Currently, no vaccines exist for a significant number of historically important viral pathogens and newly emerging viral zoonotic disease threats. In part, this situation results from the incompatibility of existing methodologies with the challenges posed by a wide array of emerging viruses. The extent of attenuation mediated by approaches such as serial passaging of viruses, viral recombination and directed molecular evolution is unpredictable and this characteristic contributes to the lengthy production times for many vaccines made using these strategies. Likewise, a number of vaccines constructed using these methodologies have demonstrated poor safety profiles due to the inherent uncertainty in the number of attenuation determinants introduced. In this study we aim to further define a novel strategy to intuitively construct live-attenuated viral (LAV) vaccines applicable to the development of vaccines to a broad array of acute viral diseases. Our approach is based on the manipulation of host strategies for the regulation of protein translation. We hypothesize that use of rare codons as attenuation determinants for vaccine candidates will produce more stably attenuated viruses that can be rationally engineered with predictable replication phenotypes within host cells. Moreover, we have demonstrated that these substitutions can be introduced into various places in viral genomes, unlike amino acid substitutions which are conventionally employed to attenuate viruses. We have also designed a second strategy to further improve the safety of vaccines that restricts the replication of vaccine viruses in tissues that are responsible for engendering disease pathology. By introducing the target sequences for tissue-specific miRNAs into the viral genome we have demonstrated the ability to specifically block infection of target cells expressing the cognate miRNA, while permitting normal unaltered levels of replication in the cell populations required for the induction of a protective immune response. Importantly, this strategy is compatible with the modification of existing vaccines to improve their safety profiles. The approaches defined in this study have broad implications for the rapid development of prophylactic agents to a variety of disease threats.

Public Health Relevance

This study is aimed at further characterizing a novel platform for the development of vaccines for viral pathogens that are important for biodefense and the control of new and existing disease agents in other countries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065359-09
Application #
8462543
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$131,535
Indirect Cost
$13,091
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Waggoner, Jesse J; Gresh, Lionel; Mohamed-Hadley, Alisha et al. (2016) Single-Reaction Multiplex Reverse Transcription PCR for Detection of Zika, Chikungunya, and Dengue Viruses. Emerg Infect Dis 22:1295-7
Ziegler, Christopher M; Eisenhauer, Philip; Bruce, Emily A et al. (2016) The Lymphocytic Choriomeningitis Virus Matrix Protein PPXY Late Domain Drives the Production of Defective Interfering Particles. PLoS Pathog 12:e1005501
Barbour, Alan G (2016) Infection resistance and tolerance in Peromyscus spp., natural reservoirs of microbes that are virulent for humans. Semin Cell Dev Biol :
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
Levin, Mattias; King, Jasmine J; Glanville, Jacob et al. (2016) Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy. J Allergy Clin Immunol 137:1535-44
Chomel, Bruno B; Molia, Sophie; Kasten, Rickie W et al. (2016) Isolation of Bartonella henselae and Two New Bartonella Subspecies, Bartonellakoehlerae Subspecies boulouisii subsp. nov. and Bartonella koehlerae Subspecies bothieri subsp. nov. from Free-Ranging Californian Mountain Lions and Bobcats. PLoS One 11:e0148299
Kern, Aurelie; Zhou, Chensheng W; Jia, Feng et al. (2016) Live-vaccinia virus encapsulation in pH-sensitive polymer increases safety of a reservoir-targeted Lyme disease vaccine by targeting gastrointestinal release. Vaccine 34:4507-13
Zeltina, Antra; Bowden, Thomas A; Lee, Benhur (2016) Emerging Paramyxoviruses: Receptor Tropism and Zoonotic Potential. PLoS Pathog 12:e1005390
Waggoner, Jesse J; Ballesteros, Gabriela; Gresh, Lionel et al. (2016) Clinical evaluation of a single-reaction real-time RT-PCR for pan-dengue and chikungunya virus detection. J Clin Virol 78:57-61
Sanman, Laura E; Qian, Yu; Eisele, Nicholas A et al. (2016) Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. Elife 5:e13663

Showing the most recent 10 out of 434 publications