Immunobridging efficacy of a tetravalent dengue vaccine against dengue and against hospitalized dengue from children/adolescents to adults in highly endemic countries

Abstract

Background: The recombinant tetravalent live-attenuated dengue vaccine based on the YF 17D vaccine virus backbone (CYD-TDV) demonstrated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue of any serotype from month 13 to month 25 (VCD-DENV-AnyM13→M25) in the CYD14 (2-14-y-olds) and CYD15 (9-16-y-olds) phase 3 trials. Fifty percent plaque reduction neutralization test (PRNT50) titers are a potential surrogate for immunobridging VE to adults.

Methods: Using PRNT50 calibration datasets, we applied immunobridging approaches using baseline and/or M13 PRNT50 titers to estimate VE against VCD-DENV-AnyM0→M25 and against hospitalized VCD (HVCD)-DENV-AnyM0→M72 in hypothetical 18-45-y-old and 46-50-y-old CYD14 and CYD15 cohorts.

Results: Baseline and M13 geometric mean PRNT50 titers were greater in 18-45-y-olds and in 46-50-y-olds vs 9-16-y-olds for most comparisons. Estimated VE (95% CIs against VCD-DENV-AnyM0→M25 ranged from 75.3% to 90.9% (52.5% to 100%) for 18-45-y-olds and 74.8% to 92.0% (53.4% to 100%) for 46-50-y-olds. Estimated VE (95% CIs) against HVCD-DENV-AnyM0→M72 ranged from 58.8% to 78.1% (40.9 to 98.9%) for 18-45-y-olds and 57.2% to 78.4% (40.5 to 97.6%) for 46-50-y-olds. Corresponding predictions among baseline-seropositive individuals yielded comparable or higher VE estimates.

Conclusions: VE M0→M25 against DENV-Any and VE against HVCD-DENV-AnyM0→M72 are both expected to be higher in 18-45 and 46-50-y-olds vs CYD14 and CYD15 9-16-y-olds.

Keywords: CYD-TDV; dengue vaccine; immunobridging; neutralizing antibodies; surrogate endpoint; vaccine efficacy.

Figure 1.

Reverse cumulative distribution functions (rcdfs) of month 0 and month 13 50% plaque reduction neutralization test (PRNT₅₀) neutralizing antibodies by serotype. (A) Month 0 (top row) and month 13 (bottom row) PRNT₅₀ titers by age cohort in CYD14 and CYD15, CYD22 and CYD65-COL. (B) Month 0 (top row) and month 13 (bottom row) PRNT₅₀ titers by age cohort in CYD14 and CYD15, CYD22 and CYD65-PHL. Month 0 PRNT₅₀ titers: vaccine and placebo groups; Month 13 PRNT₅₀ titers: vaccine group (participants who were randomized to receive three vaccinations). The CYD22 and CYD14 and CYD15 rcdfs were previously shown in and are included here for comparison. CYD14 and CYD15 results shown are for controls only (i.e. VCD-free through month 25). For CYD65 (that did not have a placebo group), baseline titers were pooled over all vaccine groups (1, 2 or 3 vaccinations).

Figure 2.

Results bridging VE(25) to the hypothetical CYD14 and CYD15 18–45-y-old cohort based on CYD65 data. Estimated multiplicative VE against VCD-DENV-Any through month 25 is shown with 95% bootstrap CIs with the sensitivity parameter ɸ (ratio of VE curves) varying from 0.8 to 1.2 and ρ (ratio of background risk curves) equal to 1.0. Estimated ignorance intervals and 95% estimated uncertainty intervals (EUIs) are given in the lower-right corner of each plot.

Figure 3.

Bridging VE(25) to the hypothetical CYD14 and CYD15 18–45-y-old cohort based on CYD65 data. Estimated multiplicative VE against VCD-DENV-Any through month 25 is shown with 95% bootstrap CIs with the fixed sensitivity parameter ɸ (ratio of VE curves) varying from 0.8 to 1.2 and ρ (ratio of background risk curves) equal to 0.8. Estimated ignorance intervals and 95% estimated uncertainty intervals (EUIs) are given in the lower-right corner of each plot.

Figure 4.

Bridging VE(72) to the hypothetical CYD14 and CYD15 18–45-y-old cohort based on CYD65 data. Estimated multiplicative VE against HVCD-DENV-Any through month 72 with 95% bootstrap CIs for the sensitivity parameter ɸ (ratio of VE curves) varying from 0.8 to 1.2 and ρ (ratio of background risk curves) equal to 1.0 or 0.8. Estimated ignorance intervals and 95% estimated uncertainty intervals (EUIs) are given in the upper-left corner of each plot.

Figure 5.

Bridging VE(72) to the hypothetical CYD14 and CYD15 18–45-y-old cohort based on CYD22 and CYD65 data. Estimated multiplicative VE against HVCD-DENV-Any through month 72 is shown with 95% bootstrap CIs with the sensitivity parameter ɸ (ratio of VE curves) varying from 0.8 to 1.2 and ρ (ratio of background risk curves) equal to 1.0 or 0.8. Estimated ignorance intervals and 95% estimated uncertainty intervals (EUIs) are given in the upper-left corner of each plot.