Analysis of Neutralizing Antibodies as a Correlate of Instantaneous Risk of Hospitalized Dengue in Placebo Recipients of Dengue Vaccine Efficacy Trials.

Abstract

BACKGROUND\nIn the CYD14 (NCT01373281) and CYD15 (NCT01374516) dengue vaccine efficacy trials, Month 13 neutralizing antibody (nAb) titers correlated inversely with risk of symptomatic, virologically confirmed dengue (VCD) between Month 13 (one month post-final-dose) and Month 25. We assessed nAb titer as a correlate of instantaneous risk of hospitalized VCD (HVCD), for which participants were continually surveilled for 72 months.\n\n\nMETHODS\nUsing longitudinal nAb titers from the per-protocol immunogenicity subsets, we estimated hazard ratios (HRs) of HVCD by current nAb titer value for three correlate/endpoint pairs: average titer across all four serotypes/HVCD of any serotype (HVCD-Any), serotype-specific titer/homologous HVCD, and serotype-specific titer/heterologous HVCD.\n\n\nRESULTS\nBaseline-seropositive placebo recipients with higher average titer had lower instantaneous risk of HVCD-Any in 2-16-year-olds and in 9-16-year-olds (HR 0.26 or 0.15 per 10-fold increase in average titer by two methods, 95% CIs 0.14 to 0.45 and 0.07 to 0.34, respectively) pooled across both trials. Results were similar for homologous HVCD. There was evidence suggesting increased HVCD-Any risk in participants with low average titer (1:10 to 1:100) compared to seronegative participants (HR 1.85, 95% CI 0.93 to 3.68).\n\n\nCONCLUSIONS\nNatural infection-induced nAbs were inversely associated with hospitalized dengue, upon exceeding a relatively low threshold.