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The latter could lead to novel strategies for vaccine protection against infectious diseases where traditional approaches have failed. Here we show for the flavivirus<jats:named-content content-type=\"genus-species\">Murray Valley encephalitis virus<\/jats:named-content>(MVEV) that incorporation of the internal ribosome entry site (IRES) of<jats:named-content content-type=\"genus-species\">Encephalomyocarditis virus<\/jats:named-content>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-\u03b2) 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-\u03b2 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.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The family<jats:named-content content-type=\"genus-species\">Flaviviridae<\/jats:named-content>includes a number of important human pathogens, such as<jats:named-content content-type=\"genus-species\">Dengue virus<\/jats:named-content>,<jats:named-content content-type=\"genus-species\">Yellow fever virus<\/jats:named-content>,<jats:named-content content-type=\"genus-species\">Japanese encephalitis virus<\/jats:named-content>,<jats:named-content content-type=\"genus-species\">West Nile virus<\/jats:named-content>, and<jats:named-content content-type=\"genus-species\">Hepatitis C virus<\/jats:named-content>. Flaviviruses infect large numbers of individuals on all continents. For example, as many as 100 million people are infected annually with<jats:named-content content-type=\"genus-species\">Dengue virus<\/jats:named-content>, and 150 million people suffer a chronic infection with<jats:named-content content-type=\"genus-species\">Hepatitis C virus<\/jats:named-content>. However, protective vaccines against dengue and hepatitis C are still missing, and improved vaccines against other flaviviral diseases are needed. The present study investigated the effects of a redesigned flaviviral genome and the coexpression of an antiviral protein (interferon) on virus replication, pathogenicity, and immunogenicity. Our findings may aid in the rational design of a new class of well-tolerated and safe vaccines.<\/jats:p>","DOI":"10.1128\/jvi.03051-13","type":"journal-article","created":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T01:47:51Z","timestamp":1386208071000},"page":"2056-2070","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Internal Ribosome Entry Site-Based Attenuation of a Flavivirus Candidate Vaccine and Evaluation of the Effect of Beta Interferon Coexpression on Vaccine Properties"],"prefix":"10.1128","volume":"88","author":[{"given":"Michael","family":"Frese","sequence":"first","affiliation":[{"name":"John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia"},{"name":"Faculty of Education, Science, Technology and Mathematics, University of Canberra, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Lee","sequence":"additional","affiliation":[{"name":"Faculty of Education, Science, Technology and Mathematics, University of Canberra, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian","family":"Larena","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pek Siew","family":"Lim","sequence":"additional","affiliation":[{"name":"Faculty of Education, Science, Technology and Mathematics, University of Canberra, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudha","family":"Rao","sequence":"additional","affiliation":[{"name":"Faculty of Education, Science, Technology and Mathematics, University of Canberra, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus I.","family":"Matthaei","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Khromykh","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Ramshaw","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia"},{"name":"Faculty of Education, Science, Technology and Mathematics, University of Canberra, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Lobigs","sequence":"additional","affiliation":[{"name":"Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1155761"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307473110"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002142"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002197"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2012.11.013"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2008.04.020"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2422"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2004.00204.x"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(02)00349-7"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09907"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3133"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1586\/erv.11.9"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.11.7158"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2008.09.019"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0040353"},{"key":"e_1_3_2_17_2","first-page":"6201","article-title":"Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity","volume":"61","author":"Odaka M","year":"2001","unstructured":"OdakaMStermanDHWiewrodtRZhangYKieferMAminKMGaoGPWilsonJMBarsoumJKaiserLRAlbeldaSM. 2001. 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