Volume 72, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


ChimeriVax™-dengue (DEN) viruses are live attenuated vaccine candidates. They are constructed by replacing the premembrane (prM) and envelope (E) genes of the yellow fever (YF) 17D virus vaccine with the corresponding genes from wild-type DEN viruses (serotypes 1–4) isolated from humans. In this study, the growth kinetics of ChimeriVax™-DEN1-4 and parent viruses (wild-type DEN-1-4 and YF 17D) were assessed in human myeloid dendritic cells (DCs) and in three hepatic cell lines (HepG2, Huh7, and THLE-3). In DC, ChimeriVax™-DEN-1-4 showed similar growth kinetics to their parent viruses, wild-type DEN virus (propagated in Vero cells), or YF 17D virus (peak titers ~3–4.5 log plaque-forming units (PFU)/mL at 48–72 hours post-infection). Parent wild-type DEN-1-4 viruses derived from C6/36 mosquito cells did not show any growth at a multiplicity of infection of 0.1 in DCs, except for DEN-2 virus, which grew to a modest titer of 2.5 log PFU/mL at 48 hours post-infection. ChimeriVax™-DEN1-4 grew to significantly lower titers (2–5 log PFU/mL) than YF 17D virus in hepatic cell lines THLE-3 and HepG2, but not in Huh7 cells. These experiments suggest that ChimeriVax™-DEN1-4 viruses replicate similarly to YF-VAX in DCs, but at a lower level than YF 17D virus in hepatic cell lines. The lack of growth of chimeric viruses in human hepatic cells suggests that these viruses may be less hepatotropic than YF 17D virus vaccine in humans.


