Volume 95, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



A tetravalent live attenuated vaccine composed of chimeras of yellow fever 17D and the four dengue viruses (chimeric yellow fever dengue [CYD]) manufactured by Sanofi Pasteur has completed phase III clinical testing in over 35,000 children 2–16 years of age. The vaccine was recently licensed in four countries. During the first 2 years of observation, CYD vaccine efficacy ranged between 30% and 79% in 10 different countries with an overall efficacy of 56.8%. During year 3, there was an overall efficacy against hospitalization of 16.7%, but a relative risk of hospitalization of 1.6 among children younger than 9 years and 4.95 in children 5 years of age and younger. Vaccination of seronegative children resulted in universal broad dengue neutralizing antibody responses, but poor protection against breakthrough dengue cases. Unless proven otherwise, such breakthrough cases in vaccinated subjects should be regarded as vaccine antibody-enhanced (ADE). The provenance of these cases can be studied serologically using original antigenic sin immune responses in convalescent sera. In conventional dengue vaccine efficacy clinical trials, persons vaccinated as seronegatives may be hospitalized with breakthrough ADE infections, whereas in the placebo group, dengue infection of monotypic immunes results in hospitalization. Vaccine efficacy trial design must identify dengue disease etiology by separately measuring efficacy in seronegatives and seropositives. The reason(s) why CYD vaccine failed to raise protective dengue virus immunity are unknown. To achieve a safe and protective dengue vaccine, careful studies of monotypic CYD vaccines in humans should precede field trials of tetravalent formulations.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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  1. Sanofi Pasteur, 2016. Dengvaxia® First Dengue Vaccine Approved in Brazil. Available at: http://www.sanofipasteur.com/en/articles/Dengvaxia-First-Dengue-Vaccine-Approved-in-Brazil.aspx. [Google Scholar]
  2. Sanofi Pasteur, 2016. Sanofi Pasteur's Dengue Vaccine Approved in the Philippines. Available at: http://www.sanofipasteur.com/en/articles/sanofi-pasteur-dengue-vaccine-approved-in-the-philippines.aspx. [Google Scholar]
  3. Sanofi Pasteur, 2016. Dengvaxia®, World's First Dengue Vaccine, Approved in Mexico. http://www.sanofipasteur.com/en/articles/dengvaxia-world-s-first-dengue-vaccine-approved-in-mexico.aspx. [Google Scholar]
  4. Outbreak News Today, 2016. El Salvador Becomes the 4th Country to Approve Dengue Vaccine. Available at: http://outbreaknewstoday.com/el-salvador-becomes-the-4th-country-to-approve-dengue-vaccine-53510/. [Google Scholar]
  5. 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 T, , 2004. Safety and efficacy of chimeric yellow fever-dengue virus tetravalent vaccine formulations in nonhuman primates. J Virol 78: 47614775.[Crossref] [Google Scholar]
  6. Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, Muhammad Ismail HI, Reynales H, Limkittikul K, Rivera-Medina DM, Tran HN, Bouckenooghe A, Chansinghakul D, Cortes M, Fanouillere K, Forrat R, Frago C, Gailhardou S, Jackson N, Noriega F, Plennevaux E, Wartel TA, Zambrano B, Saville M, , 2015. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 373: 11951206.[Crossref] [Google Scholar]
  7. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, Luong CQ, Rusmil K, Wirawan DN, Nallusamy R, Pitisuttithum P, Thisyakorn U, Yoon IK, van der Vliet D, Langevin E, Laot T, Hutagalung Y, Frago C, Boaz M, Wartel TA, Tornieporth NG, Saville M, Bouckenooghe A, , 2014. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 384: 13581365.[Crossref] [Google Scholar]
