Volume 98, Issue 3
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



We conducted an open label, dose escalation Phase 1 clinical trial of a tetravalent dengue DNA vaccine (TVDV) formulated in Vaxfectin to assess safety and immunogenicity. A total of 40 dengue- and flavivirus-naive volunteers received either low-dose (1 mg) TVDV alone ( = 10, group 1), low-dose TVDV (1 mg) formulated in Vaxfectin ( = 10, group 2), or high-dose TVDV (2 mg, group 3) formulated in Vaxfectin ( = 20). Subjects were immunized intramuscularly with three doses on a 0-, 30-, 90-day schedule and monitored. Blood samples were obtained after each immunization and various time points thereafter to assess anti-dengue antibody and interferon gamma (IFNγ) T-cell immune responses. The most common adverse events (AEs) across all groups included mild to moderate pain and tenderness at the injection site, which typically resolved within 7 days. Common solicited signs and symptoms included fatigue (42.5%), headache (45%), and myalgias (47.5%). There were no serious AEs related to the vaccine or study procedures. No anti-dengue antibody responses were detected in group 1 subjects who received all three immunizations. There were minimal enzyme-linked immunosorbent assay and neutralizing antibody responses among groups 2 and 3 subjects who completed the immunization schedule. By contrast, IFNγ T-cell responses, regardless of serotype specificity, occurred in 70%, 50%, and 79% of subjects in groups 1, 2, and 3, respectively. The largest IFNγ T-cell responses were among group 3 subjects. We conclude that TVDV was safe and well-tolerated and elicited predominately anti-dengue T-cell IFNγ responses in a dose-related fashion.

[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. Bhatt S, 2013. The global distribution and burden of dengue. Nature 496: 504507.
  2. Beckett CG, 2011. Evaluation of a prototype dengue-1 DNA vaccine in a phase 1 clinical trial. Vaccine 29: 960968.
  3. Hartikka J, 2001. Vaxfectin enhances the humoral immune response to plasmid DNA-encoded antigens. Vaccine 19: 19111923.
  4. Hartikka J, Bozoukova V, Yang CK, Ye M, Rusalov D, Shlapobersky M, Vilalta A, Wei Q, Rolland A, Smith LR, , 2009. Vaxfectin, a cationic lipid-based adjuvant for protein-based influenza vaccines. Vaccine 27: 63996403.
  5. Margalith M, Vilalta A, , 2006. Sustained protective rabies neutralizing antibody titers after administration of cationic lipid-formulated pDNA vaccine. Genet Vaccines Ther 4: 2.
  6. Sullivan SM, Doukas J, Hartikka J, Smith L, Rolland A, , 2010. Vaxfectin: a versatile adjuvant for plasmid DNA- and protein-based vaccines. Expert Opin Drug Deliv 7: 14331446.
  7. Porter KR, Ewing D, Chen L, Wu SJ, Hayes CG, Ferrari M, Teneza-Mora N, Raviprakash K, , 2012. Immunogenicity and protective efficacy of a vaxfectin-adjuvanted tetravalent dengue DNA vaccine. Vaccine 30: 336341.
  8. Smith LR, 2010. Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin. Vaccine 28: 25652572.
  9. Simmons M, Porter KR, Hayes CG, Vaughn DW, Putnak R, , 2006. Characterization of antibody responses to combinations of a dengue virus type 2 DNA vaccine and two dengue virus type 2 protein vaccines in rhesus macaques. J Virol 80: 95779585.
  10. Putnak JR, 2008. Comparative evaluation of three assays for measurement of dengue virus neutralizing antibodies. Am J Trop Med Hyg 79: 115122.
  11. Thomas SJ, , 2014. Developing a dengue vaccine: progress and future challenges. Ann N Y Acad Sci 1323: 140159.
  12. Sabchareon A, 2012. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 380: 15591567.
  13. Villar L, 2015. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 372: 113123.
  14. Capeding MR, 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.
  15. Sirivichayakul C, Sabchareon A, Limkittikul K, Yoksan S, , 2014. Plaque reduction neutralization antibody test does not accurately predict protection against dengue infection in Ratchaburi cohort, Thailand. Virol J 11: 48.
  16. Rothman AL, Kanesa-thasan N, West K, Janus J, Saluzzo JF, Ennis FA, , 2001. Induction of T lymphocyte responses to dengue virus by a candidate tetravalent live attenuated dengue virus vaccine. Vaccine 19: 46944699.
  17. Balas C, Kennel A, Deauvieau F, Sodoyer R, Arnaud-Barbe N, Lang J, Guy B, , 2011. Different innate signatures induced in human monocyte-derived dendritic cells by wild-type dengue 3 virus, attenuated but reactogenic dengue 3 vaccine virus, or attenuated nonreactogenic dengue 1–4 vaccine virus strains. J Infect Dis 203: 103108.
  18. Guy B, 2008. Cell-mediated immunity induced by chimeric tetravalent dengue vaccine in naive or flavivirus-primed subjects. Vaccine 26: 57125721.
  19. Thakur A, Pedersen LE, Jungersen G, , 2012. Immune markers and correlates of protection for vaccine induced immune responses. Vaccine 30: 49074920.
  20. Halstead SB, , 2013. Identifying protective dengue vaccines: guide to mastering an empirical process. Vaccine 31: 45014507.
  21. Li J, Valentin A, Beach RK, Alicea C, Felber BK, Pavlakis GN, , 2015. DNA is an efficient booster of dendritic cell-based vaccine. Hum Vaccin Immunother 11: 19271935.
  22. Lillie PJ, 2012. Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans. Clin Infect Dis 55: 1925.
  23. Vandermeulen G, Vanvarenberg K, De Beuckelaer A, De Koker S, Lambricht L, Uyttenhove C, Reschner A, Vanderplasschen A, Grooten J, Preat V, , 2015. The site of administration influences both the type and the magnitude of the immune response induced by DNA vaccine electroporation. Vaccine 33: 31793185.

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  • Received : 27 May 2017
  • Accepted : 25 Nov 2017

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