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  1. Rothman AL, Ennis FA, 1999. Immunopathogenesis of dengue hemorrhagic fever. Virology 257 : 1–6.
  2. Guirakhoo F, Arroyo J, Pugachev KV, Miller C, Zhang Z-X, Weltzin R, Georgakopoulos K, Catalan J, Ocran S, Soike K, Ratterree M, Monath TP, 2001. Construction, safety, and immunogenicity in nonhuman primates of a chimeric yellow fever-dengue virus tetravalent vaccine. J Virol 75 : 7290–7304.
  3. Lane P, Brocker, 1999. Developmental regulation of dendritic cell function. Curr Opin Immunol 11 : 308–313.
  4. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu Y-J, Pulendran B, Palucka K, 2000. Immunobiology of dendritic cells. Annu Rev Immunol 18 : 767–811.
  5. Wu S-JL, Grouard-Vogel G, Wellington S, Mascola JR, Bratchel E, Putvatana R, Louder MK, Filgueira L, Marovich MA, Wong HK, Blauvelt A, Murphy GS, Robb ML, Innes BL, Birx DL, Hayes CG, Schlesinger Frankel S, 2000. Human skin Langherans cells are targets of dengue virus infection. Nat Med 6 : 816–820.
  6. Ho L-J, Wang J-J, Shaio M-F, Kao C-L, Chang D-M, Han S-W, Lai J-H, 2001. Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. J Immunol 166 : 1499–1506.
  7. Libraty DH, Pichyangkul S, Ajariyakhajorn C, Endy TP, Ennis FA, 2001. Human dendritic cells are activated by dengue virus infection: Enhancement by gamma interferon and implications for disease pathogenesis. J Virol 75 : 3501–3508.
  8. Marovich M, Grouard-Vogel G, Louder M, Eller M, Sun W, Wu SJ, Putvatana R, Murphy G, Tassaneetrithep B, Burguess T, 2001. Human dendritic cells as targets of dengue virus infection. J Investig Dermatol Symp Proc 6 : 219–224.
  9. Tassaneetrithep B, Burgess TH, Granelli-Piperno A, Trumpf-heller C, Finke J, Wellington S, Eller MA, Pattanapanyasat K, Sarasombath S, Birx DL, Steinman RM, Schlesinger S, Birx DL, Steinman RM, Schlesinger S, Marovich MA, 2003. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J Exp Med 197 : 823–829.
  10. Navarro-Sanchez E, Altmeyer R, Amara A, Schwartz O, Fieschi F, Virelizier J-L, Arenzana-Seisdedos F, Desprès P, 2003. Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep 4 : 723–728.
  11. Johnston LJ, Halliday GM, King NJC, 2000. Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus. J Invest Dermatol 114 : 560–568.
  12. Monath TP, Barrett AD, 2003. Pathogenesis and pathophysiology of yellow fever. Adv Virus Res 60 : 343–395.
  13. Courageot MP, Catteau A, Despres P, 2003. Mechanisms of dengue virus-induced cell death. Adv Virus Res 60 : 157–186.
  14. Marianneau P, Steffan AM, Royer C, Drouet MT, Jaeck D, Kirn A, Deubel V, 1999. Infection of primary cultures of human Kupffer cells by dengue virus: no viral progeny synthesis, but cytokine production is evident. J Virol 73 : 5201–5206.
  15. Duarte dos Santos CN, Frenkiel MP, Courageot MP, Rocha CF, Vazeille-Falcoz MC, Wien MW, Rey FA, Deubel V, Despres P, 2000. Determinants in the envelope E protein and viral RNA helicase NS3 that influence the induction of apoptosis in response to infection with dengue type 1 virus. Virology 274 : 292–308.
  16. Hilgard P, Stockert R, 2000. Heparan sulfate proteoglycans initiate dengue virus infection of hepatocytes. Hepatology 32 : 1069–1077.
  17. Lin YL, Liu CC, Lei HY, Yeh TM, Lin YS, Chen RM, Liu HS, 2000. Infection of five human liver cell lines by dengue-2 virus. J Med Virol 60 : 425–431.
  18. Marianneau P, Cardona A, Edelman L, Deubel V, Despres P, 1997. Dengue virus replication in human hepatoma cells activates NF-kappaB which in turn induces apoptotic cell death. J Virol 71 : 3244–3249.
  19. Marianneau P, Megret F, Olivier R, Morens DM, Deubel V, 1996. Dengue 1 virus binding to human hepatoma HepG2 and simian Vero cell surfaces differs. J Gen Virol 77 : 2547–2554.
  20. Martin M, Tsai TF, Cropp B, Chang GJ, Holmes DA, Tseng J, Shieh W, Zaki SR, Al-Sanouri I, Cutrona AF, Ray G, Weld LH, Cetron MS, 2001. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 358 : 98–104.
  21. Rosen L, Khin MM, UT, 1989. Recovery of virus from the liver of children with fatal dengue: reflections on the pathogenesis of the disease and its possible analogy with that of yellow fever. Res Virol 140 : 351–360.
  22. Monath TP, 2004. Yellow fever vaccine. Plotkin SA, Orenstein WA, eds. Vaccines. Fourth edition. Philadelphia: W. B. Saunders, 1095–1176.
  23. Guirakhoo F, Weltzin R, Chambers TJ, Zhang ZX, Soike K, Ratterree M, Arroyo J, Georgakopoulos K, Catalan J, Monath TP, 2000. Recombinant chimeric yellow fever-dengue type 2 virus is immunogenic and protective in nonhuman primates. J. Virol 74 : 5477–5485.
  24. Monath TP, Levenbook I, Soike K, Zhang Z-X, Ratterree M, Draper K, Barrett ADT, Nichols R, Weltzin R, Arroyo J, Guirakhoo F, 2000. Chimeric yellow fever 17D-Japanese encephalitis virus vaccine: Dose-response effectiveness and extended safety testing in rhesus monkeys. J Virol 74 : 1742–1751.
  25. Taweechaisupapong S, Sriurairatana S, Angsubhakorn S, Yoksan S, Bhamarapravati N, 1996. In vivo and in vitro studies on the morphological change in the monkey epidermal Langerhans cells following exposure to dengue 2 (16681) virus. Southeast Asian J Trop Med Public Health 27 : 664–672.
  26. Taweechaisupapong S, Sriurairatana S, Angsubhakorn S, Yoksan S, Khin MM, Sahaphong S, Bhamarapravati N, 1996. Langerhans cell density and serological changes following intradermal immunisation of mice with dengue 2 virus. J Med Microbiol 45 : 138–145.
  27. Bielefeldt-Ohmann H, Meyer M, Fitzpatrick DR, Mackenzie JS, 2001. Dengue virus binding to human leukocyte cell lines: receptor usage differs between cell types and virus strains. Virus Res 73 : 81–89.
  28. Cologna R, Rico-Hesse R, 2003. American genotype structures decrease dengue virus output from human monocytes and dendritic cells. J Virol 77 : 3929–3938.
  29. Johnson AJ, Guirakhoo F, Roehrig JT, 1994. The envelope glycoproteins of dengue 1 and dengue 2 viruses grown in mosquito cells differ in their utilization of potential glycosylation sites. Virology 203 : 241–249.
  30. Guirakhoo F, Pugachev K, Arroyo J, Miller C, Zhang ZX, Weltzin R, Georgakopoulos K, Catalan J, Ocran S, Draper K, Monath TP, 2002. Viremia and immunogenicity in nonhuman primates of a tetravalent yellow fever-dengue chimeric vaccine: genetic reconstructions, dose adjustment, and antibody responses against wild-type dengue virus isolates. Virology 298 : 146–159.
  31. Guirakhoo F, Pugachev K, Zhang Z, Myers G, Levenbook I, Draper K, Lang J, Ocran S, Mitchell F, Parsons M, Brown N, Brandler S, Fournier C, Barrere B, Rizvi F, Travassos A, Nichols R, Trent D, Monath TP, 2004. Safety and efficacy of chimeric yellow fever-dengue tetravalent vaccine formulations in non-human primates. J Virol 78 : 4761–4775.
  32. Marianneau P, Steffan A-M, Royer C, Drouet M-T, Kirn A, Deubel V, 1998. Differing infection patterns of dengue and yellow fever viruses in a human hepatoma cell line. J Infect Dis 178 : 1270–1278.
  33. Tinnefeld L, Haase J, Museteanu C, Tinnefeld L, Haase J, Museteanu C, 1977. A contribution to infection with yellow fever virus 17D in chicken embryos. Zentralbl Bakteriol 237 : 453–469.
  34. Blaney JE, Johnson DH, Manipon GG, Firestone CY, Hanson CT, Murphy BR, Whitehead SS, 2002. Genetic basis of attenuation of dengue virus type 4 small plaque mutants with restricted replication in suckling mice and in SCID mice transplanted with human liver cells. Virology 300 : 125–139.

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  • Received : 16 Mar 2004
  • Accepted : 06 Aug 2004

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