Volume 70, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


The vector competence of mosquitoes for chimeric viruses being developed as vaccines to protect against dengue (DEN) virus infection were evaluated in a cooperative agreement with Acambis, Inc. Chimeric viruses have been constructed that contain the premembrane (prM) and envelope (E) genes of each of the wild-type (wt) DEN virus serotypes, DEN-1, DEN-2, DEN-3, and DEN-4, in the yellow fever (YF) vaccine virus (strain 17D) YF-VAX backbone. It was previously shown that the replication profile of ChimeriVax™-DEN2 virus in C6/36 cells and in mosquitoes corresponded to that of YF-VAX virus; replication was restricted in C6/36 cells, and were poorly infected via an artificial infectious blood meal. Thus, there is very little risk of transmission by mosquitoes of ChimeriVax-DEN2 vaccine virus through the bite of a mosquito. However, because ChimeriVax™-DEN 1, 2, 3, 4 viruses will be administered to humans simultaneously, growth of a mixture of ChimeriVax™-DEN 1, 2, 3, 4 viruses was assessed in both C6/36 cells in culture and in the mosquito, which is the primary vector of both YF and DEN viruses. Mosquitoes were intrathoracically (IT) inoculated with virus or fed a virus-laden blood meal, and the replication kinetics of ChimeriVax™-DEN 1, 2, 3, 4 were compared with the wt DEN and YF-VAX viruses. A quantitative real-time reverse transcriptase-polymerase chain reaction assay was developed as a method to detect and differentiate replication of each of the four ChimeriVax™-DEN serotypes in the ChimeriVax™-DEN 1, 2, 3, 4 tetravalent mixture. Growth of the chimeric viruses in C6/36 cells and in IT-inoculated was lower than that of YF-VAX virus; in previous studies was shown to be refractory to infection by YF-VAX virus. The growth rate of each chimeric virus was similar whether it was a single serotype infection, or part of the tetravalent mixture, and no interference by one chimeric virus over another chimeric serotype was observed. ChimeriVax™-DEN viruses infected mosquitoes poorly via an infectious blood meal compared with wt DEN viruses. Therefore, it is unlikely that a mosquito feeding on a viremic vaccinee, would become infected with the chimeric viruses. Thus, there is very little potential for transmission by mosquitoes of the ChimeriVax-DEN vaccine viruses.


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  1. Gubler DJ, 1988. Dengue. Monath TP, ed. The Arboviruses: Epidemiology and Ecology. Boca Raton, FL: CRC Press, 223–260.
  2. Gubler DJ, 1998. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11 : 480–496. [Google Scholar]
  3. Koraka P, Zeller H, Niedrig M, Osterhaus AD, Groen J, 2002. Reactivity of serum samples from patients with a flavivirus infection measured by immunofluorescence assay and ELISA. Microbes Infect 4 : 1209–1215. [Google Scholar]
  4. Gubler DJ, 1998. The global pandemic of dengue/dengue haemorrhagic fever: current status and prospects for the future. Ann Acad Med Singapore 27 : 227–234. [Google Scholar]
  5. Division of Disease Prevention and Control CDP, 1997. Re-emergence of dengue in the Americas. Epidemiol Bull 18 : 1–6. [Google Scholar]
  6. Gubler DJ, 1998. Epidemic dengue and dengue hemorrhagic fever: a global public health problem in the 21st century. Scheld W, Armstrong D, Hughes J, eds. Emerging Infections. Washington, DC: American Society for Microbiology Press, 1–14.
