Volume 89, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Immunogenicity and safety of a recombinant, live-attenuated, tetravalent dengue disease vaccine (CYD-TDV) was evaluated in children/adolescents in Brazil. In this observer-blind, placebo-controlled, phase II single-center study, children/adolescents (ages 9–16 years) were randomized to receive CYD-TDV or placebo at 0, 6, and 12 months. Immunogenicity was assessed using a 50% plaque neutralization test. Overall, 150 participants were enrolled (CYD-TDV: = 100; placebo: = 50). Injection site pain and headache were the most common solicited injection site and systemic reactions. Unsolicited adverse events (AEs) and serious AEs were similar between groups. No serious AEs were vaccine-related. Geometric mean titers against all dengue virus serotypes increased with CYD-TDV vaccination and were 267, 544, 741, and 432 1/dil for serotypes 1–4, respectively, after dose 3, representing a mean fold increase from baseline of 5, 6, 6, and 20, respectively. CYD-TDV vaccination elicited a neutralizing antibody response against serotypes 1–4 and was well-tolerated in children/adolescents in a dengue-endemic region.

[open-access] This is an Open Access article distributed under the terms of the American Society of Tropical Medicine and Hygiene's Re-use License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Article metrics loading...

Loading full text...

Full text loading...



  1. Simmons CP, Farrar JJ, Nguyen VC, Wills B, , 2012. Dengue. N Engl J Med 366: 14231432.[Crossref]
  2. World Health Organization, 2009. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control. Available at: http://whqlibdoc.who.int/publications/2009/9789241547871_eng.pdf. Accessed October 21, 2013.
  3. World Health Organization, 2012. Dengue and Dengue Haemorrhagic Fever. Fact Sheet Number 117. Available at: http://www.who.int/mediacentre/factsheets/fs117/en/. Accessed October 21, 2013.
  4. Teixeira MG, Costa MC, Barreto F, Barreto ML, , 2009. Dengue: twenty-five years since reemergence in Brazil. Cad Saude Publica 25 (Suppl 1): S7S18.
  5. Figueiredo LTM, , 2010. Dengue in Brazil during 1999–2009: a review. Dengue Bull 34: 612.
  6. Siqueira JB, Camilo F, , 2011. Dengue no Brasil: tendências e mudanças na epidemiologia, com ênfase nas epidemias de 2008 e 2010. , ed. Saúde Brasil 2010: uma análise da situação de saúde e de evidências selecionadas de im-pacto de ações de vigilância em saúde/Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento de Análise de Situação em Saúde, 1st ed. Saúde, Brasil: Ministério da Saúde, 157171.
  7. Cardoso IM, Cabidelle AD, Borges PD, Lang CF, Calenti FG, Nogueira LD, Falqueto A, Cerutti JC, , 2011. Dengue: clinical forms and risk groups in a high incidence city in the southeastern region of Brazil. Rev Soc Bras Med Trop 44: 430435.[Crossref]
  8. Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, Jiwariyavej V, Dulyachai W, Pengsaa K, Wartel TA, Moureau A, Saville M, Bouckenooghe A, Viviani S, Tornieporth NG, Lang J, , 2012. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 380: 15591567.[Crossref]
  9. Capeding RZ, Luna IA, Bomasang E, Lupisan S, Lang J, Forrat R, Wartel A, Crevat D, , 2011. Live-attenuated, tetravalent dengue vaccine in children, adolescents and adults in a dengue endemic country: randomized controlled phase I trial in the Philippines. Vaccine 29: 38633872.[Crossref]
  10. Guirakhoo 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 MJ, Monath TP, , 2006. Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax-DEN2) vaccine: phase I clinical trial for safety and immunogenicity: effect of yellow fever pre-immunity in induction of cross neutralizing antibody responses to all 4 dengue serotypes. Hum Vaccin 2: 6067.[Crossref]
  11. Morrison D, Legg TJ, Billings CW, Forrat R, Yoksan S, Lang J, , 2010. A novel tetravalent dengue vaccine is well tolerated and immunogenic against all 4 serotypes in flavivirus-naive adults. J Infect Dis 201: 370377.[Crossref]
  12. Qiao M, Shaw D, Forrat R, Wartel-Tram A, Lang J, , 2011. Priming effect of dengue and yellow fever vaccination on the immunogenicity, infectivity, and safety of a tetravalent dengue vaccine in humans. Am J Trop Med Hyg 85: 724731.[Crossref]
  13. Lanata CF, Andrade T, Gil AI, Terrones C, Valladolid O, Zambrano B, Saville M, Crevat D, , 2012. Immunogenicity and safety of tetravalent dengue vaccine in 2–11 year-olds previously vaccinated against yellow fever: randomized, controlled, phase II study in Piura, Peru. Vaccine 30: 59355941.[Crossref]
