Abstract

Highly pathogenic arenaviruses, Lassa, Junun, Machupo, are dominant viral species among NIAID Category A Priority Pathogens. The development of safe and efficacious vaccines against these pathogens with particular emphasis on multivalent and cross protective strategy and advanced platform technology is one of the priorities of NIH/NIAID. The main goal of this project is an advanced development and optimization of alphavirus-based VLPV (virus-like-particle-vectors) technology (patent is pending) as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses. Using this technology and rational vaccine design we will develop: (i) a bivalent LASV vaccine with enhanced immunogenicity and cross-protective potential against distantly-related LASV genotypes, and (ii) a bivalent JUNV&MACV vaccine. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for preclinical testing in nonhuman primates.
SPECIFIC AIM I : Rational Design of Multivalent VLPV Expressing Arenaviral Glycoproteins with Enhanced Immunogenicity and Cross-Reactivity. The goal of this aim is to design: (i) VLPV expressing LASV GP able to induce strong CD8+ T cell responses to distantly-related LASV lineages, I and IV, through the conventional MHC I peptide presentation and through cross-priming;ii) VLPV expressing JUNV&MACV GP to induce neutralizing Abs against both pathogens;and iii) to optimize alphavirus bi-cistronic replicon structures for product development.
SPECIFIC AIM II : Selection of Immunogenic and Cross-Reactive Recombinant VLPV Vaccines in Experimental Animals. In-process Safety Testing.
SPECIFIC AIM III : Pre-Clinical Safety, Immunogenicity, and Efficacy in NHP. Tox Lot vaccine products will be tested for Safety, Immunogenicity, and Efficacy in the NHP challenge model we recently developed. The main goal of this project is an advanced development and optimization of Virus-Like-Particle-Vectors technology as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses, Lassa-Junin-Machupo. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for Safety, Immunogenicity, and Efficacy Studies in non-human primates

Public Health Relevance

The main goal of this project is an advanced development and optimization of Virus- Like-Particle-Vectors technology as a generic platform for preventive biodefense vaccines against highly pathogenic arenaviruses, Lassa-Junin-Machupo. The VLPV technology will be transferred to a manufacturing environment and scaled-up to produce GLP-grade vaccines for Safety, Immunogenicity, and Efficacy Studies in non-human primates

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093450-03
Application #
8249031
Study Section
Special Emphasis Panel (ZAI1-NLE-M (J3))
Program Officer
Repik, Patricia M
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$822,732
Indirect Cost
$222,866

  Institution

Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292

  Publications

Wang, Min; Jokinen, Jenny; Tretyakova, Irina et al. (2018) Alphavirus vector-based replicon particles expressing multivalent cross-protective Lassa virus glycoproteins. Vaccine 36:683-690
Warner, Nikole L; Jokinen, Jenny D; Beier, Juliane I et al. (2018) Mammarenaviral Infection Is Dependent on Directional Exposure to and Release from Polarized Intestinal Epithelia. Viruses 10:
Lukashevich, Igor S; Pushko, Peter (2016) Vaccine platforms to control Lassa fever. Expert Rev Vaccines 15:1135-50
Beier, Juliane I; Jokinen, Jenny D; Holz, Gretchen E et al. (2015) Novel mechanism of arenavirus-induced liver pathology. PLoS One 10:e0122839
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
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; 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
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
Tretyakova, Irina; Lukashevich, Igor S; Glass, Pamela et al. (2013) Novel vaccine against Venezuelan equine encephalitis combines advantages of DNA immunization and a live attenuated vaccine. Vaccine 31:1019-25
Lukashevich, Igor S (2013) The search for animal models for Lassa fever vaccine development. Expert Rev Vaccines 12:71-86

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