1921
Volume 96, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

    oa Phase 1 Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults in the United States

  • Alexander C. Schmidt1, Leyi Lin2, Luis J. Martinez2, Richard C. Ruck2, Kenneth H. Eckels2, Alix Collard1, Rafael De La Barrera2, Kristopher M. Paolino2, Jean-François Toussaint1, Edith Lepine3, Bruce L. Innis3, Richard G. Jarman2, Stephen J. Thomas2
  • View Affiliations Hide Affiliations
    * Address correspondence to Stephen J. Thomas, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910. E-mail: [email protected]

    FN1Financial support: This study was cofunded by the U.S. Army Medical Research and Materiel Command, Military Infectious Diseases Research Program and GlaxoSmithKline Biologicals SA. Manuscript development was funded by GlaxoSmithKline Biologicals SA.

    FN2Disclosure: Alix Collard, Edith Lepine, Jean-François Toussaint, Alexander C. Schmidt, and Bruce Innis are employed by the GSK group of companies. Edith Lepine, Alexander C. Schmidt, Bruce Innis, and Jean-François Toussaint also declare owing stocks, stock options, and/or restricted shares. Leyi Lin, Luis J. Martinez, Rafael De La Barrera, Richard G. Jarman, Kristopher Paolino, and Richard C. Ruck have nothing to disclose. Kenneth H. Eckels has an issued and licensed patent DENV PIV Vaccine with royalties paid to GSK. Stephen J. Thomas declares having received travel support as part of the cooperative agreement between the GSK group of companies and U.S. Army, which was put in place to codevelop the dengue vaccine candidate being reported. These statements are made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.

    FN3Authors' addresses: Alexander C. Schmidt and Alix Collard, GlaxoSmithKline Vaccines, Rixensart, Belgium, E-mails: [email protected] and [email protected]. Leyi Lin, Richard C. Ruck, Richard G. Jarman, and Stephen J. Thomas, Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, E-mails: [email protected], [email protected], [email protected], and [email protected]. Luis J. Martinez, Walter Reed Army Institute of Research, Silver Spring, MD, E-mail: [email protected]. Kenneth H. Eckels and Rafael De La Barrera, Pilot Bioproduction Facility, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD, E-mails: [email protected] and [email protected]. Kristopher M. Paolino, Translational Medicine Branch, Walter Reed Army Institute of Research, Silver Spring, MD, E-mail: [email protected]. Jean-François Toussaint, GlaxoSmithKline Vaccines, Vaccine Discovery and Development, Viral Disease Area Program, Rixensart, Belgium, E-mail: [email protected]. Edith Lepine, GlaxoSmithKline Vaccines, Laval, Canada, E-mail: [email protected]. Bruce L. Innis, GlaxoSmithKline Vaccines, King of Prussia, PA, E-mail: [email protected].

    Notes

    Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the official views of the U.S. Army or the U.S. Department of Defense. All authors participated in the design or implementation or analysis, and interpretation of the study as well as in the development of this manuscript. All authors had full access to the data, gave final approval before submission, and agree to be accountable for all aspects of the work. The corresponding author was responsible for submission of the publication.

  • Publisher: The American Society of Tropical Medicine and Hygiene
  • Source: The American Journal of Tropical Medicine and Hygiene, Volume 96, Issue 6, 7 Jun 2017, p. 1325 - 1337
  • DOI: https://doi.org/10.4269/ajtmh.16-0634

Abstract

Abstract

The safety and immunogenicity of four formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV), formulated at 1 or 4 μg with aluminum hydroxide (alum) or at 1 μg with an adjuvant system (AS01 or AS03), were evaluated in a first-time-in-human, placebo-controlled, randomized, observer-blind, phase 1 trial in the continental United States. Two doses of vaccine or placebo were administered intramuscularly 4 weeks apart to 100 healthy adults 18–39 years of age, randomized 1:1:1:1:1 to receive one of four DPIV formulations or saline placebo. The response to a third dose was evaluated in a subset of nine participants remote from primary vaccination. Humoral immunogenicity was assessed using a 50% microneutralization assay. All DPIV formulations were well tolerated. No vaccine-related serious adverse events were observed through 12 months after the second vaccine dose. In all DPIV groups, geometric mean antibody titers peaked at Day 56, waned through 6 months after the second vaccine dose, and then stabilized. In the nine subjects where boosting was evaluated, a strong anamnestic response was observed. These results support continuation of the clinical development of this dengue vaccine candidate (clinicaltrials.gov: NCT01666652).

[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.

Loading

Article metrics loading...

The graphs shown below represent data from March 2017
/content/journals/10.4269/ajtmh.16-0634
2017-03-13
2021-01-23
Loading full text...

Full text loading...

