Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults

A Phase 1b randomized study

Richard Rupp, Gary Joseph Luckasen, Judith Lee Kirstein, Jorge E. Osorio, Joseph D. Santangelo, Marsha Raanan, Mary Kathryn Smith, Derek Wallace, Gilad S. Gordon, Dan T. Stinchcomb

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Introduction: A safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1-4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. Methods: In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18-45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1-4 at Day 120. Results: The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84-100%; DEN-2: 96-100%; DEN-3: 83-100%; and DEN-4: 33-77%. More than 80% of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1-3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. Conclusions: All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250).

Original languageEnglish (US)
Pages (from-to)6351-6359
Number of pages9
JournalVaccine
Volume33
Issue number46
DOIs
StatePublished - Nov 17 2015

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Dengue Vaccines
dengue
Appointments and Schedules
immune response
vaccines
Safety
dosage
Dengue virus
Flavivirus
serotypes
seroconversion
Health Priorities
Dengue Virus
Dengue
headache
Myalgia
injection site
endpoints
Fatigue
Headache

Keywords

  • Clinical trial
  • Dose titration
  • Immunogenicity
  • Live attenuated tetravalent dengue vaccine
  • Multiple administration
  • Recombinant chimeric dengue vaccine
  • Safety

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • veterinary(all)
  • Molecular Medicine

Cite this

Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults : A Phase 1b randomized study. / Rupp, Richard; Luckasen, Gary Joseph; Kirstein, Judith Lee; Osorio, Jorge E.; Santangelo, Joseph D.; Raanan, Marsha; Smith, Mary Kathryn; Wallace, Derek; Gordon, Gilad S.; Stinchcomb, Dan T.

In: Vaccine, Vol. 33, No. 46, 17.11.2015, p. 6351-6359.

Research output: Contribution to journalArticle

Rupp, R, Luckasen, GJ, Kirstein, JL, Osorio, JE, Santangelo, JD, Raanan, M, Smith, MK, Wallace, D, Gordon, GS & Stinchcomb, DT 2015, 'Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults: A Phase 1b randomized study', Vaccine, vol. 33, no. 46, pp. 6351-6359. https://doi.org/10.1016/j.vaccine.2015.09.008
Rupp, Richard ; Luckasen, Gary Joseph ; Kirstein, Judith Lee ; Osorio, Jorge E. ; Santangelo, Joseph D. ; Raanan, Marsha ; Smith, Mary Kathryn ; Wallace, Derek ; Gordon, Gilad S. ; Stinchcomb, Dan T. / Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults : A Phase 1b randomized study. In: Vaccine. 2015 ; Vol. 33, No. 46. pp. 6351-6359.
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abstract = "Introduction: A safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1-4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. Methods: In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18-45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1-4 at Day 120. Results: The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52{\%}), fatigue (43{\%}) and myalgia (29{\%}). The incidence of injection site pain ranged from 29 to 64{\%} and 5 to 52{\%} among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84-100{\%}; DEN-2: 96-100{\%}; DEN-3: 83-100{\%}; and DEN-4: 33-77{\%}. More than 80{\%} of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1-3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. Conclusions: All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250).",
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T2 - A Phase 1b randomized study

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AU - Luckasen, Gary Joseph

AU - Kirstein, Judith Lee

AU - Osorio, Jorge E.

AU - Santangelo, Joseph D.

AU - Raanan, Marsha

AU - Smith, Mary Kathryn

AU - Wallace, Derek

AU - Gordon, Gilad S.

AU - Stinchcomb, Dan T.

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N2 - Introduction: A safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1-4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. Methods: In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18-45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1-4 at Day 120. Results: The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84-100%; DEN-2: 96-100%; DEN-3: 83-100%; and DEN-4: 33-77%. More than 80% of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1-3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. Conclusions: All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250).

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KW - Immunogenicity

KW - Live attenuated tetravalent dengue vaccine

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KW - Recombinant chimeric dengue vaccine

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