MOP/LAS chimeric vaccine against Lassa fever
Principal Investigator: Igor Lukashevich
Abstract: 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.
Funding Period: 2003-12-01 - 2009-04-30
more information: NIH RePORT
- Safety, immunogenicity, and efficacy of the ML29 reassortant vaccine for Lassa fever in small non-human primatesIgor S Lukashevich
Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, United States
Vaccine 26:5246-54. 2008..The ML29 reassortant is a promising vaccine candidate for Lassa fever...
- Molecular characterization of a reassortant virus derived from Lassa and Mopeia virusesDmitry A Moshkoff
Institute of Human Virology, University of Maryland Biotechnology Institute, 725 West Lombard Street, Baltimore, MD 21201, USA
Virus Genes 34:169-76. 2007..ML29 mutations in its genomic termini may have implications for the genetic stability and replication efficiency of ML29 reassortant...
- Advanced vaccine candidates for Lassa feverIgor S Lukashevich
Department of Pharmacology and Toxicology, School of Medicine, and Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Kentucky, USA
Viruses 4:2514-57. 2012..The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered...
- The search for animal models for Lassa fever vaccine developmentIgor S Lukashevich
Department of Pharmacology and Toxicology, School of Medicine and the Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY 40202, USA
Expert Rev Vaccines 12:71-86. 2013..All of these challenges will be addressed in this review in the context of available and novel animal models recently described for evaluation of LF vaccine candidates...
- Transcriptome analysis of human peripheral blood mononuclear cells exposed to Lassa virus and to the attenuated Mopeia/Lassa reassortant 29 (ML29), a vaccine candidateJuan Carlos Zapata
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
PLoS Negl Trop Dis 7:e2406. 2013..The remarkable differential expression of thrombomodulin, a key regulator of inflammation and coagulation, suggests its involvement with vascular abnormalities and mortality in Lassa fever disease. ..
- Genetic variation in vitro and in vivo of an attenuated Lassa vaccine candidateJuan C Zapata
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
J Virol 88:3058-66. 2014..In conclusion, the preclinical studies of ML29 as a Lassa virus vaccine candidate have been advanced, showing high levels of protection in nonhuman primates and acceptable stability both in vitro and in vivo. ..
- A recombinant Yellow Fever 17D vaccine expressing Lassa virus glycoproteinsPeter J Bredenbeek
Department of Medical Microbiology, Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
Virology 345:299-304. 2006..This study demonstrates the potential to develop an YFV17D-based bivalent vaccine against two viruses that are endemic in the same area of Africa...
- A ML29 reassortant virus protects guinea pigs against a distantly related Nigerian strain of Lassa virus and can provide sterilizing immunityRicardo Carrion
Southwest Foundation for Biomedical Research, San Antonio, TX, USA
Vaccine 25:4093-102. 2007..These results indicate that simultaneous replication of ML29 and LASV attenuates the virulence of LASV infection...