Volume 75, Issue 5
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Four chimeric yellow fever (YF) 17D-dengue (DEN) candidate vaccine viruses (ChimeriVax™-DEN; Acambis, Cambridge, MA) were characterized in and mosquitoes collected from Thailand. The four vaccine viruses contained the relevant and genes of wild-type dengue viruses (DENV; serotypes 1–4) substituted for the equivalent genes in the YF vaccine virus (17D) backbone. Each chimera conferred protection against the homologous DENV serotype; a tetravalent mix of all four chimeras stimulates an immune response against all serotypes. Field-collected mosquitoes from Thailand were fed on blood containing each of the viruses under study and held 21 days after infection. Infection and dissemination rates were based on antigen detection in the body or head tissues, respectively. All four wild-type DENV serotypes infected and disseminated, but the candidate vaccine viruses were highly attenuated in mosquitoes with respect to infection and especially with respect to dissemination. Considering the low level viremias anticipated in humans vaccinated with these viruses, it is predicted that the risks of infection and transmission by mosquitoes in nature is minimal.


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  1. Gubler DJ, Kuno G, 1997. Dengue and Dengue Hemorrhagic Fever. Wallingford, UK: CAB International.
  2. Kantachuvessiri A, 2002. Dengue hemorrhagic fever in Thai society. Southeast Asian J Trop Med Public Health 33 : 56–62. [Google Scholar]
  3. Brandler S, Brown N, Ermak TH, Mitchell F, Parsons M, Zhang Z, Lang J, Monath TP, Guirakhoo F, 2005. Replication of chimeric yellow fever virus-dengue serotype 1–4 vaccine strains in dendritic and hepatoc cells. Am J Trop Med Hyg 72 : 74–81. [Google Scholar]
  4. 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]
  5. 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. [Google Scholar]
  6. 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]
  7. Guirakhoo F, Pugachev K, Arroyo J, Miller C, Zhang ZX, Weltzin R, Georgakopoulos K, Catlan 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]
  8. 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. [Google Scholar]
  9. Girakhoo F, Kitchener S, Morrison D, Forrat R, McCarthy K, Nichols R, Yoksan S, Duan X, Ermak TH, Kanesa-Thasan N, Bedford P, Lang J, Quentin-Millet M-J, Monath TP, 2006. Live attenuated chimeric yellow fever dengue type 2 (ChimeriVaxTM-DEN2) vaccine: phase I clinical trials for safety and immunogenicity. Human Vaccines 2 : 60–67. [Google Scholar]
  10. 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. [Google Scholar]
  11. Monath TP, Arroyo J, Miller C, Guirakhoo F, 2001. West Nile virus vaccine. Curr Drug Targets Infect Disord 1 : 37–50. [Google Scholar]
  12. Monath TP, McCarthy K, Bedford P, Johnson CT, Nichols R, Yoksan S, Marchesani R, Knauber M, Wells KH, Arroyo J, Guirakhoo F, 2002. Clinical proof of principle for ChimeriVaxTM: recombinant live, attenuated vaccines against flavivirus infections. Vaccine 20 : 1004–1018. [Google Scholar]
  13. Monath TP, Guirakhoo F, Nichols R, Yosan S, Schrader R, Murphy C, Blum P, Woodward S, McCarthy K, Mathis D, Johnson C, Bedford P, 2003. Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax™-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen. J Infect Dis 188 : 1213–1230. [Google Scholar]
  14. Monath TP, Myers GA, Beck RA, Knauber M, Scappaticci K, Pullano T, Archambault WT, Catalan J, Miller C, Zhang Z-X, Shin S, Pugachev K, Draper K, Levenbrook IS, Guirakhoo F, 2005. Safety testing for neurovirulence of novel live, attenuated flavivirus vaccines: infant mice provide an accurate surrogate for the test in monkeys. Biologicals 33 : 131–144. [Google Scholar]
  15. Pugachev KV, Guirakhoo F, Trent DW, Monath TP, 2003. Traditional and novel approaches to flavivirus vaccines. Int J Parasitol 33 : 567–582. [Google Scholar]
