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Three novel recombinant dengue type 3 (DEN3) virus vaccine candidates have been generated from a DEN3 virus isolated from a mild outbreak of dengue fever in the Sleman area of central Java in Indonesia in 1978. Antigenic chimeric viruses were prepared by replacing the membrane precursor and envelope (ME) proteins of recombinant DEN4 (rDEN4) virus with those from DEN3 Sleman/78 in the presence (rDEN3/4
30(ME)) and the absence (rDEN3/4(ME)) of the 30 mutation, a previously described 30-nucleotide deletion in the 3' untranslated region. In addition, a full-length infectious cDNA clone was generated from the DEN3 isolate and used to produce rDEN3 virus and the vaccine candidate rDEN330. The chimeric viruses rDEN3/4(ME) and rDEN3/430(ME) appear to be acceptable vaccine candidates since they were restricted in replication in severe combined immune deficiency mice transplanted with human hepatoma cells, in rhesus monkeys, and in Aedes and Toxorynchites mosquitoes, and each was protective in rhesus monkeys against DEN3 virus challenge. The rDEN3/4(ME) and rDEN3/430(ME) viruses were comparable in all parameters evaluated, indicating that antigenic chimerization resulted in the observed high level of attenuation. Surprisingly, rDEN330 was not attenuated in any model tested when compared with wild-type rDEN3 and therefore, is not a vaccine candidate at present. Thus, the rDEN3/4(ME) and rDEN3/430(ME) antigenic chimeric viruses can be considered for evaluation in humans and for inclusion in a tetravalent dengue vaccine.
Received April 19, 2004. Accepted for publication June 22, 2004.
Acknowledgments: We are grateful to Dr. Marisa St. Claire and Tammy Tobery (BioQual, Rockville, MD) and Lara Gilmore (Walter Reed Army Institute of Research, Silver Spring, MD) for expert technical assistance.
Authors’ address: Joseph E. Blaney Jr., Christopher T. Hanson, Cai-Yen Firestone, Kathryn A. Hanley, Brian R. Murphy, and Stephen S. Whitehead, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50, Room 6515, 50 South Drive, MSC 8007, Bethesda, MD 20892-8007, Telephone: 301-594-1630, Fax: 301-480-4873, E-mails: jblaney{at}niaid.nih.gov, chanson{at}niaid.nih.gov, cfirestone{at}niaid.nih.gov, khanley{at}niaid.nih.gov, bmurphy{at}niaid.nih.gov, and swhitehead{at}niaid.nih.gov.
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