A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand

Abstract

Background: Despite the strong association between secondary dengue virus (DENV) infections and dengue hemorrhagic fever (DHF), the majority of secondary infections are subclinical or mild. The determinants of clinical severity remain unclear, though studies indicate a titer-dependent and time-dependent role of cross-protective anti-DENV antibodies.

Methods: Data from 2 sequential prospective cohort studies were analyzed for subclinical and symptomatic DENV infections in schoolchildren in Kamphaeng Phet, Thailand (1998-2002 and 2004-2007). Children experiencing ≥ 1 DENV infection were selected as the population for analysis (contributing 2169 person-years of follow-up).

Results: In total, 1696 children had ≥ 1 DENV infection detected during their enrollment; 268 experienced 2 or more infections. A shorter time interval between infections was associated with subclinical infection in children seronegative for DENV at enrollment, for whom a second-detected DENV infection is more likely to reflect a true second infection (average of 2.6 years between infections for DHF, 1.9 for DF, and 1.6 for subclinical infections).

Conclusions: These findings support a pathogenesis model where cross-reactive antibodies wane from higher-titer, protective levels to lower-titer, detrimental levels. This is one of the first studies of human subjects to suggest a window of cross-protection following DENV infection since Sabin's challenge studies in the 1940s.

Keywords: antibodies; dengue; epidemiology; immunity; pathogenesis; prospective cohort study.

Figure 1.

Illustration of hypothesized shifts in risk of dengue virus (DENV) illness and cross-reactive antibodies over time (theoretical, not based upon data). A, Schematic of shifts in risk of illness following primary DENV infection. B, Schematic of shifts in risk of illness following secondary DENV infection.

Figure 2.

Flowchart of the children that experienced at least one dengue virus (DENV) infection, detailing the numbers remaining at risk for a second infection each year, the numbers of cases, and their severities. * Withdrawals may represent (1) children that “graduated” out of the study by turning 16 years of age, (2) children that were no longer at risk for a second infection because the study ended (eg, if a child's first detected infection occurred in 2002, the study period [spanning 1998–2002 and 2004–2007] would have ended before a second infection could be detected), and (3) children that “dropped out” while still eligible for enrollment in an ongoing study. Abbreviations: Asx, Subclinical/asymptomatic; Sx, Symptomatic; DF, Dengue fever; DHF, Dengue hemorrhagic fever.

Figure 3.

Probability of asymptomatic infection by year since the first-detected infection in the cohort studies, by whether a child had detectable hemagglutination inhibition (HI) antibodies at enrollment (HI-positive) or was negative by HI at enrollment (HI-negative). Error bars indicate the 95% confidence intervals for the proportions.

Figure 4.

Odds ratios (ORs) for experiencing a symptomatic versus an subclinical second infection, given that a second infection occurred. Results are stratified by hemagglutination inhibition (HI) antibody profile at enrollment (HI positive [Pos] or HI negative [Neg]) and whether the total HI antibody response to the first infection was higher than the mean (High rise) or lower than the mean (Low rise). ORs compare the odds of symptomatic infection for years 2 and 3 in each stratum to the odds of symptomatic infection in year 1 for the reference stratum (children who were HI-positive and demonstrated a high antibody response to infection).