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
Torres, Rodrigo; Lan, Benson; Latif, Yama et al. (2014) Structural snapshots along the reaction pathway of Yersinia pestis RipA, a putative butyryl-CoA transferase. Acta Crystallogr D Biol Crystallogr 70:1074-85
Houghton, Raymond L; Reed, Dana E; Hubbard, Mark A et al. (2014) Development of a prototype lateral flow immunoassay (LFI) for the rapid diagnosis of melioidosis. PLoS Negl Trop Dis 8:e2727
Strotmeier, Jasmin; Mahrhold, Stefan; Krez, Nadja et al. (2014) Identification of the synaptic vesicle glycoprotein 2 receptor binding site in botulinum neurotoxin A. FEBS Lett 588:1087-93
Koellhoffer, Jayne F; Dai, Zhou; Malashkevich, Vladimir N et al. (2014) Structural characterization of the glycoprotein GP2 core domain from the CAS virus, a novel arenavirus-like species. J Mol Biol 426:1452-68
Bennett, Shannon N; Gu, Se Hun; Kang, Hae Ji et al. (2014) Reconstructing the evolutionary origins and phylogeography of hantaviruses. Trends Microbiol 22:473-82
Burtnick, Mary N; Brett, Paul J; DeShazer, David (2014) Proteomic analysis of the Burkholderia pseudomallei type II secretome reveals hydrolytic enzymes, novel proteins, and the deubiquitinase TssM. Infect Immun 82:3214-26
Koskiniemi, Sanna; Garza-Sánchez, Fernando; Sandegren, Linus et al. (2014) Selection of orphan Rhs toxin expression in evolved Salmonella enterica serovar Typhimurium. PLoS Genet 10:e1004255
Sabouri, Amir H; Marcondes, Maria Cecilia Garibaldi; Flynn, Claudia et al. (2014) TLR signaling controls lethal encephalitis in WNV-infected brain. Brain Res 1574:84-95
Vigant, Frederic; Hollmann, Axel; Lee, Jihye et al. (2014) The rigid amphipathic fusion inhibitor dUY11 acts through photosensitization of viruses. J Virol 88:1849-53
Relman, David A (2014) "Inconvenient truths" in the pursuit of scientific knowledge and public health. J Infect Dis 209:170-2

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