  16. Pugachev KV, Guirakhoo F, Monath TP, 2005. New developments in flavivirus vaccines with special attention to yellow fever. Curr Opin Infect Dis 18 : 387–394. [Google Scholar]
  17. Pugachev KV, Guirakhoo F, Mitchell F, Ocran SW, Parsons M, Johnson BW, Kosey OL, Lanciotti RS, Roehrig JT, Trent DW, Monath TP, 2004. Construction of yellow fever/St. Louis encephalitis chimeric virus and the use of chimeras as a diagnostic tool. Am J Trop Med Hyg 5 : 639–645. [Google Scholar]
  18. Johnson BW, Chambers TV, Crabtree MB, Arroyo J, Monath TP, Miller BR, 2003. Growth characteristics of the veterinary vaccine candidate ChimeriVax TM-West Nile (WN) virus in Aedes and Culex mosquitoes. Med Vet Entomol 17 : 235–265. [Google Scholar]
  19. Johnson BW, Chambers TV, Crabtree MB, Guirakhoo F, Monath TP, Miller BR, 2004. Analysis of the replication kinetics of the ChimeriVAxTM-DEN 1, 2, 3, 4 tetravalent virus mixture in Aedes aegypti by real-time reverse transcription–polymerase chain reaction. Am J Trop Med Hyg 70 : 89–97. [Google Scholar]
  20. Bhatt TR, Crabtree MB, Guirakhoo F, Monath TP, Miller BR, 2000. Growth characteristics of the 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]
  21. 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]
  22. Seligman SJ, Gould EA, 2004. Live flavivirus vaccines: Reason for caution. Lancet 363 : 2073–2075. [Google Scholar]
  23. Monath TP, 2004. Yellow fever vaccine. Plotkin SA, Orenstein WA, eds. Vaccines. Fourth edition. Philadelphia: W. B. Saunders, 1095–1176.
  24. Murphy BR, Blaney JE Jr, Whitehead SS, 2004. Arguments for live flavivirus vaccines. Lancet 364 : 499–500. [Google Scholar]
  25. Higgs S, Olson KE, Kamrud KI, Powers AM, Beaty BJ, 1997. Viral expression systems and viral infections in insects. Crampton JM, Beard CB, Louis C, eds. The Molecular Biology of Disease Vectors: A Methods Manual. Chapman and Hall, UK, 1997. pp. 457–483.
  26. Schoepp RJ, Beaty BJ, 1984. Titration of dengue viruses by immunofluorescence in microtiter plates. J Clin Microbiol 20 : 1017–1019. [Google Scholar]
  27. Gould EA, Buckley A, Cammack N, 1985. Use of a biotin-streptavidin interaction to improve flavivirus detection by immunofluorescence and ELISA tests. J Virol Methods 11 : 41–48. [Google Scholar]
  28. Olson KE, Higgs S, Gaines PJ, Powers AM, Davis BS, Kamrud KI, Carlson JO, Blair CD, Beaty BJ, 1996. Genetically engineered resistance in mosquitoes to dengue virus transmission. Science 272 : 884–886. [Google Scholar]
  29. Whitman L, 1939. Failure of Aedes aegypti to transmit yellow fever cultured virus (17D). Am J Trop Med Hyg 19 : 19–26. [Google Scholar]
  30. Bennett KE, Olson KE, de Lourdes Munoz M, Fernandez-Salas I, Farfan-Ale JA, Higgs S, Black WC, Beaty BJ, 2002. Variation in vector competence for dengue 2 virus among 24 collections of Aedes aegypti from Mexico and the United States. Am J Trop Med Hyg 67 : 85–92. [Google Scholar]
  31. Black WC IV, Bennett KE, Gorrochotegui-Escalante N, Barillas-Mury CV, Fernandez-Salas I, de Lourdes Munoz M, Farfan-Ale JA, Olson KE, Beaty BJ, 2002. Flavivirus susceptibility in Aedes aegypti. Arch Med Res 33 : 379–388. [Google Scholar]
  32. Bruce-Chwatt LJ, 1950. Recent studies on insect vectors of yellow fever and malaria in British West Africa. J Trop Med Hyg 53 : 71–79. [Google Scholar]
  33. Gubler DJ, Tan NR, Saipan H, Sulianti Saroso J, 1979a. Variation in susceptibility to oral infection with dengue viruses among geographic strains of Aedes aegypti. Am J Trop Med Hyg 28 : 1045–1052. [Google Scholar]
  34. Gubler DJ, Nalim S, Tan R, Saipan H, Sulianti Saroso J, 1979b. Variation in susceptibility to oral infection with dengue viruses. Am J Trop Med Hyg 28 : 1045–1052. [Google Scholar]
  35. Gubler DJ, Novak R, Mitchell CJ, 1982. Arthropod vector competence-epidemiological, genetic, and biological considerations. Steiner WWM, Rai KS, Narang S, eds. Recent Developments in the Genetics of Insect Disease Vectors. Champaign, IL: Stipes Publishing, 343–378.