  14. Poo J, Galan F, Forrat R, Zambrano B, Lang J, Dayan GH, , 2011. Live-attenuated tetravalent dengue vaccine in dengue-naive children, adolescents, and adults in Mexico City: randomized controlled phase 1 trial of safety and immunogenicity. Pediatr Infect Dis J 30: e9e17.[Crossref]
  15. Sin LY, Wilder-Smith A, Archuleta S, Shek L, Chong CY, Nam LH, Yong LC, Oh ML, Bouckenooghe A, Crevat D, Wartel A, , 2012. Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2–45 y: phase II randomized controlled trial in Singapore. Hum Vaccin Immunother 8: 12591271.[Crossref]
  16. Villar LA, Rivera-Medina DM, Arredondo-García JL, Boaz M, Starr-Spires L, Thakur M, Zambrano B, Miranda MC, Rivas E, Dayan GH, , 2013. Safety and immunogenicity of a recombinant tetravalent dengue vaccine in 9–16-year-olds: a randomized, controlled, Phase II trial in Latin America. Pediatr Infect Dis J 32: 11021109.[Crossref]
  17. 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: 54775485.[Crossref]
  18. 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: 72907304.[Crossref]
  19. Teixeira MG, Costa MC, Coelho G, Barreto ML, , 2008. Recent shift in age pattern of dengue hemorrhagic fever, Brazil. Emerg Infect Dis 14: 1663.[Crossref]
  20. San Martin JL, Brathwaite O, Zambrano B, Solorzano JO, Bouckenooghe A, Dayan GH, Guzman MG, , 2010. The epidemiology of dengue in the americas over the last three decades: a worrisome reality. Am J Trop Med Hyg 82: 128135.[Crossref]
  21. Roehrig JT, Hombach J, Barrett ADT, , 2008. Guidelines for plaque-reduction neutralization testing of human antibodies to dengue viruses. Viral Immunol 21: 123132.[Crossref]
  22. Russell PK, Nisalak A, Sukhavachana P, Vivona S, , 1967. A plaque reduction test for dengue virus neutralizing antibodies. J Immunol 99: 285290.
  23. Timiryasova TM, Bonaparte MI, Luo P, Zedar R, Hu BT, Hildreth SW, , 2013. Optimization and validation of a plaque reduction neutralization test for the detection of neutralizing antibodies to four serotypes of dengue virus used in support of dengue vaccine development. Am J Trop Med Hyg 88: 962970.[Crossref]
  24. Edelman R, Hombach J, , 2008. Guidelines for the clinical evaluation of dengue vaccines in endemic areas: summary of a World Health Organization Technical Consultation. Vaccine 26: 41134119.[Crossref]
  25. Clopper C, Pearson ES, , 1934. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26: 404413.[Crossref]
  26. Guy B, Guirakhoo F, Barban V, Higgs S, Monath TP, Lang J, , 2010. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses. Vaccine 28: 632649.[Crossref]
  27. Guy B, Barrere B, Malinowski C, Saville M, Teyssou R, Lang J, , 2011. From research to phase III: preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine. Vaccine 29: 72297241.[Crossref]
  28. Tran NH, Luong CQ, Vu TQH, Forrat R, Lang J, Vu QD, Bouckenooghe A, Wartel TA, , 2012. Safety and immunogenicity of recombinant, live attenuated tetravalent dengue vaccine (CYD- TDV) in healthy Vietnamese adults and children. J Vaccines Vaccin 3: 162.
  29. Dayan G, Thakur M, Boaz M, Johnson C, , 2013. Safety and immunogenicity of three tetravalent dengue vaccine formulations in healthy adults in the USA. Vaccine 31: 50475054.[Crossref]
  30. Jentes ES, Poumerol G, Gershman MD, Hill DR, Lemarchand J, Lewis RF, Staples JE, Tomori O, Wilder-Smith A, Monath TP, , 2011. The revised global yellow fever risk map and recommendations for vaccination, 2010: consensus of the Informal WHO Working Group on Geographic Risk for Yellow Fever. Lancet Infect Dis 11: 622632.[Crossref]
  31. Makino Y, Tadano M, Saito M, Maneekarn N, Sittisombut N, Sirisanthana V, Poneprasert B, Fukunaga T, , 1994. Studies on serological cross-reaction in sequential flavivirus infections. Microbiol Immunol 38: 951955.[Crossref]
  32. van Panhuis WG, Gibbons RV, Endy TP, Rothman AL, Srikiatkhachorn A, Nisalak A, Burke DS, Cummings DA, , 2010. Inferring the serotype associated with dengue virus infections on the basis of pre- and postinfection neutralizing antibody titers. J Infect Dis 202: 10021010.[Crossref]
  33. Zompi S, Montoya M, Pohl MO, Balmaseda A, Harris E, , 2012. Dominant cross-reactive B cell response during secondary acute dengue virus infection in humans. PLoS Negl Trop Dis 6: e1568.[Crossref]

Data & Media loading...

  • Received : 30 May 2013
  • Accepted : 20 Sep 2013

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