  7. Monath TP, 1994. Dengue: the risk to developed and developing countries. Proc Natl Acad Sci USA 91 : 2395–2400. [Google Scholar]
  8. Rothman AL, Ennis FA, 1999. Immunopathogenesis of dengue hemorrhagic fever. Virology 257 : 1–6. [Google Scholar]
  9. Porterfield JS, 1986. Antibody-dependent enhancement of viral infectivity. Adv Virus Res 31 : 335–355. [Google Scholar]
  10. Tirado SM, Yoon KJ, 2003. Antibody-dependent enhancement of virus infection and disease. Viral Immunol 16 : 69–86. [Google Scholar]
  11. Gubler DJ, Clark GG, 1995. Dengue/dengue hemorrhagic fever: the emergence of a global health problem. Emerg Infect Dis 1 : 55–57. [Google Scholar]
  12. Chambers TJ, Nestorowicz A, Mason PW, Rice CM, 1999. Yellow fever/Japanese encephalitis chimeric viruses: construction and biological properties. J Virol 73 : 3095–3101. [Google Scholar]
  13. Guirakhoo F, Zhang ZX, Chambers TJ, Delagrave S, Arroyo J, Barrett AD, Monath TP, 1999. Immunogenicity, genetic stability, and protective efficacy of a recombinant, chimeric yellow fever-Japanese encephalitis virus (ChimeriVax-JE) as a live, attenuated vaccine candidate against Japanese encephalitis. Virology 257 : 363–372. [Google Scholar]
  14. Monath TP, Soike K, Levenbook I, Zhang ZX, Arroyo J, Delagrave S, Myers G, Barrett AD, Shope RE, Ratterree M, Chambers TJ, Guirakhoo F, 1999. Recombinant, chimaeric live, attenuated vaccine (ChimeriVax) incorporating the envelope genes of Japanese encephalitis (SA14–14–2) virus and the capsid and nonstructural genes of yellow fever (17D) virus is safe, immunogenic and protective in non-human primates. Vaccine 17 : 1869–1882. [Google Scholar]
  15. Guirakhoo R, Weltzin R, Chambers T, Zhang Z-X, Soike K, Ratterree M, Arroyo J, Georgakopoulos K, Catalan J, Monath T, 2000. Recombinant chimeric yellow fever-dengue type 2 virus is immunogenic and protective in nonhuman primates. J Virol 74 : 5477–5485. [Google Scholar]
  16. Guirakhoo F, Arroyo J, Pugachev KV, Miller C, Zhang ZX, 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. [Google Scholar]
  17. Arroyo J, Miller CA, Catalan J, Monath TP, 2001. Yellow fever vector live-virus vaccines. West Nile virus vaccine development. Trends Mol Med 7 : 350–354. [Google Scholar]
  18. Arroyo J, Guirakhoo F, Fenner S, Zhang ZX, Monath TP, Chambers TJ, 2001. Molecular basis for attenuation of neurovirulence of a yellow fever virus/Japanese encephalitis virus chimera vaccine (ChimeriVax-JE). J Virol 75 : 934–942. [Google Scholar]
  19. Monath TP, 2001. Prospects for development of a vaccine against the West Nile virus. Ann N Y Acad Sci 951 : 1–12. [Google Scholar]
  20. Monath TP, Arroyo J, Miller C, Guirakhoo F, 2001. West Nile virus vaccine. Curr Drug Targets Infect Disord 1 : 37–50. [Google Scholar]
  21. Monath TP, 1991. Yellow fever: Victor, Victoria? conqueror, conquest? Epidemics and research in the last forty years and prospects for the future. Am J Trop Med Hyg 45 : 1–43. [Google Scholar]
  22. Marianneau P, Georges-Courbot M, Deubel V, 2001. Rarity of adverse effects after 17D yellow-fever vaccination. Lancet 358 : 84–85. [Google Scholar]
  23. Whitman L, 1939. Failure of Aedes aegypti to transmit yellow fever cultured virus (17D). Am J Trop Med 19 : 19–26. [Google Scholar]
  24. Bhatt TR, Crabtree MB, Guirakhoo F, Monath TP, Miller BR, 2000. Growth characteristics of the chimeric Japanese encephalitis virus vaccine candidate, ChimeriVax-JE (YF/JE SA14–14–2), in Culex tritaeniorhynchus, Aedes albopictus, and Aedes aegypti mosquitoes. Am J Trop Med Hyg 62 : 480–484. [Google Scholar]
