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VACCINATION OF RHESUS MACAQUES AGAINST DENGUE-2 VIRUS WITH A PLASMID DNA VACCINE ENCODING THE VIRAL PRE-MEMBRANE AND ENVELOPE GENES

A nucleic acid vaccine for dengue-2 virus was developed, consisting of a plasmid DNA vector with the pre-membrane (prM) and envelope (E) genes expressed from a cytomegalovirus promoter. The DNA was adsorbed onto gold microspheres for administration by a gene gun. Expression was demonstrated by transfection of mouse cells in culture where the prM and E antigens were detected intracellularly, and the E antigen was detected in the culture supernatant fluid, similar to a natural infection. The vaccine elicited neutralizing antibodies to dengue-2 virus and antigen-specific cytotoxic T lymphocyte responses in mice. Several vaccination regimens were evaluated in rhesus macaques for the ability to elicit neutralizing antibodies and protect against viremia after challenge with live dengue-2 virus. Neutralizing antibodies were measured in three of three animals that received four 2-µg doses of DNA and in two of six animals that received two 1-µg doses. No antibodies were detected in three animals that received a single 1-µg dose. When dengue virus challenge was performed one month after vaccination, the three animals that received four 2-µg doses exhibited 0, 0, and 1 day of viremia compared with unimmunized controls which exhibited 4, 4, and 6 days of viremia. Three animals that received two 1-µg doses also exhibited 0, 0, and 1 day of viremia, whereas three animals that received a single 1-µg dose exhibited 2, 3, and 5 days of viremia compared with unimmunized controls, which exhibited 4 days of viremia each. When challenge was performed 7 months after vaccination, three animals that received two 1-µg doses exhibited 0, 3, and 5 days of viremia compared with unimmunized controls, which exhibited 4, 5, and 9 days of viremia. These results suggest that a regimen consisting of two 1-µg doses of DNA can confer satisfactory protection at one month, but not at seven months, after vaccination. Long-term protection following DNA vaccination may require revaccination, higher doses of DNA, or a vaccine that contains additional epitopes or adjuvants.

Received September 7, 2002. Accepted for publication December 4, 2002.

Acknowledgments: We thank the personnel of the Division of Veterinary Medicine of Walter Reed Army Institute of Research for animal husbandry and technical assistance with the animal experiments. We also gratefully acknowledge David Barvir, Stacie Bailey, and Kelly Jones for performing the virus neutralizing antibody assays and virus isolation assays.

Disclaimer: The views expressed here are those of the authors and should not be construed as official or to reflect the views of the United States Government.

Authors’ addresses: Robert Putnak, Department of Virus Diseases, Walter Reed Army Institute of Research, Suite 3A12, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, Telephone: 301-319-9426, Fax: 301-319-9661, E-mail: Robert.putnak{at}na.amedd.army.mil. James Fuller, PowderJect Vaccines, Inc., 585 Science Drive, Madison WI 53711, Telephone: 608-231-3150 extension 220, Fax: 608-231-6990. Lorna VanderZanden, Technology Applications Division, Defense Threat Reduction Agency, 6801 Telegraph Road, Alexandria, VA 22310-3398, Telephone: 703-325-9625, Fax: 703-325-7560. Bruce L. Innis, Clinical R&D and Medical Affairs, Vaccines, N.A., Glaxo-SmithKline, Mailcode UP4330, 1250 S. Collegeville Road, Collegeville, PA 19426-0989, Telephone: 610-917-6142, Fax: 610-917-4287 (present address: Clinical R&D and Medical Affairs, Vaccines N.A., GlaxoSmithKline, Renaissance Park, Mailcode RN0220, 2301 Renaissance Boulevard, Building 510, PO Box 61540, King of Prussia, PA 19406-2772). David W. Vaughn, Military Infectious Diseases Research Program, U.S. Army Medical Research and Materiel Command, Fort Detrick, Frederick, MD 21702, Telephone: 301-619-7882.

Reprint requests: John Petalas, Department of Virus Diseases, Walter Reed Army Institute of Research, Suite 3A12, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, Telephone: 301-319-9245, Fax: 301-319-9661.

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