Live-attenuated dengue vaccine development
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Dengue (DENV) virus strains for each of the four DENV serotypes were modified by passage in primary dog kidney (PDK) cell cultures with final manufacture of vaccine lots in fetal rhesus monkey diploid cell cultures. “Strain sets” consisting of serially-passaged DENV were inoculated in rhesus monkeys along with unmodified parent viruses for each strain. Vaccine candidates were compared with unmodified parent viruses by measuring viremia and immune responses. All except one DENV-1 strain demonstrated reduced infection in monkeys after PDK cell passage. A DENV-3 strain lost all monkey infectivity after PDK cell passage. Twelve vaccine candidates were selected for Phase 1 human trials through this selection process.


Article metrics loading...

Loading full text...

Full text loading...



  1. Simmons JS, St. John JH, Reynolds FHK, 1931. Experimental studies of dengue. Philippine J Sci 44 : 1–252.
  2. Hotta S, 1952. Experimental studies in dengue I. Isolation, identification, and modification of the virus. J Infect Dis 90 : 1–9.
  3. Sabin AB, Schlesinger RW, 1945. Production of immunity to dengue with virus modified by propagation in mice. Science 101 : 640–642.
  4. Wisseman CL Jr, Sweet BH, Rosenzweig EC, Eylar OR, 1963. Attenuated living type 1 dengue vaccines. Am J Trop Med Hyg 12 : 620–623.
  5. Eckels KH, Brandt WE, Harrison VR, McCown JM, Russell PK, 1976. Isolation of a temperature-sensitive dengue-2 virus under conditions suitable for vaccine development. Infect Immun 14 : 1221–1227.
  6. Halstead SB, 1978. Studies on the attenuation of dengue 4. Asian J Infect Dis 2 : 112–117.
  7. Halstead SB, Marchette NJ, 2003. Biological properties of dengue viruses following serial passage in primary dog kidney cells: studies at the University of Hawaii. Am J Trop Med Hyg 69 (in press).
  8. Bhamarapravati N, Yoksan S, Chayanuyayothin T, Angsuphakorn S, Bunyaratvej A, 1987. Immunization with a live attenuated dengue-2-virus candidate vaccine (16681-PDK 53): clinical, immunological and biological responses in adult volunteers. Bull World Health Organ 65 : 189–195.
  9. Bhamarapravati N, Yoksan S, 1989. Study of bivalent dengue vaccine in volunteers (letter). Lancet 1 : 1077.
  10. Hoke CH Jr, Malinoski FJ, Eckels KH, Scott RM, Dubois DR, Summers PL, Simms T, Burrous J, Hasty SE, Bancroft WH, 1990. Preparation of an attenuated dengue 4 (341750 Carib) virus vaccine. II. Safety and immunogenicity in humans. Am J Trop Med Hyg 43 : 219–226.
  11. Halstead SB, Casals J, Shotwell H, Palumbo N. 1973. Studies on the immunization of monkeys against dengue I. Protection derived from single and sequential virus infections. Am J Trop Med Hyg 22 : 365–374.
  12. Halstead SB, Palumbo NE, 1973. Studies on the immunization of monkeys against dengue. II. Protection following inoculation of combinations of viruses. Am J Trop Med Hyg 22 : 375–381.
  13. Kraiselburd E, Gubler DJ, Kessler MJ, 1985. Quantity of dengue virus required to infect rhesus monkeys. Trans R Soc Trop Med Hyg 79 : 248–251.
  14. Angsubphakorn S, Moe JB, Marchette NJ, Palumbo NE, Yoksan S, Bhamarapravati N, 1987. Neurovirulence effects of dengue-2 viruses on the rhesus (Macaca mulatta) brain and spinal cord. Southeast Asian J Trop Med Public Health 18 : 52–55.
  15. Angsubphakorn S, Moe JB, Marchette NJ, Latendresse JR, Palumbo NE, Yoksan S, Bhamarapravati N, 1987. Neurovirulence detection of dengue virus using rhesus and cynomolgus monkeys. J Virol Methods 18: 13–24.
  16. Angsubphakorn S, Yoksan S, Bhamarapravati N, Moe JB, Marchette NJ, Pradermwong A, Sahaphong S, 1988. Dengue-4 vaccine: neurovirulence, viraemia and immune responses in rhesus and cynomolgus monkeys. Trans R Soc Trop Med Hyg 82 : 746–749.
  17. Edelman R, Tacket CO, Wasserman SS, Vaughn DW, Eckels KH, Dubois DR, Summers PL, Hoke CH, 1994. A live-attenuated dengue-1 vaccine candidate (45AZ5) passaged in primary dog kidney cell culture is attenuated and immunogenic for humans. J Infect Dis 170 : 1448–1455.
  18. Sukhavachana P, Nisalak A, Halstead SB, 1966. Tissue culture techniques for the study of dengue viruses. Bull World Health Organ 35: 65–66.
  19. Putnak R, Barvir DA, Burrous J, Dubois DR, D’Andrea VM, Hoke CH, Sadoff JC, Eckels KH, 1996. Development of a purified, inactivated, dengue-2 virus vaccine prototype in Vero cells: immunogenicity and protection in mice and rhesus monkeys. J Infect Dis 174: 1176–1184.
  20. Russell PK, Nisalak A, Sukhavachana P, Vivona S, 1967. A plaque reduction test for dengue virus neutralization antibodies. J Immunol 99 : 285–290.
  21. Innis BL, Eckels KH, Kraiselburd E, Dubois DR, Meadors GF, Gubler DJ, Burke DS, Bancroft WH, 1988. Virulence of a live dengue virus vaccine candidate: a possible new marker of dengue virus attenuation. J Infect Dis 158 : 876–880.
  22. McKee KT, Bancroft WH, Eckels KH, Redfield RR, Summers PL, Russell PK, 1987. Lack of attenuation of a candidate dengue 1 vaccine (45AZ5) in human volunteers. Am J Trop Med Hyg 36 : 435–442.
  23. Eckels KH, Scott RM, Bancroft WH, Brown J, Dubois DR, Summers PL, Russell PK, Halstead SB, 1984. Selection of attenuated dengue 4 viruses by serial passage in primary kidney cells. V. Human response to immunization with a candidate vaccine prepared in fetal rhesus lung cells. Am J Trop Med Hyg 33 : 684–689.

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error