  8. Villar L, Dayan GH, Arredondo-Garcia JL, Rivera DM, Cunha R, Deseda C, Reynales H, Costa MS, Morales-Ramirez JO, Carrasquilla G, Rey LC, Dietze R, Luz K, Rivas E, Montoya MC, Supelano MC, Zambrano B, Langevin E, Boaz M, Tornieporth N, Saville M, Noriega F, the CYD15 Study Group; , 2014. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 372: 113123.[Crossref] [Google Scholar]
  9. Halstead SB, Russell PK, , 2016. Protective and immunological behavior of chimeric yellow fever dengue vaccine. Vaccine 34: 16431647.[Crossref] [Google Scholar]
  10. Guy B, Jackson N, , 2016. Dengue vaccine: hypotheses to understand CYD-TDV-induced protection. Nat Rev Microbiol 14: 4554.[Crossref] [Google Scholar]
  11. Guirakhoo F, Kitchener S, Morrison D, Forat R, McCarthy K, Nichols R, Yoksan S, , 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] [Google Scholar]
  12. Guy B, Saville M, Lang J, , 2010. Development of Sanofi Pasteur tetravalent dengue vaccine. Hum Vaccin 6: 696705.[Crossref] [Google Scholar]
  13. Dayan GH, 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] [Google Scholar]
  14. Halstead SB, , 1979. In vivo enhancement of dengue infection with passively transferred antibody. J Infect Dis 140: 527533.[Crossref] [Google Scholar]
  15. Guirakhoo F, Weltzin R, Chambers TJ, Zhang Z, 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] [Google Scholar]
  16. Sabin AB, , 1952. Research on dengue during World War II. Am J Trop Med Hyg 1: 3050. [Google Scholar]
  17. Guzman MG, Kouri G, Bravo J, Valdes L, Vazquez S, Halstead SB, , 2002. Effect of age on outcome of secondary dengue 2 infections. Int J Infect Dis 6: 118124.[Crossref] [Google Scholar]
  18. Anders KL, Nguyet NM, Chau NV, Hung NT, Thuy TT, Lien le B, Farrar J, Wills B, Hien TT, Simmons CP, , 2011. Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. Am J Trop Med Hyg 84: 127134.[Crossref] [Google Scholar]
  19. Guzman MG, Kouri G, Valdes L, Bravo J, Vazquez S, Halstead SB, , 2002. Enhanced severity of secondary dengue 2 infections occurring at an interval of 20 compared with 4 years after dengue 1 infection. PAHO J Epidemiol 11: 223227. [Google Scholar]
  20. Anderson KB, Gibbons RV, Cummings DA, Nisalak A, Green S, Libraty DH, Jarman RG, Srikiatkhachorn A, Mammen MP, Darunee B, Yoon IK, Endy TP, , 2013. A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand. J Infect Dis 209: 360368.[Crossref] [Google Scholar]
  21. Guzman MG, Kouri GP, Bravo J, Soler M, Vazquez S, Morier L, , 1990. Dengue hemorrhagic fever in Cuba, 1981: a retrospective seroepidemiologic study. Am J Trop Med Hyg 42: 179184. [Google Scholar]
  22. Guzman MG, Kouri G, Valdes L, Bravo J, Alvarez M, Vazquez S, Delgado I, Halstead SB, , 2000. Epidemiologic studies on dengue in Santiago de Cuba, 1997. Am J Epidemiol 152: 793799.[Crossref] [Google Scholar]
  23. Alvarez M, Rodriguez R, Bernardo L, Vasquez S, Morier L, Gonzalez D, Castro O, Kouri G, Halstead SB, Guzman MG, , 2006. Dengue hemorrhagic fever caused by sequential dengue 1–3 infections at a long interval: Havana epidemic, 2001–2002. Am J Trop Med Hyg 75: 11131117. [Google Scholar]
  24. Halstead SB, , 2013. Identifying protective dengue vaccines: guide to mastering an empirical process. Vaccine 31: 45014507.[Crossref] [Google Scholar]
  25. Fibriansah G, Tan JL, Smith SA, de Alwis R, Ng TS, Kostyuchenko VA, Jadi RS, Kukkaro P, de Silva AM, Crowe JE, Lok SM, , 2015. A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. Nat Commun 6: 6341.[Crossref] [Google Scholar]
  26. Weiskopf D, Sette A, , 2014. T-cell immunity to infection with dengue virus in humans. Front Immunol 5: 93.[Crossref] [Google Scholar]
