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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057156-09
Application #
8377052
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$815,425
Indirect Cost
$110,855
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Matz, L M; Kamdar, K Y; Holder, M E et al. (2018) Challenges of Francisella classification exemplified by an atypical clinical isolate. Diagn Microbiol Infect Dis 90:241-247
Langsjoen, Rose M; Haller, Sherry L; Roy, Chad J et al. (2018) Chikungunya Virus Strains Show Lineage-Specific Variations in Virulence and Cross-Protective Ability in Murine and Nonhuman Primate Models. MBio 9:
Pandey, Aseem; Lin, Furong; Cabello, Ana L et al. (2018) Activation of Host IRE1?-Dependent Signaling Axis Contributes the Intracellular Parasitism of Brucella melitensis. Front Cell Infect Microbiol 8:103
Russell-Lodrigue, Kasi E; Killeen, Stephanie Z; Ficht, Thomas A et al. (2018) Mucosal bacterial dissemination in a rhesus macaque model of experimental brucellosis. J Med Primatol 47:75-77
Raja, B; Goux, H J; Marapadaga, A et al. (2017) Development of a panel of recombinase polymerase amplification assays for detection of common bacterial urinary tract infection pathogens. J Appl Microbiol 123:544-555
Nunes, Marcio R T; Contreras-Gutierrez, María Angélica; Guzman, Hilda et al. (2017) Genetic characterization, molecular epidemiology, and phylogenetic relationships of insect-specific viruses in the taxon Negevirus. Virology 504:152-167
Rossetti, Carlos A; Drake, Kenneth L; Lawhon, Sara D et al. (2017) Systems Biology Analysis of Temporal In vivo Brucella melitensis and Bovine Transcriptomes Predicts host:Pathogen Protein-Protein Interactions. Front Microbiol 8:1275
Paterson, Andrew S; Raja, Balakrishnan; Mandadi, Vinay et al. (2017) A low-cost smartphone-based platform for highly sensitive point-of-care testing with persistent luminescent phosphors. Lab Chip 17:1051-1059
Park, Arnold; Yun, Tatyana; Vigant, Frederic et al. (2016) Nipah Virus C Protein Recruits Tsg101 to Promote the Efficient Release of Virus in an ESCRT-Dependent Pathway. PLoS Pathog 12:e1005659
Pandey, Aseem; Cabello, Ana; Akoolo, Lavoisier et al. (2016) The Case for Live Attenuated Vaccines against the Neglected Zoonotic Diseases Brucellosis and Bovine Tuberculosis. PLoS Negl Trop Dis 10:e0004572

Showing the most recent 10 out of 384 publications