Dengue vaccine strain

Dengue vaccine strain - JOURNAL OF VIROLOGY, Nov. 2003, p....

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J OURNAL OF VIROLOGY, Nov. 2003, p. 11436–11447 Vol. 77, No. 21 0022-538X/03/$08.00 1 0 DOI: 10.1128/JVI.77.21.11436–11447.2003 Copyright © 2003, American Society for Microbiology. All Rights Reserved. Dengue 2 PDK-53 Virus as a Chimeric Carrier for Tetravalent Dengue Vaccine Development Claire Y.-H. Huang, 1 * Siritorn Butrapet, 1,2 Kiyotaka R. Tsuchiya, 1 Natth Bhamarapravati, 2 Duane J. Gubler, 1 and Richard M. Kinney 1 Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services, Fort Collins, Colorado 80522, 1 and Center for Vaccine Development, Institute of Science and Technology for Development, Mahidol University at Salaya, Nakhonpathom 73170, Thailand 2 Received 4 June 2003/Accepted 24 July 2003 Attenuation markers of the candidate dengue 2 (D2) PDK-53 vaccine virus are encoded by mutations that reside outside of the structural gene region of the genome. We engineered nine dengue virus chimeras con- taining the premembrane (prM) and envelope (E) genes of wild-type D1 16007, D3 16562, or D4 1036 virus within the genetic backgrounds of wild-type D2 16681 virus and the two genetic variants (PDK53-E and PDK53-V) of the D2 PDK-53 vaccine virus. Expression of the heterologous prM-E genes in the genetic backgrounds of the two D2 PDK-53 variants, but not that of wild-type D2 16681 virus, resulted in chimeric viruses that retained PDK-53 characteristic phenotypic markers of attenuation, including small plaque size and temperature sen- sitivity in LLC-MK 2 cells, limited replication in C6/36 cells, and lack of neurovirulence in newborn ICR mice. Chimeric D2/1, D2/3, and D2/4 viruses replicated efFciently in Vero cells and were immunogenic in AG129 mice. Chimeric D2/1 viruses protected adult AG129 mice against lethal D1 virus challenge. Two tetravalent virus formulations, comprised of either PDK53-E- or PDK53-V-vectored viruses, elicited neutralizing antibody titers in mice against all four dengue serotypes. These antibody titers were similar to the titers elicited by monovalent immunizations, suggesting that viral interference did not occur in recipients of the tetravalent formulations. The results of this study demonstrate that the unique attenuation loci of D2 PDK-53 virus make it an attractive vector for the development of live attenuated ±avivirus vaccines. Dengue (DEN) viruses, which comprise four serotypes (D1 to D4), are members of the Flavivirus genus and contain a single-stranded positive-sense genomic RNA of approximately 11 kb. The RNA genome organization is 5 9 NCR-C-prM-E- NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5-3 9 NCR (where NCR is noncoding region, C is capsid, prM is premembrane, E is envelope, and NS is nonstructural protein). The structural pro- teins (C, prM, and E) and the NS proteins are translated as a single polyprotein precursor which is processed by cellular and viral proteases (37). DEN viruses are the leading cause of mos- quito-transmitted viral disease in humans. DEN virus trans- mission results in an estimated 100 million cases of dengue fever and up to several hundred thousand cases of its more se-
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Dengue vaccine strain - JOURNAL OF VIROLOGY, Nov. 2003, p....

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