Internal ribosome entry site-based attenuation of a flavivirus candidate vaccine and evaluation of the effect of beta interferon coexpression on vaccine properties

Frese, Michael, Lee, Eva, Larena, Maximilian, Lim, Pek Siew, Rao, Sudha, Matthaei, Klaus I., Khromykh, Alexander, Ramshaw, Ian and Lobigs, Mario (2014) Internal ribosome entry site-based attenuation of a flavivirus candidate vaccine and evaluation of the effect of beta interferon coexpression on vaccine properties. Journal of Virology, 88 4: 2056-2070. doi:10.1128/JVI.03051-13


Author Frese, Michael
Lee, Eva
Larena, Maximilian
Lim, Pek Siew
Rao, Sudha
Matthaei, Klaus I.
Khromykh, Alexander
Ramshaw, Ian
Lobigs, Mario
Title Internal ribosome entry site-based attenuation of a flavivirus candidate vaccine and evaluation of the effect of beta interferon coexpression on vaccine properties
Journal name Journal of Virology   Check publisher's open access policy
ISSN 0022-538X
1098-5514
Publication date 2014-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1128/JVI.03051-13
Open Access Status DOI
Volume 88
Issue 4
Start page 2056
End page 2070
Total pages 15
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
Formatted abstract
Infectious clone technologies allow the rational design of live attenuated viral vaccines with the possibility of vaccine-driven coexpression of immunomodulatory molecules for additional vaccine safety and efficacy. The latter could lead to novel strategies for vaccine protection against infectious diseases where traditional approaches have failed. Here we show for the flavivirus Murray Valley encephalitis virus (MVEV) that incorporation of the internal ribosome entry site (IRES) of Encephalomyocarditis virus between the capsid and prM genes strongly attenuated virulence and that the resulting bicistronic virus was both genetically stable and potently immunogenic. Furthermore, the novel bicistronic genome organization facilitated the generation of a recombinant virus carrying an beta interferon (IFN-β) gene. Given the importance of IFNs in limiting virus dissemination and in efficient induction of memory B and T cell antiviral immunity, we hypothesized that coexpression of the cytokine with the live vaccine might further increase virulence attenuation without loss of immunogenicity. We found that bicistronic mouse IFN-β coexpressing MVEV yielded high virus and IFN titers in cultured cells that do not respond to the coexpressed IFN. However, in IFN response-sufficient cell cultures and mice, the virus produced a self-limiting infection. Nevertheless, the attenuated virus triggered robust innate and adaptive immune responses evidenced by the induced expression of Mx proteins (used as a sensitive biomarker for measuring the type I IFN response) and the generation of neutralizing antibodies, respectively. 
Keyword Virology
Virology
VIROLOGY
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online: 4 December 2013.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Mon, 17 Mar 2014, 22:33:10 EST by Anthony Yeates on behalf of School of Chemistry & Molecular Biosciences