  36. Gubler DJ, Rosen L, 1976. Variation among geographic strains of Aedes albopictus in susceptibility to infection with dengue viruses. Am J Trop Med Hyg 25 : 318–325. [Google Scholar]
  37. Knox TB, Kay BH, Hall RA, Ryan PA, 2003. Enhanced vector competence of Aedes aegypti (Diptera: Culicidae) from the Torres Strait compared with mainland Australia for dengue 2 and 4 viruses. J Med Ent 40 : 950–956. [Google Scholar]
  38. Kramer LD, Ebel GD, 2003. Dynamics of flavivirus infection in mosquitoes. Adv Virus Res 60 : 187–232. [Google Scholar]
  39. Lorenz L, Beaty BJ, Aitken THG, Wallis GP, Tabachnick WJ, 1984. The effect of colonization upon Aedes aegypti susceptibility to oral infection with yellow fever virus. Am J Trop Med Hyg 33 : 690–694. [Google Scholar]
  40. Miller BR, Mitchell CJ, 1991. Genetic selection of a flavivirus-refractory strain of the yellow fever mosquito Aedes aegypti. Am J Trop Med Hyg 45 : 399–407. [Google Scholar]
  41. Rosen L, Roseboom LE, Gubler DJ, Lein 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 : 1219–1224. [Google Scholar]
  42. Tardieux I, Poupel O, Lapchin L, Rodhain F, 1990. Variation among strains of Aedes aegypti in susceptibility to oral infection with dengue virus type 2. Am J Trop Med Hyg 43 : 308–313. [Google Scholar]
  43. Tesh RB, Gubler DJ, Rosen L, 1976. Variation among geographic strains of Aedes albopictus in susceptibility to infection with chickungunya virus. Am J Trop Med Hyg 25 : 326–335. [Google Scholar]
  44. Vazeille-Falcoz M, Mousson L, Rhodhain F, Chungue E, Failloux AB, 1999. Variation in oral susceptibility to dengue type 2 virus populations of Aedes aegypti from the islands of Tahiti and Moorea, French Polynesia. Am J Trop Med Hyg 60 : 292–299. [Google Scholar]
  45. Hindle E, 1929. An experimental study of yellow fever. Trans R Soc Trop Med Hyg 22 : 405–430. [Google Scholar]
  46. Aitken TH, Downs WG, Shope RE, 1977. Aedes aegypti strain fitness for yellow fever virus transmission. Am J Trop Med Hyg 26 : 985–989. [Google Scholar]
  47. Beaty BJ, Aitken THG, 1979. In vitro transmission of yellow fever virus by geographic strains of Aedes aegypti. Mosquito News 39 : 232–238. [Google Scholar]
  48. Wallis GP, Tabachnick WJ, Powell JR, 1984. Genetic heterogeneity among Caribbean populations of Aedes aegypti. Am J Trop Med Hyg 33 : 492–498. [Google Scholar]
  49. Powell JR, 1985. Geographic genetic differentiation and Arbovirus competency: Aedes aegypti and yellow fever. Parassitologia 27 : 13–20. [Google Scholar]
  50. Tabachnick WJ, Wallis GP, Aitken TH, Miller BR, Amato GD, Lorenz L, Powell JR, Beaty BJ, 1985. Oral infection of Aedes aegpti with yellow fever virus: Geographic variation and genetic considerations. Am J Trop Med Hyg 34 : 1219–1224. [Google Scholar]
  51. Jupp PG, Kemp A, 2002. Laboratory vector competence experiments with yellow fever virus and five South African mosquito species including Aedes aegypti. Trans R Soc Trop Med Hyg 96 : 493–498. [Google Scholar]
  52. Lourenco-de-Oliveira R, Vazeille M, de Filippis AM, Failloux AB, 2002. Aedes aegypti in Brazil: Genetically differentiated populations with high susceptibility to dengue and yellow fever viruses. Trans R Soc Trop Med Hyg 98 : 43–54. [Google Scholar]
