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Journal of Virology, December 2007, p. 13412-13423, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01799-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Increased Immunogenicity of a DNA-Launched Venezuelan Equine Encephalitis Virus-Based Replicon DNA Vaccine{triangledown}

Karl Ljungberg,1,2* Alan C. Whitmore,1,2 Meagan E. Fluet,1,2 Timothy P. Moran,1,2 Reed S. Shabman,1,2 Martha L. Collier,1,2 Annette A. Kraus,2 Joseph M. Thompson,1,2 David C. Montefiori,3 Clayton Beard,4 and Robert E. Johnston1,2,4

Carolina Vaccine Institute, 9th Floor Burnett-Womack, West Drive, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7292,1 Department of Microbiology and Immunology, M. E. Jones Building, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7290,2 Laboratory for AIDS Vaccine Research and Development, Department of Surgery, SORF Building, Duke University Medical Center, Durham, North Carolina 27710,3 Global Vaccines Inc., P.O. Box 14827, Research Triangle Park, North Carolina 277094

Received 16 August 2007/ Accepted 24 September 2007

A novel genetic vaccine that is based on a Venezuelan equine encephalitis virus (VEE) replicon launched from plasmid DNA is described. The plasmid encodes a VEE replicon under the transcriptional control of the cytomegalovirus immediate-early promoter (VEE DNA). The VEE DNA consistently expressed 3- to 15-fold more green fluorescent protein in vitro than did a conventional DNA vaccine. Furthermore, transfection with the DNA-launched VEE replicon induced apoptosis and type I interferon production. Inoculation of mice with VEE DNA encoding human immunodeficiency virus type 1 gp160 significantly increased humoral responses by several orders of magnitude compared to an equal dose of a conventional DNA vaccine. These increases were also observed at 10- and 100-fold-lower doses of the VEE DNA. Cellular immune responses measured by gamma interferon and interleukin 2 enzyme-linked immunospot assay were significantly higher in mice immunized with the VEE DNA at decreased doses. The immune responses induced by the VEE DNA-encoded antigen, however, were independent of an intact type I interferon signaling pathway. Moreover, the DNA-launched VEE replicon induced an efficient prime to a VEE replicon particle (VRP) boost, increasing humoral and cellular immunity by at least 1 order of magnitude compared to VEE DNA only. Importantly, immunization with VEE DNA, as opposed to VRP, did not induce any anti-VRP neutralizing antibodies. Increased potency of DNA vaccines and reduced vector immunity may ultimately have an impact on the design of vaccination strategies in humans.

* Corresponding author. Mailing address: Carolina Vaccine Institute, 9th Floor Burnett-Womack, West Drive, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292. Phone: (919) 966-4026. Fax: (919) 843-9624. E-mail: Karl_Ljungberg{at}med.unc.edu

{triangledown} Published ahead of print on 3 October 2007.

Journal of Virology, December 2007, p. 13412-13423, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01799-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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