Antibody-dependent enhancement of severe dengue disease in humans

Abstract

For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.

Fig. 1

Longitudinal analyses of the hazard of severe dengue disease or any dengue case by preexisting DENV-Ab titer for the full pediatric dengue cohort. Hazard ratios with 95% CIs (A, C, E, and G) and cumulative hazard for an average child (B, D, F, and H) with preexisting DENV-Ab titers binned by fourfold dilution. Cox proportional hazard models were adjusted for sex, epidemic season, age, and number of previous DENV infections. Average child = female, age 5 to 9, 2007–2008 epidemic season, and one previous DENV infection.

Fig. 2

Continuous hazard ratio curves for severe dengue disease or any dengue case by preexisting DENV-Ab titer for the pediatric dengue cohort. Cox proportional hazard models were fit without (A) or with (B) control for number of previous infections. Models were also adjusted for sex, epidemic season, and age

Fig. 3

Preexisting DENV-Ab titers in severe or nonsevere secondary dengue cases compared with matched controls drawn randomly from the pediatric dengue cohort. (A to C) Five controls were matched to each case and were of the same sex and age, had evidence of prior DENV infection, provided a blood sample within 1 to 2 months of the case’s preinfection sample, but did not have a dengue case that year. Conditional logistic regression was used to compare preexisting DENV-Ab titers of severe cases and nonsevere cases each to matched controls, with titers >1:320 as reference. Odds ratios with 95% CIs are shown. (D to F) Distributions of preexisting DENV-Ab titers for severe and nonsevere secondary dengue cases and matched controls (one control for each case). Error bars show one SD, triangles show distribution medians, and brackets indicate significant differences in medians (severe and nonsevere cases compared with Wilcoxon rank sum test, black bracket).

Fig. 4

Odds ratios for severe as compared with nonsevere dengue by preinfection DENV-Ab titer. (A to C) Logistic regression models were adjusted for sex, epidemic season, infecting DENV type, age, and number of previous DENV infections. DENV-naïve children were used as the reference group. Odds ratios with 95% CIs are shown.