  53. Miller BR, Beaty BJ, Aitken TM, Eckels KH, Russell PK, 1982. Dengue-2 vaccine: Oral infection, transmission, and lack of evidence for reversion in the mosquito, Aedes aegypti. Am J Trop Med Hyg 32 : 1232–1237. [Google Scholar]
  54. Bancroft WH, Scott RM, Brandt WE, McCown JM, Eckels KH, Hayes DE, Gould DJ, Russell PK, 1982. Dengue-2 vaccine: infection of Aedes aegypti mosquitoes by feeding on viremic recipients. Am J Trop Med Hyg 31 : 1229–1231. [Google Scholar]
  55. Schoepp RJ, Beaty BJ, Eckels KH, 1990. Dengue 3 virus infection of Aedes albopictus and Aedes aegypti: Comparison of parent and progeny candidate vaccine viruses. Am J Trop Med Hyg 42 : 89–96. [Google Scholar]
  56. Schoepp RJ, Beaty BJ, Eckels KH, 1991. Infection of Aedes albopictus and Aedes aegypti mosquitoes with dengue parent and progeny candidate vaccine viruses: A possible marker of human attenuation. Am J Trop Med Hyg 45 : 202–210. [Google Scholar]
  57. Blaney JE Jr, Durbin AP, Murphy BR, Whitehead SS, 2006. Development of a live attenuated dengue virus vaccine using reverse genetics. Vir Immunol 19 : 10–32. [Google Scholar]
  58. Troyer JM, Hanley KA, Whitehead SS, Strickman D, Karron RA, Durbin AP, Murphy BR, 2001. A live attenuated recombinant dengue-4 virus vaccine candidate with restricted capacity for dissemination in mosquitoes and lack of transmission from vaccines to mosquitoes. Am J Trop Med Hyg 65 : 414–419. [Google Scholar]
  59. Chen BQ, Beaty BJ, 1982. Japanese encephalitis vaccine (2–8 strain) and parent (SA 14 strain) viruses in Culex tritaeniorhynchus mosquitoes. Am J Trop Med Hyg 31 : 403–407. [Google Scholar]
  60. Roubaud E, Colas-Belcour J, Stefanopoulo GJ, 1937. Transmission de la fievre jaune par un moustique palearetique repandu dans la region parisienne, l’ Aedes geniculatus Oliv. C.R. Acad Sci 205 : 182. [Google Scholar]
  61. Whitman L, 1938. Multiplication of the virus of yellow fever in Aedes aegypti. J Exp Med 66 : 133–143. [Google Scholar]
  62. Miller BR, Adkins D, 1988. Biological characterization of plaque-size variants of yellow fever virus in mosquitoes and mice. Acta Virol 32 : 227–234. [Google Scholar]
  63. Jennings AD, Gibson CA, Miller BR, Mathews JH, Mitchell CJ, Roehrig JT, Wood DJ, Taffs F, Sil BK, Whitby SN, Whitby JE, Monath TP, Minor PD, Sanders PG, Barrett ADT, 1994. Analysis of a yellow fever virus isolated from a fatal case of vaccine-associated human encephalitis. J Inf Dis 169 : 512–518. [Google Scholar]
  64. Davis NC, Lloyd W, Frobisher M Jr, 1932. Transmission of neurotropic yellow fever virus by Stegomyia mosquitoes. J Exp Med 56 : 853–865. [Google Scholar]
  65. Roubaud E, Stephanopoulo GJ, 1933. Recherches sur la transmission par la voic stegomyienne du virus neurotrop murin de la fievre jaune. Bull Soc Pathol Exot 26 : 305–309. [Google Scholar]
  66. Peltier M, Durieux C, Jonchere H, Arquie E, 1939. La transmission par piqure de Stegomyia, du virus amaril neurotrope present dans le sang des personnes recemment vaccinees, estelle possible dans les regions ou ce moustique existe en abondance? Rev Immunol (Paris) 5 : 172–195. [Google Scholar]

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  • Received : 01 May 2006
  • Accepted : 21 Jun 2006

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