物免受埃博拉和拉沙病毒的攻击。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应答，并提示了基于沙粒病毒、丝状病毒和可能的其他新兴病原体的甲病毒载体工程化多价疫苗的可能性。
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.