Research Article: Epidemiology of Infant Dengue Cases Illuminates Serotype-Specificity in the Interaction between Immunity and Disease, and Changes in Transmission Dynamics

Date Published: December 11, 2015

Publisher: Public Library of Science

Author(s): Hannah Clapham, Derek A. T. Cummings, Ananda Nisalak, Siripen Kalayanarooj, Butsaya Thaisomboonsuk, Chonticha Klungthong, Stefan Fernandez, Anon Srikiatkhachorn, Louis R. Macareo, Justin Lessler, Julia Reiser, In-Kyu Yoon, Aravinda M de Silva.

Abstract: BackgroundInfants born to dengue immune mothers acquire maternal antibodies to dengue. These antibodies, though initially protective, decline during the first year of life to levels thought to be disease enhancing, before reaching undetectable levels. Infants have long been studied to understand the interaction between infection and disease on an individual level.Methods/FindingsConsidering infants (cases <1 year old) as a unique group, we analyzed serotype specific dengue case data from patients admitted to a pediatric hospital in Bangkok, Thailand. We show differences in the propensity of serotypes to cause disease in individuals with dengue antibodies (infants and post-primary cases) and in individuals without dengue antibodies (primary cases). The mean age of infant cases differed among serotypes, consistent with previously observed differential waning of maternal antibody titers by serotype. We show that trends over time in epidemiology of infant cases are consistent with those observed in the whole population, and therefore with trends in the force of infection.Conclusions/SignificanceInfants with dengue are informative about the interaction between antibody and the dengue serotypes, confirming that in this population DENV-2 and DENV-4 almost exclusively cause disease in the presence of dengue antibody despite infections occurring in others. We also observe differences between the serotypes in the mean age in infant cases, informative about the interaction between waning immunity and disease for the different serotypes in infants. In addition, we show that the mean age of infant cases over time is informative about transmission in the whole population. Therefore, ongoing surveillance for dengue in infants could provide useful insights into dengue epidemiology, particularly after the introduction of a dengue vaccine targeting adults and older children.

Partial Text: DENV is a flavivirus that exists as four serotypes. Infection with one serotype leads to long-term immunity to that serotype. There is also a short-term period of cross-protection to other serotypes [1, 2] followed by an indeterminate period during which infection by another serotype may lead to more severe disease [3]. One theory for this increased severity is antibody dependent enhancement, whereby non-neutralizing antibodies bind to the virus and facilitate viral entry into cells and increased viral replication [4]. The overwhelming majority of hospitalized cases in regions where all four serotypes circulate are due to post-primary infections [5]. Infants born to dengue-immune mothers receive dengue antibodies, and, over the first year of life, experience an accelerated version of the susceptibility pattern that individuals experience during a lifetime in endemic areas: there is a short period of universal protection lasting a few months after birth, followed by a period also lasting a few months in which infections are more likely to be severe possibly through the action of antibody dependent enhancement [6].

The serotype distribution in primary infant cases was more similar to the post-primary cases than to primary cases in non-infants (Table 1 and Fig 1). For both post-primary and infant primary cases, around 35% of cases were DENV-1 and and 31% of cases were DENV-2. This is significantly different to primary non-infant cases where a much greater 57% of cases were DENV-1 and only 5% were DENV-2. For DENV-3 there are slight, non-significant differences between post-primary and infant primary with 22% of post-primary and 27% of primary infant cases due to DENV-3, and these are both significantly less than the 37% of primary non-infant cases that were due to DENV-3. For DENV-4 there are significant differences across all 3 groups with 12% of post-primary cases, 4% of infant primary cases and only 1% of primary non-infant cases due to DENV-4 (Table 1 and Fig 1). Although disease was still more common in post-primary compared to primary cases for DENV-1 and DENV-3 (73% of cases were post-primary), primary infections with these two serotypes caused a substantial amount of disease in dengue naïve individuals. For DENV-2 and DENV-4 however, almost all of the cases of these serotypes were post-primary cases (92% and 96%, respectively). The percentage of cases that were untyped was the same for the primary infant and non-infant cases (both 40%), compared to post-primary cases (53%) (Table 2 and Fig 2).

The serotype distributions of hospitalized dengue cases in different immune groups, as presented in this paper, add to the evidence that differences in the outcome of infection by each serotype depends on immune status. The paucity of primary cases of DENV-2 and DENV-4 has been shown in previous studies in Thailand [5]. The presence of infant primary cases with these serotypes, suggests that dengue naive individuals ≥1 year of age are exposed to these serotypes, but that these exposures do not result in hospitalized disease. There are two non-mutually exclusive ways to interpret these findings: (1) DENV-1 and DENV-3 were more likely to cause disease in non-immune individuals compared to DENV-2 and DENV-4, or (2) DENV-2 and DENV-4 were more likely to cause disease in an enhanced post-primary infection than DENV-1 and DENV-3. These results from the infants suggest that the former is the most likely explanation, with the correlations between the annual case numbers in each group (infant primary, primary non-infant and post-primary) being lower for DENV-2 and DENV-4, than for DENV-1 and DENV-3, suggesting the immune status of the population plays a larger role in the dynamics of DENV-2 and DENV-4. These differences may also explain previously seemingly contradictory results where a relationship was shown between infant DHF and increased levels of enhancing activity in sera for DENV2 [6], but not DENV3 [10]. In addition, there is a suggestion that DENV-4 is under represented in the infant primary cases compared to the secondary cases. This could be explained by a lower force of infection for DENV-4 (consistent with the fewer observed cases) leading to fewer exposures in this early time period. Differences between the serotypes in the propensity to cause disease in immune and non-immune individuals should be considered in the context of vaccination trial results with seemingly differential efficacy across serotypes, as with the Sanofi Phase 2b results [24]. Could the observed effect of the vaccination for DENV2 be because of the differential outcomes of DENV2 exposure in naïve and non-naïve individuals?



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