Research ArticleInfectious Disease

The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model

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Science Translational Medicine  16 Mar 2016:
Vol. 8, Issue 330, pp. 330ra36
DOI: 10.1126/scitranslmed.aaf1517
  • Fig. 1. Screening, enrollment, and follow-up of flavivirus-seronegative subjects for vaccination with the dengue vaccine TV003 and challenge with DENV-2 6 months later.

    As described in the text, 48 subjects were randomly assigned to receive TV003 or placebo on study day 0. The treatment assignment was masked to study staff and volunteers. On study day 180, all eligible subjects (41) received the challenge virus rDEN2Δ30. PI, principal investigator.

  • Table 1. Summary of viremia after administration of TV003 (CIR287, n = 24).
    AdmixtureVaccine
    components
    % with
    viremia
    Mean peak
    titer ± SE
    (log10 PFU/ml)*
    Maximum titer
    (log10 PFU/ml)
    Mean day of
    onset (range)
    Mean duration
    in days (range)
    TV003DEN1Δ30210.7 ± 0.21.77.6 (2–10)5.0 (2–7)
    DEN2/4Δ3040.5 ± 0.00.58.0 (all 8)1.0 (all 1)
    DEN3-3Δ30/31-7164630.6 ± 0.11.38.6 (6–14)3.5 (1–7)
    DEN4Δ30170.6 ± 0.11.08.0 (6–10)1.3 (1–2)
    Total %71

    *Lower limit of detection = 0.5 log10 PFU/ml.

    • Table 2. Serologic response of flavivirus-naïve subjects after vaccination with TV003.
      Peak geometric mean titer, reciprocal (median)*
      nDEN1DEN2DEN3DEN4
      2447 (29)84 (78)152 (167)270 (276)
      Range<5–4991–71031–53343–5025
      % with PRNT50 ≥1:10
      nDEN1DEN2DEN3DEN4
      2491.7100100100
      Multivalent responses (cumulative)
      nTetraTriBiMono
      2491.7%8.3% (100)00

      *Titer calculated only for those subjects who had a PRNT50 ≥10. The peak titer is calculated from titers obtained through study 90 after vaccination (days 28, 56, and 90).

      • Table 3. Clinical response to rDEN2Δ30 in subjects who had received TV003 or control 6 months earlier.

        ALT, alanine transaminase; PT, prothrombin time; PTT, partial thromboplastin time.

        AEPrimary treatment
        TV003 (n = 21)Placebo (n = 20)
        Injection site
          Erythema9.5%0.0%
          Pain0.0%0.0%
          Tenderness0.0%0.0%
          Induration0.0%0.0%
        Systemic
          Viremia0.0%100.0%*
          Fever0.0%0.0%
          Headache23.8%30.0%
          Rash0.0%80.0%*
          Neutropenia0.0%20.0%
          Elevated ALT0.0%5.0%
          Myalgia4.8%20.0%
          Arthralgia0.0%10.0%
          Retro-orbital pain9.5%25.0%
          Fatigue14.3%15.0%
          Nausea14.3%20.0%
          Photophobia4.8%0.0%
          Elevated PT0.0%0.0%
          Elevated PTT4.8%0.0%
          Thrombocytopenia0.0%10.0%

        *P < 0.0001, two-sided.

        P = 0.048, two-sided.

        • Table 4. Most of the TV003 recipients demonstrate no boost to DENV-2 after challenge.
          SubjectPRNT50
          day 180
          Peak PRNT50
          post-
          challenge
          Ratio PRNT50
          post/pre-
          challenge*
          149.719.10.4
          272.048.10.7
          350.638.30.8
          466.556.60.9
          555.649.60.9
          675.378.41.0
          7260.2324.51.2
          8119.9160.91.3
          9196.5301.21.5
          1014.823.11.6
          1158.297.11.7
          1255.9145.42.6
          1312.349.34.0
          1451.9209.94.0
          1519.680.84.1
          1645.2227.55.0
          1727.3139.65.1
          1840.3251.86.2
          1946.0637.113.9
          2019.3373.619.4
          2148.81336.127.4
          Geomean49.6123.52.5

          *Samples with a post/pre-PRNT50 ratio ≥4.0 are bolded.

          Supplementary Materials

          • www.sciencetranslationalmedicine.org/cgi/content/full/8/330/330ra36/DC1

            Fig. S1. Components of the LATV dengue vaccines TV003 and CYD (Dengvaxia).

            Table S1. Incidence of specific AEs in TV003 recipients compared to controls.

            Table S2. Interval between TV003 and challenge.

            Other supplemental material S1. Clinical protocol for the study “A Phase 1 Evaluation of the Protective Efficacy of a Single Dose of the Live Attenuated Tetravalent Dengue Vaccine TV003 to Protect Against Infection with Attenuated DENV-2, rDEN2Δ30-7169.”

            Other supplemental material S1. Consent form for the study “A Phase 1 Evaluation of the Protective Efficacy of a Single Dose of the Live Attenuated Tetravalent Dengue Vaccine TV003 to Protect Against Infection with Attenuated DENV-2, rDEN2Δ30-7169.”

            Other supplemental material S2. Excel file of screening and enrollment data.

          • Supplementary Material for:

            The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model

            Beth D. Kirkpatrick, Stephen S. Whitehead, Kristen K. Pierce, Cecilia M. Tibery, Palmtama L. Grier, Noreen A. Hynes, Catherine J. Larsson, Beulah P. Sabundayo, Kawsar R. Talaat, Anna Janiak, Marya P. Carmolli, Catherine J. Luke, Sean A. Diehl, Anna P. Durbin*

            *Corresponding author. E-mail: adurbin1{at}jhu.edu

            Published 16 March 2016, Sci. Transl. Med. 8, 330ra36 (2016)
            DOI: 10.1126/scitranslmed.aaf1517

            This PDF file includes:

            • Fig. S1. Components of the LATV dengue vaccines TV003 and CYD (Dengvaxia).
            • Table S1. Incidence of specific AEs in TV003 recipients compared to controls.
            • Table S2. Interval between TV003 and challenge.

            [Download PDF]

            Other Supplementary Material for this manuscript includes the following:

            • Other supplemental material S1 (Microsoft Word format). Clinical protocol for the study “A Phase 1 Evaluation of the Protective Efficacy of a Single Dose of the Live Attenuated Tetravalent Dengue Vaccine TV003 to Protect Against Infection with Attenuated DENV-2, rDEN2Δ30-7169.”
            • Other supplemental material S1 (Microsoft Word format). Consent form for the study “A Phase 1 Evaluation of the Protective Efficacy of a Single Dose of the Live Attenuated Tetravalent Dengue Vaccine TV003 to Protect Against Infection with Attenuated DENV-2, rDEN2Δ30-7169.”
            • Other supplemental material S2. Excel file of screening and enrollment data.

            [Supplementary Files S1 to S2]

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