  25. Johnson BW, Chambers TV, Crabtree MB, Bhatt TR, Guirakhoo F, Monath TP, Miller BR, 2002. Growth characteristics of ChimeriVax-DEN-2 vaccine virus in Aedes aegypti and Aedes albopictus mosquitoes. Am J Trop Med Hyg 67 : 260–265. [Google Scholar]
  26. Johnson BW, Chambers TV, Crabtree MB, Arroyo J, Monath TP, Miller BR, 2003. Growth characteristics of the veterinary vaccine candidate ChimeriVax™-West Nile (WN) virus in Aedes and Culex mosquitoes. Med Vet Entomol 17 : 235–243. [Google Scholar]
  27. 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. [Google Scholar]
  28. Miller BR, Mitchell CJ, Ballinger ME, 1989. Replication, tissue tropisms and transmission of yellow fever virus in Aedes albopictus. Trans R Soc Trop Med Hyg 83 : 252–255. [Google Scholar]
  29. Lanciotti RS, Kerst AJ, Nasci RS, Godsey MS, Mitchell CJ, Savage HM, Komar N, Panella NA, Allen BC, Volpe KE, Davis BS, Roehrig JT, 2000. Rapid detection of West Nile virus from human clinical specimens, field-collected mosquitoes, and avian samples by a TaqMan reverse transcriptase-PCR assay. J Clin Microbiol 38 : 4066–4071. [Google Scholar]
  30. Rosen L, Roseboom LE, Gubler DJ, Lien JC, Chaniotis BN, 1985. Comparative susceptibility of mosquito species and strains to oral and parenteral infection with dengue and Japanese encephalitis viruses. Am J Trop Med Hyg 34 : 603–615. [Google Scholar]
  31. Miller BR, 1987. Increased yellow fever virus infection and dissemination rates in Aedes aegypti mosquitoes orally exposed to freshly grown virus. Trans R Soc Trop Med Hyg 81 : 1011–1012. [Google Scholar]
  32. Weaver SC, Lorenz LH, Scott TW, 1993. Distribution of western equine encephalomyelitis virus in the alimentary tract of Culex tarsalis (Diptera: Culicidae) following natural and artificial blood meals. J Med Entomol 30 : 391–397. [Google Scholar]
  33. Turell MJ, Spring AR, Miller MK, Cannon CE, 2002. Effect of holding conditions on the detection of West Nile viral RNA by reverse transcriptase-polymerase chain reaction from mosquito (Diptera: Culicidae) pools. J Med Entomol 39 : 1–3. [Google Scholar]
  34. Kramer LD, Chiles RE, Do TD, Fallah HM, 2001. Detection of St. Louis encephalitis and western equine encephalomyelitis RNA in mosquitoes tested without maintenance of a cold chain. J Am Mosq Control Assoc 17 : 213–215. [Google Scholar]
  35. Armstrong PM, Rico-Hesse R, 2001. Differential susceptibility of Aedes aegypti to infection by the American and Southeast Asian genotypes of dengue type 2 virus. Vector Borne Zoonotic Dis 1 : 159–168. [Google Scholar]
  36. Gubler DJ, Rosen L, 1976. A simple technique for demonstrating transmission of dengue virus by mosquitoes without the use of vertebrate hosts. Am J Trop Med Hyg 25 : 146–150. [Google Scholar]
  37. Durbin AP, Karron RA, Sun W, Vaughn DW, Reynolds MJ, Perreault JR, Thumar B, Men R, Lai CJ, Elkins WR, Chanock RM, Murphy BR, Whitehead SS, 2001. Attenuation and immunogenicity in humans of a live dengue virus type-4 vaccine candidate with a 30 nucleotide deletion in its 3′-untranslated region. Am J Trop Med Hyg 65 : 405–413. [Google Scholar]
  38. Gubler DJ, Suharyono W, Tan R, Abidin M, Sie A, 1981. Viraemia in patients with naturally acquired dengue infection. Bull World Health Organ 59 : 623–630. [Google Scholar]
  39. Chambers TJ, Hahn CS, Galler R, Rice CM, 1990. Flavivirus genome organization, expression, and replication. Annu Rev Microbiol 44 : 649–688. [Google Scholar]
  40. Lindenbach B, Rice C, 2001. Flaviviridae: the viruses and their replication. Knipe D, Howley P, eds. Fields Virology. Philadelphia: Lipincott William and Wilkins, 991–1043.

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  • Received : 26 Aug 2003
  • Accepted : 30 Sep 2003

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