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

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
Name
University of Louisville
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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; 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
Hayes, Melissa W; Carrion Jr, Ricardo; Nunneley, Jerritt et al. (2012) Pathogenic Old World arenaviruses inhibit TLR2/Mal-dependent proinflammatory cytokines in vitro. J Virol 86:7216-26
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
Jiang, Xiaohong; Dalebout, Tim J; Bredenbeek, Peter J et al. (2011) Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs. Vaccine 29:1248-57