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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; Khromykh, Alexander A; Ramshaw, Ian; Lobigs, Mario

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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...[Show more]

dc.contributor.authorFrese, Michael
dc.contributor.authorLee, Eva
dc.contributor.authorLarena, Maximilian
dc.contributor.authorLim, Pek Siew
dc.contributor.authorRao, Sudha
dc.contributor.authorMatthaei, Klaus
dc.contributor.authorKhromykh, Alexander A
dc.contributor.authorRamshaw, Ian
dc.contributor.authorLobigs, Mario
dc.date.accessioned2015-12-10T23:32:47Z
dc.identifier.issn0022-538X
dc.identifier.urihttp://hdl.handle.net/1885/68996
dc.description.abstractInfectious 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.
dc.publisherAmerican Society for Microbiology
dc.rightsAuthor/s retain copyright
dc.sourceJournal of Virology
dc.titleInternal ribosome entry site-based attenuation of a flavivirus candidate vaccine and evaluation of the effect of beta interferon coexpression on vaccine properties
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume88
dc.date.issued2014
local.identifier.absfor060500 - MICROBIOLOGY
local.identifier.ariespublicationU3488905xPUB1888
local.type.statusPublished Version
local.contributor.affiliationFrese, Michael, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLee, Eva, University of Canberra
local.contributor.affiliationLarena, Maximilian, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLim, Pek Siew, University of Canberra
local.contributor.affiliationRao, Sudha, University of Canberra
local.contributor.affiliationMatthaei, Klaus, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationKhromykh, Alexander A, University of Queensland
local.contributor.affiliationRamshaw, Ian, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLobigs, Mario, College of Medicine, Biology and Environment, ANU
local.bibliographicCitation.issue4
local.bibliographicCitation.startpage2056
local.bibliographicCitation.lastpage2070
local.identifier.doi10.1128/JVI.03051-13
dc.date.updated2015-12-10T11:22:11Z
local.identifier.scopusID2-s2.0-84893454599
local.identifier.thomsonID000331125500019
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

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