1921
Volume 103, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

Dengue disease and its causative agents, the dengue viruses (DENV-1–4), cause high morbidity in tropical and subtropical regions. We evaluated three dosing regimens of the investigational tetravalent AS03-adjuvanted dengue-purified inactivated vaccine (DPIV+AS03). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03 according to the following regimens: 0–1 month (M), 0–1–6 M, or 0–3 M. Participants received DPIV+AS03 or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03 for 28 days (D) after each dose; 2) to demonstrate the added value of a booster dose (0–1–6 M versus 0–1 M) based on neutralizing antibody titers to each DENV type (DENV-1–4) at 28 D after the last dose; and, if this objective was met, 3) to demonstrate the benefit of a longer interval between the first and second doses (0–1 M versus 0–3 M). Adverse events (AEs) within 7 D after vaccination tended to be more frequent after DPIV+AS03 doses than placebo; the number of grade 3 AEs was low (≤ 4.5% after DPIV+AS03; ≤ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03 appeared higher for three-dose (0–1–6 M) than two-dose (0–1 M and 0–3 M) regimens. No serious AEs were considered related to vaccination, and no potential immune-mediated diseases were reported during the study. All three schedules were well tolerated. Both primary immunogenicity objectives were demonstrated. The 0–3 M and 0–1–6 M regimens were more immunogenic than the 0–1 M regimen.

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

Loading

Article metrics loading...

The graphs shown below represent data from March 2017
/content/journals/10.4269/ajtmh.19-0738
2020-04-27
2020-09-28
Loading full text...

Full text loading...

/deliver/fulltext/14761645/103/1/tpmd190738.html?itemId=/content/journals/10.4269/ajtmh.19-0738&mimeType=html&fmt=ahah

References

  1. World Health Organization, 2018. Dengue vaccine: WHO position paper–September 2018. Wkly Epidemiol Rec 93: 457476.
    [Google Scholar]
  2. Stanaway JD et al., 2016. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis 16: 712723.
    [Google Scholar]
  3. Dayan G et al., 2015. Prospective cohort study with active surveillance for fever in four dengue endemic countries in Latin America. Am J Trop Med Hyg 93: 1823.
    [Google Scholar]
  4. Holbrook MR, 2017. Historical perspectives on flavivirus research. Viruses 9: 97.
    [Google Scholar]
  5. WHO, 2017. Updated Questions and Answers Related to Information Presented in the Sanofi Pasteur Press Release on 30 November 2017 with Regards to the Dengue Vaccine Dengvaxia®. Available at: http://www.who.int/immunization/diseases/dengue/q_and_a_dengue_vaccine_dengvaxia/en/. Accessed June 7, 2018.
    [Google Scholar]
  6. Bowman LR, Donegan S, McCall PJ, 2016. Is dengue vector control deficient in effectiveness or evidence? Systematic review and meta-analysis. PLoS Negl Trop Dis 10: e0004551.
    [Google Scholar]
  7. Torresi J, Ebert G, Pellegrini M, 2017. Vaccines licensed and in clinical trials for the prevention of dengue. Hum Vaccin Immunother 13: 10591072.
    [Google Scholar]
  8. Elong Ngono A, Shresta S, 2019. Cross-reactive T cell immunity to dengue and zika viruses: new insights into vaccine development. Front Immunol 10: 1316.
    [Google Scholar]
  9. Hadinegoro SR et al., 2015. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 373: 11951206.
    [Google Scholar]
  10. Cohet C, van der Most R, Bauchau V, Bekkat-Berkani R, Doherty TM, Schuind A, Tavares Da Silva F, Rappuoli R, Garcon N, Innis BL, 2019. Safety of AS03-adjuvanted influenza vaccines: a review of the evidence. Vaccine 37: 30063021.
    [Google Scholar]
  11. Barban V, Mantel N, De Montfort A, Pagnon A, Pradezynski F, Lang J, Boudet F, 2018. Improvement of the dengue virus (DENV) nonhuman primate model via a reverse translational approach based on dengue vaccine clinical efficacy data against DENV-2 and -4. J Virol 92: e0044018.
    [Google Scholar]
  12. Borges MB et al., 2019. Detection of post-vaccination enhanced dengue virus infection in macaques: an improved model for early assessment of dengue vaccines. PLoS Pathog 15: e1007721.
    [Google Scholar]
  13. Schmidt AC et al., 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.
    [Google Scholar]
  14. Diaz C et al., 2018. Phase I randomized study of a tetravalent dengue purified inactivated vaccine in healthy adults from Puerto Rico. Am J Trop Med Hyg 98: 14351443.
    [Google Scholar]
  15. International Conference on Harmonisation, 1994. Topic E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf. Accessed May 1, 2019.
    [Google Scholar]
  16. FDA, 2007. Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Available at: https://www.fda.gov/media/73679/download. Accessed May 1, 2019.
    [Google Scholar]
  17. Weiskopf D et al., 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.
    [Google Scholar]
  18. Tran NH et al., 2019. Long-term immunogenicity and safety of tetravalent dengue vaccine (CYD-TDV) in healthy populations in Singapore and Vietnam: 4-year follow-up of randomized, controlled, phase II trials. Hum Vaccin Immunother 6: 113.
    [Google Scholar]
  19. Ahmad Z, Poh CL, 2019. The conserved molecular determinants of virulence in dengue virus. Int J Med Sci 16: 355365.
    [Google Scholar]
  20. Eder S et al., 2011. Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIARO(R), IC51. Vaccine 29: 26072612.
    [Google Scholar]
  21. Grifoni A et al., 2017. Patterns of cellular immunity associated with experimental infection with rDEN2Δ30 (Tonga/74) support its suitability as a human dengue virus challenge strain. J Virol 91: e0213316.
    [Google Scholar]
  22. Mongkolsapaya J et al., 2003. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med 9: 921927.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.19-0738
Loading
/content/journals/10.4269/ajtmh.19-0738
Loading

Data & Media loading...

Supplemental information, tables, and figures

  • Received : 04 Oct 2019
  • Accepted : 25 Mar 2020
  • Published online : 27 Apr 2020
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