Arenaviruses are emerging pathogens that are carried by rodents and occasionally transmitted to man with lethal consequences. Our studies focus on Lassa fever virus due to its virulence for human beings. Lassa virus accounts for 300,000 annual infections and thousands deaths in West Africa. The sizeable disease burden and the possibility that LAS virus can be used as a biological warfare agent make a strong case for effective vaccine development. In contrast to the well-studied model of arenavirus pathogenesis in the mouse, the virulence of Lassa fever in man, guinea pigs and non-human primates is directly related to viremia, and less related to immune-mediated pathology. Guinea pigs are a potentially useful model for elucidating the pathogenesis of Lassa virus infection and for vaccine and treatment developments. A close relative of Lassa fever virus, Mopeia virus, is not lethal in guinea pigs and monkeys, and can protect them from Lassa virus challenge. To determine the genetic basis of Lassa virus virulence we made interspecies virus recombinants between Lassa (LAS) and Mopeia (MOP) viruses. We will test the hypothesis that the Lassa L RNA segment is associated with fatal acute disease in experimental animals and that the MOP/LAS reassortant virus consisting of the L RNA of Mopeia and the S RNA of Lassa will be avirulent and will confer effective protection from a lethal Lassa virus challenge.
Our specific aims will be to: 1) compare the virulence of the reassortant MOP/LAS and LAS/MOP viruses with the virulence of the two parental, LAS and MOP viruses; 2) test the ability of the MOP/LAS reassortant to protect guinea pigs from lethal challenge with LAS virus. Virulence and protection will be measured in terms of survival, viremia, viral load in tissues, disturbances in clinical chemistry and hematology. Pro-inflammatory cyto/chemokines, TNF-alpha, IL-1beta, IL-6, and IL-8, will be monitored because clinical and experimental data showed involvement of these factors in LHF pathogenesis. Our long-range goal is to understand LAS virus pathogenesis and to develop effective treatments and vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VACC (02))
Program Officer
Repik, Patricia M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Lukashevich, Igor S; Pushko, Peter (2016) Vaccine platforms to control Lassa fever. Expert Rev Vaccines 15:1135-50
Tretyakova, Irina; Nickols, Brian; Hidajat, Rachmat et al. (2014) Plasmid DNA initiates replication of yellow fever vaccine in vitro and elicits virus-specific immune response in mice. Virology 468-470:28-35
Zapata, Juan C; Goicochea, Marco; Nadai, Yuka et al. (2014) Genetic variation in vitro and in vivo of an attenuated Lassa vaccine candidate. J Virol 88:3058-66
Zapata, Juan Carlos; Carrion Jr, Ricardo; Patterson, Jean L et al. (2013) Transcriptome analysis of human peripheral blood mononuclear cells exposed to Lassa virus and to the attenuated Mopeia/Lassa reassortant 29 (ML29), a vaccine candidate. PLoS Negl Trop Dis 7:e2406
Lukashevich, Igor S (2013) The search for animal models for Lassa fever vaccine development. Expert Rev Vaccines 12:71-86
Zapata, Juan C; Poonia, Bhawna; Bryant, Joseph et al. (2013) An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity. Virol J 10:52
Lukashevich, Igor S (2012) Advanced vaccine candidates for Lassa fever. Viruses 4:2514-57
Carrion Jr, Ricardo; Bredenbeek, Peter; Jiang, Xiaohong et al. (2012) Vaccine Platforms to Control Arenaviral Hemorrhagic Fevers. J Vaccines Vaccin 3:
Goicochea, Marco A; Zapata, Juan C; Bryant, Joseph et al. (2012) Evaluation of Lassa virus vaccine immunogenicity in a CBA/J-ML29 mouse model. Vaccine 30:1445-52
Lukashevich, Igor S; Carrion Jr, Ricardo; Salvato, Maria S et al. (2008) Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primates. Vaccine 26:5246-54

Showing the most recent 10 out of 16 publications