Recombinant Vesicular Stomatitis Virus Vaccine Vectors Expressing Filovirus Glycoproteins Lack Neurovirulence in Nonhuman Primates

Abstract

The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses an individual filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). The main concern with all replication-competent vaccines, including the rVSV filovirus GP vectors, is their safety. To address this concern, we performed a neurovirulence study using 21 cynomolgus macaques where the vaccines were administered intrathalamically. Seven animals received a rVSV vector expressing the Zaire ebolavirus (ZEBOV) GP; seven animals received a rVSV vector expressing the Lake Victoria marburgvirus (MARV) GP; three animals received rVSV-wild type (wt) vector, and four animals received vehicle control. Two of three animals given rVSV-wt showed severe neurological symptoms whereas animals receiving vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP did not develop these symptoms. Histological analysis revealed major lesions in neural tissues of all three rVSV-wt animals; however, no significant lesions were observed in any animals from the filovirus vaccine or vehicle control groups. These data strongly suggest that rVSV filovirus GP vaccine vectors lack the neurovirulence properties associated with the rVSV-wt parent vector and support their further development as a vaccine platform for human use. Ebola and Marburg viruses are categorized as Category A priority pathogens by several US Government agencies as a result of their high mortality rates and potential for use as agents of bioterrorism. There are currently no vaccines or therapeutics approved for human use. A replication-competent, recombinant vesicular stomatitis virus (rVSV) vector expressing filovirus glycoproteins (GP), in place of the VSV G protein has shown promise in lethal nonhuman primate models of filovirus infection as both a single-injection preventive vaccine and a postexposure treatment. Replication-competent vaccines that are intended for use in humans usually undergo neurovirulence testing as was done for measles virus, mumps virus, yellow fever virus, and poliovirus vaccines. Here we used a conventional neurovirulence test to evaluate the safety of our rVSV-based Zaire ebolavirus and Lake Victoria marburgvirus GP vaccines in cynomolgus macaques. Importantly, we demonstrate for the first time that these rVSV filovirus GP vectors lack neurovirulence when compared to a rVSV wild-type vector.