title: Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults: A Phase 1b randomized study.
abstract: BACKGROUND
  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).
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch at Galveston, Galveston, TX, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Rupp
authors.affiliation: Medical Center of the Rockies Foundation, University of Colorado Health North Research, Loveland, CO, United States.
authors.forename: Gary Joseph
authors.initials: GJ
authors.lastname: Luckasen
authors.affiliation: Utah Research Team, Advanced Clinical Research, West Jordan, UT, United States.
authors.forename: Judith Lee
authors.initials: JL
authors.lastname: Kirstein
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States; Scientific Affairs and Policy, Takeda Vaccines, Inc., Deerfield, IL, United States.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Osorio
authors.affiliation: Operations, Takeda Vaccines Pte. Ltd, Singapore, Singapore.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Santangelo
authors.affiliation: Statistics, Quantitative Sciences, Takeda Development Center Americas Inc., Deerfield, IL, United States.
authors.forename: Marsha
authors.initials: M
authors.lastname: Raanan
authors.affiliation: Clinical Testing Laboratory, Takeda Vaccines, Inc., Deerfield, IL, United States.
authors.forename: Mary Kathryn
authors.initials: MK
authors.lastname: Smith
authors.affiliation: Clinical Development, Takeda Vaccines Pte. Ltd, Singapore, Singapore.
authors.forename: Derek
authors.initials: D
authors.lastname: Wallace
authors.affiliation: Orra Group, LLC, Boulder, CO, United States.
authors.forename: Gilad S
authors.initials: GS
authors.lastname: Gordon
authors.affiliation: Scientific Affairs and Policy, Takeda Vaccines, Inc., Deerfield, IL, United States. Electronic address: dan.stinchcomb@takeda.com.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Stinchcomb
mesh_terms: D000293:Adolescent; D000328:Adult; D003715:Dengue / Q000517:prevention & control*; D053059:Dengue Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007115:Immunization Schedule; D015994:Incidence; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D014481:United States; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D055815:Young Adult
chemical_list: D053059:Dengue Vaccines; D010919:Placebos; D014613:Vaccines, Attenuated
keywords: Clinical trial; Dose titration; Immunogenicity; Live attenuated tetravalent dengue vaccine; Multiple administration; Recombinant chimeric dengue vaccine; Safety