This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, R. Articles by Mason, P. W. Search for Related Content PubMed PubMed Citation Articles by Suzuki, R. Articles by Mason, P. W. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Dengue

 Previous Article  |  Next Article 

Journal of Virology, February 2009, p. 1870-1880, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01891-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Construction and Characterization of a Single-Cycle Chimeric Flavivirus Vaccine Candidate That Protects Mice against Lethal Challenge with Dengue Virus Type 2

Ryosuke Suzuki,^1,4 Evandro R. Winkelmann,¹ and Peter W. Mason^1,2,3*

Department of Pathology,¹ Department of Microbiology and Immunology,² Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas 77555-0436,³ Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan⁴

Received 8 September 2008/ Accepted 26 November 2008

We have previously described a novel flavivirus vaccine technology based on a single-cycle, capsid (C) gene-deleted flavivirus called RepliVAX. RepliVAX can be propagated in cells that express high levels of C but undergoes only a single cycle of infection in vaccinated hosts. Here we report that we have adapted our RepliVAX technology to produce a dengue vaccine by replacing the prM/E genes of RepliVAX WN (a West Nile virus [WNV] RepliVAX) with the same genes of dengue virus type 2 (DENV2). Our first RepliVAX construct for dengue virus (RepliVAX D2) replicated poorly in WNV C-expressing cells. However, addition of mutations in prM and E that were selected during blind passage of a RepliVAX D2 derivative was used to produce a second-generation RepliVAX D2 (designated D2.2) that displayed acceptable growth in WNV C-expressing cells. RepliVAX D2.2 grew better in DENV2 C-expressing cells than WNV C-expressing cells, but after several passages in DENV2 C-expressing cells it acquired further mutations that permitted efficient growth in WNV C-expressing cells. We tested the potency and efficacy of RepliVAX D2.2 in a well-described immunodeficient mouse model for dengue (strain AG129; lacking the receptors for both type I and type II interferons). These mice produced dose-dependent DENV2-neutralizing antibody responses when vaccinated with RepliVAX D2.2. When challenged with 240 50% lethal doses of DENV2, mice given a single inoculation of RepliVAX D2.2 survived significantly longer than sham-vaccinated animals, although some of these severely immunocompromised mice eventually died from the challenge. Taken together these studies indicate that the RepliVAX technology shows promise for use in the development of vaccines that can be used to prevent dengue.

---

* Corresponding author. Mailing address: The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0436. Phone: (409) 747-8143. Fax: (409) 747-8150. E-mail: pwmason{at}utmb.edu

Published ahead of print on 10 December 2008.

---

Journal of Virology, February 2009, p. 1870-1880, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01891-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Schrauf, S., Mandl, C. W., Bell-Sakyi, L., Skern, T. (2009). Extension of Flavivirus Protein C Differentially Affects Early RNA Synthesis and Growth in Mammalian and Arthropod Host Cells. J. Virol. 83: 11201-11210 [Abstract] [Full Text]