/deliver/fulltext/14761645/96/6/1325.html?itemId=/content/journals/10.4269/ajtmh.16-0634&mimeType=html&fmt=ahah

References

  1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI, 2013. The global distribution and burden of dengue. Nature 496: 504507.[Crossref]
    [Google Scholar]
  2. World Health Organization, 2009. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control, new edition. Geneva, Switzerland: World Health Organization.
    [Google Scholar]
  3. Murrell S, Wu SC, Butler M, 2011. Review of dengue virus and the development of a vaccine. Biotechnol Adv 29: 239247.[Crossref]
    [Google Scholar]
  4. Yauch LE, Shresta S, 2014. Dengue virus vaccine development. Adv Virus Res 88: 315372.[Crossref]
    [Google Scholar]
  5. Screaton G, Mongkolsapaya J, Yacoub S, Roberts C, 2015. New insights into the immunopathology and control of dengue virus infection. Nat Rev Immunol 15: 745759.[Crossref]
    [Google Scholar]
  6. 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]
    [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, Miranda Montoya MC, Cortes Supelano M, Zambrano B, Langevin E, Boaz M, Tornieporth N, Saville M, Noriega F, 2015. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med 372: 113123.[Crossref]
    [Google Scholar]
  9. Ishikawa T, Yamanaka A, Konishi E, 2014. A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available. Vaccine 32: 13261337.[Crossref]
    [Google Scholar]
  10. Fernandez S, Thomas SJ, De La Barrera R, Im-Erbsin R, Jarman RG, Baras B, Toussaint JF, Mossman S, Innis BL, Schmidt A, Malice MP, Festraets P, Warter L, Putnak JR, Eckels KH, 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.[Crossref]
    [Google Scholar]
  11. Martinez LJ, Lin L, Blaylock JM, Lyons AG, Bauer KM, De La Barrera R, Simmons M, Jarman RG, Currier JR, Friberg H, Danko JR, Teneza-Mora NC, Putnak JR, Eckels KH, Thomas SJ, 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.[Crossref]
    [Google Scholar]
  12. 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.[Crossref]
    [Google Scholar]
  13. 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.[Crossref]
    [Google Scholar]
  14. 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 2015.
    [Google Scholar]
  15. Thomas SJ, Eckels KH, Carletti I, De La Barrera R, Dessy F, Fernandez S, Putnak R, Toussaint JF, Sun W, Bauer K, Gibbons RV, Innis BL, 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.[Crossref]
    [Google Scholar]
  16. Simasathien S, Thomas SJ, Watanaveeradej V, Nisalak A, Barberousse C, Innis BL, Sun W, Putnak JR, Eckels KH, Hutagalung Y, Gibbons RV, Zhang C, De La Barrera R, Jarman RG, Chawachalasai W, Mammen MP Jr, 2008. Safety and immunogenicity of a tetravalent live-attenuated dengue vaccine in flavivirus naive children. Am J Trop Med Hyg 78: 426433.
    [Google Scholar]
  17. Roman F, Vaman T, Gerlach B, Markendorf A, Gillard P, Devaster JM, 2010. Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: preliminary report of an observer-blind, randomised trial. Vaccine 28: 17401745.[Crossref]
    [Google Scholar]
  18. Leroux-Roels I, Forgus S, De Boever F, Clement F, Demoitie MA, Mettens P, Moris P, Ledent E, Leroux-Roels G, Ofori-Anyinam O, 2013. Improved CD4+ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial. Vaccine 31: 21962206.[Crossref]
    [Google Scholar]
  19. George SL, Wong MA, Dube TJ, Boroughs KL, Stovall JL, Luy BE, Haller AA, Osorio JE, Eggemeyer LM, Irby-Moore S, Frey SE, Huang CY, Stinchcomb DT, 2015. Safety and immunogenicity of a live attenuated tetravalent dengue vaccine candidate in flavivirus-naive adults: a randomized, double-blind phase I clinical trial. J Infect Dis 212: 10321041.[Crossref]
    [Google Scholar]
  20. Dayan GH, Galan-Herrera JF, Forrat R, Zambrano B, Bouckenooghe A, Harenberg A, Guy B, Lang J, 2014. Assessment of bivalent and tetravalent dengue vaccine formulations in flavivirus-naive adults in Mexico. Hum Vaccin Immunother 10: 28532863.[Crossref]
    [Google Scholar]
  21. 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]
  22. Diaz C, Martinez LJ, Eckels KH, Lin L, Campos M, Jarman RG, Barrera RDL, Lepine E, Collard A, Innis BL, Febo I, Thomas SJ, Schmidt AC, 2015. Phase 1 Study of Different Formulations of a Tetravalent Dengue Purified Inactivated Vaccine (DPIV): Safety and Immunogenicity Data in Healthy Adults from Puerto Rico through Month 13. 64th ASTMH Annual Meeting, October 25–29, 2015, Philadelphia, PA.
    [Google Scholar]
  23. Eder S, Dubischar-Kastner K, Firbas C, Jelinek T, Jilma B, Kaltenboeck A, Knappik M, Kollaritsch H, Kundi M, Paulke-Korinek M, Schuller E, Klade CS, 2011. Long term immunity following a booster dose of the inactivated Japanese Encephalitis vaccine IXIARO®, IC51. Vaccine 29: 26072612.[Crossref]
    [Google Scholar]
  24. Plentz A, Jilg W, Schwarz TF, Kuhr HB, Zent O, 2009. Long-term persistence of tick-borne encephalitis antibodies in adults 5 years after booster vaccination with Encepur adults. Vaccine 27: 853856.[Crossref]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.16-0634
Loading
/content/journals/10.4269/ajtmh.16-0634
Loading

Data & Media loading...

  • Received : 02 Aug 2016
  • Accepted : 17 Jan 2017
  • Published online : 13 Mar 2017
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