Maria Salvato, PhD, Basic Science and Vaccine Research Division, Head Section of Arenavirus Research
The Salvato laboratory collaborate in investigating Arenavirus pathogenesis and vaccinology using murine, guinea pig, macaque, and marmoset models. Rhesus macaques infected with LCMV-WE serve as a model for the disease caused by Lassa virus infection of human beings. Transcriptome analyses comparing virulent and mild infections of monkeys identified almost 100 biomarkers that could predict virulent infection before viremia was clinically detectable in the circulation (Djavani et al, 2007). Although infected mice and guinea pigs share some of these biomarkers, primates have a unique response to hemorrhagic fever viruses.
Two live-attenuated Lassa vaccine candidates have been investigated: ML29 is a reassortant between Lassa virus and Mopeia virus, and YF/LAS is a recombinant between the Yellow Fever vaccine (YF17D) and the Lassa glycoprotein. The ML29 candidate is broadly cross-reactive and protects primates from Lassa fever (Lukashevich et al 2005, Carrion et al 2007, Lukashevich et al 2008). In collaboration with the Pauza laboratory, Dr. Salvato organized a study of ML29 vaccination in SIV-infected monkeys. The vaccine caused circulating SIV to disappear one week after inoculation, however SIV loads returned the next week. SIV-infected monkeys developed poorer immune responses to the vaccine than did uninfected monkeys, but they did not develop virulent arenavirus infections. The absence of “virulence biomarkers” was corroborated by transcriptome analysis. Monkeys survived a heterologous lethal challenge with LCMV-WE and the only deaths observed were by euthanasia or accompanied by the AIDS-related signs of lymphadenopathy and wasting.
The YF/LAS vaccine was effective in protecting guinea pigs and has not been tested in primates (Bredenbeek et al 2006; Jiang et al, 2010). In collaboration with the Lukashevich laboratory (recently moved to Univ. of Kentucky) the Salvato laboratory has also been exploring vaccination with DNA vectors that produce Virus-like-particles after inoculation in vivo.
Djavani MM, Crasta OR, Zapata JC, Fei Z, Folkerts O, Sobral B, Swindells M, Bryant J, Davis H, Pauza CD, Lukashevich IS, Hammamieh R, Jett M, Salvato MS. 2007. Early blood profiles of virus infection in a monkey model for Lassa Fever. J. Virol. 81: 7960-7973.
Lukashevich IS, PattersonJ, Carrion R, Moshkoff D, Ticer A, Zapata J, Brasky K, Geiger R, Hubbard GB, Bryant J, Salvato MS. 2005 A Live attenuated vaccine for Lassa fever made by reassortment of Lassa and Mopeia Viruses. J Virol 79:13934-13942
Bredenbeek, P J, Molenkamp R, Spaan WJM, Deubel V, Marianneau P, Salvato MS, Moshkoff D, Zapata J, Tikhonov I, Patterson J, Carrion R, Ticer A, Brasky K, Lukashevich IS. 2006. A recombinant Yellow Fever 17D vaccine expressiong Lassa virus glycoproteins. Virology 345(2):299-304
Lukashevich IS, Carrion R Jr, Salvato MS, Mansfield K, Brasky K, Zapata J, Cairo C, Goicochea M, Hoosien GE, Ticer A, Bryant J, Davis H, Hammamieh R, Mayda M, Jett M, Patterson J. 2008. Safety, immunogenicity and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates. Vaccine. 2008 Sep 26;26(41):5246-54.
Carrion R Jr, Patterson JL, Johnson C, Gonzales M, Moreira CR, Ticer A, Brasky K, Hubbard GB, Moshkoff D, Zapata J, Salvato MS, Lukashevich IS. 2007. A ML29 reassortant virus protects guinea pigs against a deadly related Nigerian strain of Lassa virus and can provide sterilizing immunity. Vaccine. 2007 May 16;25(20):4093-102.
Moshkoff DA, Salvato MS, Lukashevich IS.2007. Molecular characterization of a reassortant virus derived from Lassa and Mopeia viruses. Virus Genes. 2007 Apr;34(2):169-76.
Jiang X, Dalebout TJ, Bredenbeek PJ, Carrion Jr. R, Brasky K, Patterson J, Goicochea M, Bryant J, Salvato MS, Lukashevich IS. 2010. Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs. Vac 29: 1248-57.
Zapata JC, Pauza CD, Djavani MM, Rodas JD, Moshkoff D, Bryant J, Ateh E, Garcia C, Lukashevich IS, Salvato MS. Lymphocytic choriomeningitis virus (LCMV) infection of macaques: A model for Lassa fever. Antiviral Res. 2011 92: 125-138.