The alphaviruses include well developed biological weapons and highly virulent, emerging pathogens with the potential for endemic establishment in the United States. Eastern (EEEV) and western (WEEV) equine encephalitis are already native to the US, and cause fatal disease following mosquito or aerosol transmission. Venezuelan equine encephalitis virus (VEEV) causes periodic, massive epidemics of human disease that can also be fatal, including a 1971 Texas outbreak, and is also a highly aerosol-infectious weapon. Chikungunya virus (CHIKV) has for decades been an important but neglected cause of severe, chronic arthritis in Africa and Asia, and recently emerged to cause epidemics involving millions of people on islands off the eastern coast of Africa, and in the Indian subcontinent. Hundreds to thousands of excess deaths involving neurologic disease during these outbreaks suggest that CHIKV may have recently become more virulent. Importations into the Americas via viremic travelers, combined with a 2007 Italian CHIK epidemic initiated by a traveler from India, underscore the severe threat that CHIKV poses to the Americas; the risk for endemic establishment includes both neotropical/subtropical regions inhabited by Aedes aegypti, and temperate areas of the U.S. that are populated by the other efficient vector, Ae. albopictus. Vaccines are needed for all of these alphaviruses, both to prevent their potential impact as biological weapons and, especially for VEEV and CHIKV, to control transmission in endemic locations that puts the U.S. at risk for importation and endemic establishment. We will capitalize on our recent chimeric alphavirus design to optimize vaccine candidates for these 4 viruses, and to test them in rodents and nonhuman primates for attenuation, immunogenicity and efficacy.
The specific aims are to: 1) Generate and optimize lead vaccine candidates by combining attenuating mutations designed to modulate the host transcriptional shutoff virulence mechanism, and a novel genetic strategy to eliminate mosquito infectivity;2) Develop cynomolgus macaques as a nonhuman primate model for CHIKV, and characterize the course of infection in these animals, and;3) Test the final vaccines in murine and nonhuman primate models for attenuation, immunogenicity, efficacy and virulence stability, and evaluate their environmental safety by testing potential mosquito vectors and reservoir hosts, or models thereof. The resulting vaccines will be ready for final product development and clinical trials.
The encephalitic alphaviruses are endemic to the Americas and cause fatal disease following mosquito or aerosol transmission. Chikungunya virus has for decades been an important but neglected cause of severe arthritis, and recent epidemics coupled with importations into the US via viremic travelers, underscore the severe threat that it poses to the Americas. This project will provide safe, efficacious and cost-effective vaccines, both to prevent the potential impact of these alphaviruses as biological weapons, and to control transmission in endemic locations that puts the US at risk for importation and endemic establishment.
|Navarro, Juan-Carlos; Giambalvo, Dileyvic; Hernandez, Rosa et al. (2016) Isolation of Madre de Dios Virus (Orthobunyavirus; Bunyaviridae), an Oropouche Virus Species Reassortant, from a Monkey in Venezuela. Am J Trop Med Hyg 95:328-38|
|Park, Arnold; Yun, Tatyana; Hill, Terence E et al. (2016) Optimized P2A for reporter gene insertion into Nipah virus results in efficient ribosomal skipping and wild-type lethality. J Gen Virol 97:839-43|
|Aghazadeh, Amirali; Lin, Adam Y; Sheikh, Mona A et al. (2016) Universal microbial diagnostics using random DNA probes. Sci Adv 2:e1600025|
|Inglis, Fiona M; Lee, Kim M; Chiu, Kevin B et al. (2016) Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation. J Neurovirol 22:140-8|
|Hatcher, Christopher L; Mott, Tiffany M; Muruato, Laura A et al. (2016) Burkholderia mallei CLH001 Attenuated Vaccine Strain Is Immunogenic and Protects against Acute Respiratory Glanders. Infect Immun 84:2345-54|
|Chen, Hui; HagstrÃ¶m, Anna E V; Kim, Jinsu et al. (2016) Flotation Immunoassay: Masking the Signal from Free Reporters in Sandwich Immunoassays. Sci Rep 6:24297|
|Crannell, Zachary Austin; Cabada, Miguel Mauricio; Castellanos-Gonzalez, Alejandro et al. (2015) Recombinase polymerase amplification-based assay to diagnose Giardia in stool samples. Am J Trop Med Hyg 92:583-7|
|Walker, David H; Dumler, J Stephen (2015) The role of CD8 T lymphocytes in rickettsial infections. Semin Immunopathol 37:289-99|
|Mott, Tiffany M; Vijayakumar, Sudhamathi; Sbrana, Elena et al. (2015) Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development. PLoS Negl Trop Dis 9:e0003863|
|Gregory, Anthony E; Judy, Barbara M; Qazi, Omar et al. (2015) A gold nanoparticle-linked glycoconjugate vaccine against Burkholderia mallei. Nanomedicine 11:447-56|
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