  27. Weiskopf D, Angelo MA, Bangs DJ, Sidney J, Paul S, Peters B, de Silva AD, Lindow JC, Diehl SA, Whitehead S, Durbin A, Kirkpatrick B, Sette A, , 2015. The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes. J Virol 89: 120128.[Crossref] [Google Scholar]
  28. Modhiran N, Watterson D, Panetta AK, Sester DP, Liu L, Muller DA, Hume DA, Stacey KJ, Young PR, , 2015. Dengue virus NS1 is a viral toxin that activates cells via TLR4 and disrupts endothelial cell monolayer integrity. Sci Transl Med 7: 304ra142.[Crossref] [Google Scholar]
  29. Beatty RP, Puerta-Guardo H, Killingbeck S, Glasner D, Harris E, , 2015. Dengue virus non-structural protein 1 triggers endothelial permeability and vascular leak that can be inhibited by anti-NS1 antibodies. Sci Transl Med 7: 304ra141.[Crossref] [Google Scholar]
  30. Schlesinger JJ, Brandriss MW, Walsh EE, , 1987. Protection of mice against dengue 2 virus encephalitis by immunization with the dengue 2 virus non-structural glycoprotein NS1. J Gen Virol 68: 853857.[Crossref] [Google Scholar]
  31. Lu H, Xu XF, Gao N, Fan DY, Wang J, An J, , 2013. Preliminary evaluation of DNA vaccine candidates encoding dengue-2 prM/E and NS1: their immunity and protective efficacy in mice. Mol Immunol 54: 109114.[Crossref] [Google Scholar]
  32. Chao DY, Galula JU, Shen WF, Davis BS, Chang GJ, , 2015. Nonstructural protein 1-specific immunoglobulin M and G antibody capture enzyme-linked immunosorbent assays in diagnosis of flaviviral infections in humans. J Clin Microbiol 53: 557566.[Crossref] [Google Scholar]
  33. Midgley CM, Bajwa-Joseph M, Vasanawathana S, Limpitikul W, Wills B, Flanagan A, Waiyaiya E, Tran HB, Cowper AE, Chotiyarnwon P, Grimes JM, Yoksan S, Malasit P, Simmons CP, Mongkolsapaya J, Screaton GR, , 2011. An in-depth analysis of original antigenic sin in dengue virus infection. J Virol 85: 410421.[Crossref] [Google Scholar]
  34. Dorigatti I, Aguas R, Donnelly CA, Guy B, Coudeville L, Jackson N, Saville M, Ferguson NM, , 2015. Modelling the immunological response to a tetravalent dengue vaccine from multiple phase-2 trials in Latin America and south east Asia. Vaccine 33: 37463751.[Crossref] [Google Scholar]
  35. Huang CY-H, Butrapet S, Tsuchiya KR, Bhamarapravati N, Gubler DR, Kinney RM, , 2003. Dengue 2 PDK-53 virus as a chimeric carrier for tetravalent dengue vaccine. J Virol 77: 1143611447.[Crossref] [Google Scholar]
  36. Kirkpatrick BD, Durbin AP, Pierce KK, Carmolli MP, Tibery CM, Grier PL, Hynes N, Diehl SA, Elwood D, Jarvis AP, Sabundayo BP, Lyon CE, Larsson CJ, Jo M, Lovchik JM, Luke CJ, Walsh MC, Fraser EA, Subbarao K, Whitehead SS, , 2015. Robust and balanced immune responses to all 4 dengue virus serotypes following administration of a single dose of a live attenuated tetravalent dengue vaccine to healthy, flavivirus-naive adults. J Infect Dis 212: 702710.[Crossref] [Google Scholar]
  37. World Health Organization Department of Immunization Vaccines and Biologicals, 2008. Guidelines for the Clinical Evaluation of Dengue Vaccines in Endemic Areas. , ed. Geneva, Switzerland: World Health Organization, 441. [Google Scholar]
  38. 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] [Google Scholar]
  39. Hombach J, , 2009. Guidelines for clinical trials of dengue vaccine in endemic areas. J Clin Virol 46 (Suppl 2): S7S9.[Crossref] [Google Scholar]
  40. Coudeville L, Baurin N, Vergu E, , 2016. Estimation of parameters related to vaccine efficacy and dengue transmission from two large phase III studies. Vaccine (In press). doi:10.1016/j.vaccine.2015.11.023. [Google Scholar]

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  • Received : 18 Mar 2016
  • Accepted : 08 Jun 2016
  • Published online : 05 Oct 2016

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