Analysis of Hospitalized and Severe Dengue Cases Over the 6 years of Follow-up of the Tetravalent Dengue Vaccine (CYD-TDV) Efficacy Trials in Asia and Latin America

Abstract

Background: CYD-TDV, a live, attenuated, tetravalent dengue vaccine, has been approved for the prevention of symptomatic dengue in previously dengue exposed individuals. This post hoc analysis assessed hospitalized and severe virologically confirmed dengue (VCD) over the complete 6-year follow-up of 3 CYD-TDV efficacy studies (CYD14, CYD15, and CYD23/CYD57).

Methods: The main outcomes were hazard ratios (HRs) for hospitalized or severe VCD by baseline dengue serostatus, focusing on those who were seropositive, and by age at immunization (<9 years/≥9 years). Baseline dengue serostatus was measured or inferred using several methods. Hospitalized VCD cases were characterized in terms of clinical signs and symptoms and wild-type viremia level. Antibody persistence was assessed up to 5 years after the last injection.

Results: In those aged ≥9 years and baseline seropositive, CYD-TDV protected against hospitalized and severe VCD over 6 years compared to placebo (HR [95% confidence interval] multiple imputation from month 0 method, .19 [.12-.30] and .15 [.06-.39]; other methods were consistent). Vaccine protection was observed over the different study periods, being highest during the first 2 years. Evidence for a decreased risk of hospitalized and severe VCD was also observed in seropositive participants aged 6-8 years. Clinical signs and symptoms, and quantified dengue viremia from participants with hospitalized VCD were comparable between groups.

Conclusions: CYD-TDV demonstrated robust protection against hospitalized and severe VCD over the entire 6-year follow-up in participants who were seropositive and ≥9 years old. Protection was also observed in seropositive 6-8 year-olds. Clinical Trials Registration: NCT00842530, NCT01983553, NCT01373281, NCT01374516.

Keywords: CYD-TDV; VCD; dengue; serostatus.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Risk of hospitalized VCD and severe VCD in the pooled studies (CYD14, CYD15, and CYD23/57) over the 6-year period in those seropositive or seronegative by MI M0, TMLE*, and NS1 M13 (Th9) in participants aged (A) ≥9 years and (B) <9 years. Study group classified as treated (participants included in the CYD-TDV group if they received at least one injection of CYD-TDV vaccine). n represents the number of subjects fulfilling the item listed; N represents the total number of subjects selected in subcohort. NS1 M13 (Th9), dengue anti-nonstructural protein-1 (NS1) IgG ELISA at M13 with seropositivity defined as ≥9 EU/mL (threshold 9). For all MI approaches n and N are average numbers from 10 iterations of multiple imputations. For NS1 M13 (Th9) participants with VCD cases before M13 were excluded from the analyses. *TMLE data presented as relative risk (95% CI), N divided by 10; pooled TMLE data for CYD14 and CYD15. Abbreviations: CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; MI, multiple imputation; M0, baseline; TMLE, targeted minimum loss-based estimation; VCD, virologically confirmed dengue.

Figure 2.

Risk of hospitalized VCD for each time period for the pooled studies (CYD14, CYD15, CYD23/57) over the 6-year period in participants seropositive by MI M0, NS1 M13 (Th9) and aged (A) ≥9 years, (B) <9 years. Study group classified as treated (participants included in the CYD-TDV group if they received at least 1 injection of CYD-TDV vaccine). n represents the number of subjects fulfilling the item listed; N represents the total number of subjects selected in subcohort. For all MI approaches n and N are average numbers from 10 iterations of multiple imputations. For NS1 M13 (Th9) participants with VCD cases before M13 were excluded from the analyses. Years 1 and 2 correspond to the active phase of the studies, and years 5 and 6 correspond to the surveillance expansion period. Abbreviations: CI, confidence interval; VCD, virologically confirmed dengue.

Figure 3.

Risk of hospitalized VCD for each serotype in the pooled studies (CYD14, CYD15, CYD23/57) over the 6-year period in participants seropositive by MI M0, NS1 M13 (Th9) and aged (A) ≥9 years and (B) <9 years. Study group classified as treated (participants included in the CYD-TDV group if they received at least 1 injection of CYD-TDV vaccine). n represents the number of subjects fulfilling the item listed; N represents the total number of subjects selected in subcohort. NS1 M13 (Th9), dengue anti-non-structural protein-1 (NS1) IgG ELISA at M13 with seropositivity defined as ≥9 EU/mL (threshold 9). For all MI approaches n and N are average numbers from 10 iterations of multiple imputations. For NS1 M13 (Th9) participants with VCD cases before M13 were excluded from the analyses. Abbreviations: CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; MI, multiple imputation; M0, baseline; VCD, virologically confirmed dengue.