Individual and bivalent vaccines based on alphavirus replicons protect guinea pigs against infection with Lassa and Ebola viruses

Lassa and Ebola viruses cause acute, often fatal, hemorrhagic fever disease s, for which no effective vaccines are currently available. Although lethal human disease outbreaks have been confined so far to sub-Saharan Africa, t hey also pose significant epidemiological concern worldwide as demonstrated by several instances of accidental importation of the viruses into North A merica and Europe. In the present study, we developed experimental individu al vaccines for Lassa virus and bivalent vaccines for Lassa and Ebola virus es that are based on an RNA replicon vector derived from an attenuated stra in of Venezuelan equine encephalitis virus. The Lassa and Ebola virus genes were expressed from recombinant replicon RNAs that also encoded the replic ase 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 L assa virus nucleoprotein or glycoprotein genes were protected from lethal c hallenge with Lassa virus. Vaccination with particles expressing Ebola viru s glycoprotein gene also protected the animals from lethal challenge with E bola virus. In order to evaluate a single vaccine protecting against both L assa and Ebola viruses, we developed dual-expression particles that express ed glycoprotein genes of both Ebola and Lassa viruses. Vaccination of guine a 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 im mune responses can be induced against multiple vaccine antigens coexpressed from an alphavirus replicon and suggested the possibility of engineering m ultivalent vaccines based upon alphavirus vectors for arenaviruses, filovir uses, and possibly other emerging pathogens.