title: Safety and immunogenicity of three tetravalent dengue vaccine formulations in healthy adults in the USA.
abstract: BACKGROUND
  A candidate recombinant, live-attenuated, CYD tetravalent dengue vaccine (CYD-TDV) has recently demonstrated immunogenicity, efficacy and good tolerability. This study was performed to evaluate three CYD-TDV formulations in adults.
  
  
  METHODS
  This was a randomized, double-blind, multicenter, phase II trial. The vaccine formulations were: CYD-TDV 5555 (≈5log10 tissue culture infectious dose 50% [TCID50] of serotypes 1-4); CYD-TDV 5553 (≈5log10 TCID50 of serotypes 1-3 and ≈3log10 TCID50 of serotype 4); and CYD-TDV 4444 (≈4log10 TCID50 of serotypes 1-4). Vaccinations were administered at 0, 6 and 12 months. Immunogenicity was assessed using the plaque reduction neutralization test.
  
  
  RESULTS
  In total, 260 individuals were enrolled. The 5555 formulation elicited a superior serotype 4 response versus the 5553 formulation, with seropositivity rates of 89.7% and 58.3%, respectively, after the second dose (between-group difference 31.4%; 95% confidence interval 18.2-43.2). After each of the three doses, seropositivity rates for serotypes 1-3 were numerically highest with CYD-TDV 5553 and lowest with the 4444 formulation; seropositivity rates for serotype 4 were similar with the 5555 and 4444 formulations, and much lower among recipients of CYD-TDV 5553. Geometric mean titers followed the same pattern as that seen with seropositivity rates. Safety/reactogenicity results were similar for all three vaccine formulations, although the percentage of participants reporting solicited injection site reactions was lower with CYD-TDV 4444 than with the other two formulations. All serious adverse events were unrelated to vaccination.
  
  
  CONCLUSIONS
  Reducing the dose of serotype 4 antigen (5553 formulation) creates an imbalance in the immune response to CYD-TDV. Immune responses to CYD-TDV 5555 were slightly higher than to the 4444 formulation. Development of CYD-TDV 5555 has subsequently been pursued.
authors.affiliation: Sanofi Pasteur Inc., Route 611, Discovery Drive, Swiftwater, PA 18370-0187, USA. Electronic address: Gustavo.Dayan@sanofipasteur.com.
authors.forename: Gustavo H
authors.initials: GH
authors.lastname: Dayan
authors.forename: Manoj
authors.initials: M
authors.lastname: Thakur
authors.forename: Mark
authors.initials: M
authors.lastname: Boaz
authors.forename: Carol
authors.initials: C
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D000917:Antibody Formation; D003715:Dengue / Q000517:prevention & control; D053059:Dengue Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D009500:Neutralization Tests; D014481:United States; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D014766:Viremia / Q000175:diagnosis
chemical_list: D000914:Antibodies, Viral; D053059:Dengue Vaccines; D014613:Vaccines, Attenuated
keywords: CYD-TDV; Clinical trial; Dengue; Formulation; Immunogenicity; PRNT(50); RT-PCR; TCID(50); Vaccine; log(10)tissue culture infectious dose 50%; plaque reduction neutralization test; recombinant live-attenuated tetravalent dengue vaccine; reverse transcriptase-polymerase chain reaction