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Evolution of attenuating mutations in dengue-2 strain S16803 PDK50 vaccine and comparison of growth kinetics with parent virus

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Abstract

A live-attenuated dengue-2 virus strain S16803 vaccine candidate that is immunogenic and safe in humans was derived by 50 passages in primary dog kidney (PDK) cells. To identify mutations associated with attenuation of the dengue-2 PDK50 vaccine strain, we determined the nucleotide changes that arose during PDK passage of the dengue-2 virus. Thirteen mutations distinguished the PDK50 virus from low-passage parent resulting in amino acid substitutions in the premembrane (E89G), envelope (E202K, N203D), nonstructural proteins NS1 (A43T), NS2A (L181F), NS2B (I26V), and NS4B (I/T108T, L112F). In addition, the PDK50 virus contained a C to T change of nucleotide 57 in the 5′ non-coding region and four silent mutations of nucleotides 591, 987, 6471, and 8907. An infectious PDK50 cDNA clone virus was produced and characterized for growth kinetics in monkey (LLC-MK2, Vero) and mosquito (C6/36) cells. Identification of mutations in the vaccine strain and availability of an infectious clone will permit systematic analysis of the importance of individual or collective mutations on attenuation of dengue virus.

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Acknowledgments

The authors would like to thank Dr. Ken Eckels, Walter Reed Army Institute of Research, for providing the lyophilized low-passage parent and PDK10, PDK30, PDK40 and PDK50 vaccine candidate viruses. The studies were supported by the United States Army Medical Research and Materiel Command.

Disclaimer

The views expressed herein are those of the authors and do not necessarily represent those of the Department of the Army, Department of Defense or the Food and Drug Administration.

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Authors and Affiliations

  1. Division of Virus Diseases, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA

    Eileen P. Kelly

  2. Center for Biologics Evaluation and Research/Food and Drug Administration, 1401 Rockville Pike, Rockville, MD, 20852, USA

    Stephanie Polo, Wellington Sun & Barry Falgout

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  1. Eileen P. Kelly
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  2. Stephanie Polo
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Correspondence to Eileen P. Kelly.

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Kelly, E.P., Polo, S., Sun, W. et al. Evolution of attenuating mutations in dengue-2 strain S16803 PDK50 vaccine and comparison of growth kinetics with parent virus. Virus Genes 43, 18–26 (2011). https://doi.org/10.1007/s11262-011-0602-z

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  • DOI: https://doi.org/10.1007/s11262-011-0602-z

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