Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort

Abstract

The four dengue virus serotypes (DENV1-4) are mosquito-borne flaviviruses that infect ∼ 390 million people annually; up to 100 million infections are symptomatic, and 500,000 cases progress to severe disease. Exposure to a heterologous DENV serotype, the specific infecting DENV strains, and the interval of time between infections, as well as age, ethnicity, genetic polymorphisms, and comorbidities of the host, are all risk factors for severe dengue. In contrast, neutralizing antibodies (NAbs) are thought to provide long-lived protection against symptomatic infection and severe dengue. The objective of dengue vaccines is to provide balanced protection against all DENV serotypes simultaneously. However, the association between homotypic and heterotypic NAb titers and protection against symptomatic infection remains poorly understood. Here, we demonstrate that the titer of preinfection cross-reactive NAbs correlates with reduced likelihood of symptomatic secondary infection in a longitudinal pediatric dengue cohort in Nicaragua. The protective effect of NAb titers on infection outcome remained significant when controlled for age, number of years between infections, and epidemic force, as well as with relaxed or more stringent criteria for defining inapparent DENV infections. Further, individuals with higher NAb titers immediately after primary infection had delayed symptomatic infections compared with those with lower titers. However, overall NAb titers increased modestly in magnitude and remained serotype cross-reactive in the years between infections, possibly due to reexposure. These findings establish that anti-DENV NAb titers correlate with reduced probability of symptomatic DENV infection and provide insights into longitudinal characteristics of antibody-mediated immunity to DENV in an endemic setting.

Keywords: Nicaragua; cohort study; dengue virus; neutralizing antibodies; protection.

Fig. 1.

Higher median preinfection NAb titers are associated with lower probability of symptomatic 2° DENV infection. (A) The year of 2° infection (2006–2013) plotted against the median preinfection NAb titer for all children in subset 1, measured the year before 2° DENV infection. Local regression (thin lines; span = 1) and linear regression (thick lines) are shown. (B and C) Logistic regression model predictions of the association between median preinfection NAb titer and the probability of symptomatic infection (%). The predicted curves are drawn with covariate values set to the average value observed for each covariate (B: epidemic force = 1.14, age = 8.42, number of years between 1° and 2° infection = 2.67) or the value observed in the 2009–2010 season (C: epidemic force = 2.06, age = 9.78, number of years between 1° and 2° infection = 3.18).

Fig. 2.

Higher preinfection NAb titers are associated with delay in 2° symptomatic DENV infection. (A) The linear relationship between NAb titer to the 2° infecting serotype, measured immediately after 1° infection, and the number of years until symptomatic 2° infection; slope and P value are shown. (B) The number of years between 1° and 2° infection (–8) is plotted against the median preinfection NAb titer for all children in subset 1, measured in the year before 2° infection. Local regression (thin lines; span = 1) and linear regression (thick lines) are shown.

Fig. 3.

Dynamics of the magnitude and breadth of NAb titers after 1° and before subsequent infection (A and B) and between 2° infections (C and D), as measured with standard infection criteria. Plots show the number of years since previous infection against the magnitude (A and C) or breadth (B and D) of NAb titers. Thick lines showing the fold change in the magnitude (values >1 are increasing) or breadth (values <1 are more cross-reactive) of NAb titers over time were estimated with linear regression. Fold change estimates (SI Appendix, Table S9) are indicated above regression lines. *P < 0.05.