1921
Volume 98, Issue 5
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

The safety and immunogenicity of four adjuvanted formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV) were evaluated in a predominantly dengue-primed population in Puerto Rico. In this placebo-controlled, randomized, observer-blind, phase I trial, 100 healthy adults were randomized 1:1:1:1:1 to receive DPIV at Day (D)0 and D28 (1 μg per dengue virus [DENV] type 1–4 adjuvanted with either alum, AS01 or AS03, or 4 μg per DENV type adjuvanted with alum) or saline placebo. Functional antibody responses were assessed using a microneutralization assay at D56, Month (M)7, and M13. All DPIV formulations were well tolerated and no safety signals were identified through M13. The M13 according-to-protocol (ATP) immunogenicity cohort included 83 participants. The ATP analysis of immunogenicity was performed only on the 78 subjects seropositive for ≥ 1 DENV type at baseline: 69 tetravalent, three trivalent, two bivalent, and four monovalent. In all DPIV groups, geometric mean antibody titers (GMTs) increased from D0 to D56 and waned modestly through M13, while remaining well above prevaccination levels. The 4 μg + alum and the AS01- and AS03-adjuvanted formulations were highly immunogenic, with M13-neutralizing antibody GMTs against all four DENV types above 1,000. M13/D0 GMT ratios were highest in the 1 μg + AS03 group (ranging 3.2–3.7 depending on the DENV type). These results encourage continued clinical development of DPIV (ClinicalTrials.gov: NCT01702857).

[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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2018-05-09
2018-05-27
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References

  1. WHO, 2009. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control, New edition. Geneva, Switzerland: WHO Press.
  2. Bhatt S, 2013. The global distribution and burden of dengue. Nature 496: 504507.
  3. CDC, 2015. Dengue in Puerto Rico. Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/dengue/about/inpuerto.html. Accessed April 2, 2017.
  4. Rigau-Perez JG, Vorndam AV, Clark GG, , 2001. The dengue and dengue hemorrhagic fever epidemic in Puerto Rico, 1994–1995. Am J Trop Med Hyg 64: 6774.
  5. Bauer K, 2015. A phase II, randomized, safety and immunogenicity trial of a re-derived, live-attenuated dengue virus vaccine in healthy children and adults living in Puerto Rico. Am J Trop Med Hyg 93: 441453.
  6. WHO, 2016. Dengue vaccine: WHO position paper—July 2016. Wkly Epidemiol Rec 91: 349364.
  7. Edelman R, Wasserman SS, Bodison SA, Putnak RJ, Eckels KH, Tang D, Kanesa-Thasan N, Vaughn DW, Innis BL, Sun W, , 2003. Phase I trial of 16 formulations of a tetravalent live-attenuated dengue vaccine. Am J Trop Med Hyg 69: 4860.
  8. Innis BL, Eckels KH, , 2003. Progress in development of a live-attenuated, tetravalent dengue virus vaccine by the United States army medical research and materiel command. Am J Trop Med Hyg 69: 14.
  9. Simasathien S, 2008. Safety and immunogenicity of a tetravalent live-attenuated dengue vaccine in flavivirus naive children. Am J Trop Med Hyg 78: 426433.
  10. Sun W, 2009. Phase 2 clinical trial of three formulations of tetravalent live-attenuated dengue vaccine in flavivirus-naive adults. Hum Vaccin 5: 3340.
  11. Watanaveeradej V, 2011. Safety and immunogenicity of a tetravalent live-attenuated dengue vaccine in flavivirus-naive infants. Am J Trop Med Hyg 85: 341351.
  12. Thomas SJ, 2013. A phase II, randomized, safety and immunogenicity study of a re-derived, live-attenuated dengue virus vaccine in healthy adults. Am J Trop Med Hyg 88: 7388.
  13. Watanaveeradej V, 2014. Safety and immunogenicity of a rederived, live-attenuated dengue virus vaccine in healthy adults living in Thailand: a randomized trial. Am J Trop Med Hyg 91: 119128.
  14. Sanofi Pasteur, , 2017. Sanofi Updates Information on Dengue Vaccine. Available at: http://www.sanofipasteur.com/en/Documents/PDF/PR/20171130_Sanofi-Updates-Info-on-Dengue-Vaccine_EN.pdf. Accessed December 1, 2017.
  15. Fernandez S, 2015. An adjuvanted, tetravalent dengue virus purified inactivated vaccine candidate induces long-lasting and protective antibody responses against dengue challenge in rhesus macaques. Am J Trop Med Hyg 92: 698708.
  16. Schmidt AC, 2017. Phase 1 randomized study of a tetravalent dengue purified inactivated vaccine in healthy adults in the United States. Am J Trop Med Hyg 96: 13251337.
  17. Martinez LJ, 2015. Safety and immunogenicity of a dengue virus serotype-1 purified-inactivated vaccine: results of a phase 1 clinical trial. Am J Trop Med Hyg 93: 454460.
  18. Simmons M, Burgess T, Lynch J, Putnak R, , 2010. Protection against dengue virus by non-replicating and live attenuated vaccines used together in a prime boost vaccination strategy. Virology 396: 280288.
  19. Fernandez S, Cisney ED, Tikhonov AP, Schweitzer B, Putnak RJ, Simmons M, Ulrich RG, , 2011. Antibody recognition of the dengue virus proteome and implications for development of vaccines. Clin Vaccine Immunol 18: 523532.
  20. International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), 2012. Medical Dictionary for Regulatory Activities (MedDRA). Version 15.0. Available at: http://www.meddra.org. Accessed June 12, 2015.
  21. WHO, 2008. Guidelines for the Clinical Evaluation of Dengue Vaccine in Endemic Areas, WHO/IVB/08.12. Available at: http://whqlibdoc.who.int/hq/2008/WHO_IVB_08.12_eng.pdf. Accessed June 12, 2015.
  22. Tsai WY, Durbin A, Tsai JJ, Hsieh SC, Whitehead S, Wang WK, , 2015. Complexity of neutralizing antibodies against multiple dengue virus serotypes after heterotypic immunization and secondary infection revealed by in-depth analysis of cross-reactive antibodies. J Virol 89: 73487362.
  23. Leroux-Roels I, Borkowski A, Vanwolleghem T, Drame M, Clement F, Hons E, Devaster JM, Leroux-Roels G, , 2007. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 370: 580589.
  24. Couch RB, 2014. Superior antigen-specific CD4+ T-cell response with AS03-adjuvantation of a trivalent influenza vaccine in a randomised trial of adults aged 65 and older. BMC Infect Dis 14: 425.
  25. Mata E, Salvador A, Igartua M, Hernandez RM, Pedraz JL, , 2013. Malaria vaccine adjuvants: latest update and challenges in preclinical and clinical research. BioMed Res Int 2013: 282913.
  26. Chlibek R, Bayas JM, Collins H, de la Pinta ML, Ledent E, Mols JF, Heineman TC, , 2013. Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults >=50 years of age. J Infect Dis 208: 19531961.
  27. 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.
  28. Osorio JE, 2014. Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study. Lancet Infect Dis 14: 830838.
  29. de Alwis R, 2012. Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci USA 109: 74397444.
  30. Hadinegoro SR, 2015. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 373: 11951206.
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Supplementary Data

Supplemental Figures and Table

  • Received : 07 Aug 2017
  • Accepted : 29 Jan 2018

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