{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:05:10Z","timestamp":1792587910785,"version":"4.5.0"},"reference-count":56,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2012,6,1]],"date-time":"2012-06-01T00:00:00Z","timestamp":1338508800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Chikungunya virus (CHIKV) is the mosquito-borne alphavirus that is the etiologic agent of massive outbreaks of arthralgic febrile illness that recently affected millions of people in Africa and Asia. The only CHIKV vaccine that has been tested in humans, strain 181\/clone 25, is a live-attenuated derivative of Southeast Asian human isolate strain AF15561. The vaccine was immunogenic in phase I and II clinical trials; however, it induced transient arthralgia in 8% of the vaccinees. There are five amino acid differences between the vaccine and its parent, as well as five synonymous mutations, none of which involves\n            <jats:italic>cis<\/jats:italic>\n            -acting genome regions known to be responsible for replication or packaging. To identify the determinants of attenuation, we therefore tested the five nonsynonymous mutations by cloning them individually or in different combinations into infectious clones derived from two wild-type (WT) CHIKV strains, La Reunion and AF15561. Levels of virulence were compared with those of the WT strains and the vaccine strain in two different murine models: infant CD1 and adult A129 mice. An attenuated phenotype indistinguishable from that of the 181\/clone 25 vaccine strain was obtained by the simultaneous expression of two E2 glycoprotein substitutions, with intermediate levels of attenuation obtained with the single E2 mutations. The other three amino acid mutations, in nsP1, 6K, and E1, did not have a detectable effect on CHIKV virulence. These results indicate that the attenuation of strain 181\/clone 25 is mediated by two point mutations, explaining the phenotypic instability observed in human vaccinees and also in our studies.\n          <\/jats:p>","DOI":"10.1128\/jvi.06449-11","type":"journal-article","created":{"date-parts":[[2012,3,29]],"date-time":"2012-03-29T02:35:51Z","timestamp":1332988551000},"page":"6084-6096","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":194,"title":["Attenuation of Chikungunya Virus Vaccine Strain 181\/Clone 25 Is Determined by Two Amino Acid Substitutions in the E2 Envelope Glycoprotein"],"prefix":"10.1128","volume":"86","author":[{"given":"Rodion","family":"Gorchakov","sequence":"first","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eryu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Leal","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi L.","family":"Forrester","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Plante","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannan L.","family":"Rossi","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalambos D.","family":"Partidos","sequence":"additional","affiliation":[{"name":"Inviragen, Inc., Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Paige","family":"Adams","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Seymour","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Weger","sequence":"additional","affiliation":[{"name":"Inviragen, Inc., Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Borland","sequence":"additional","affiliation":[{"name":"Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Sherman","sequence":"additional","affiliation":[{"name":"Sealy Center for Structural Biology and Molecular Biophysics, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann M.","family":"Powers","sequence":"additional","affiliation":[{"name":"Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge E.","family":"Osorio","sequence":"additional","affiliation":[{"name":"Inviragen, Inc., Madison, Wisconsin, USA"},{"name":"School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott C.","family":"Weaver","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, Sealy Center for Vaccine Development, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","first-page":"797","volume-title":"Diagnostic procedures for viral, rickettsial and chlamydial infections","author":"Beaty BJ","year":"1989","unstructured":"BeatyBJ CalisherCH ShopeRE. 1989. 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