Dengue in Vietnamese Infants—Results of Infection‐Enhancement Assays Correlate with Age‐Related Disease Epidemiology, and Cellular Immune Responses Correlate with Disease Severity

Abstract

The pathogenesis of severe dengue is not well understood. Maternally derived subneutralizing levels of dengue virus-reactive IgG are postulated to be a critical risk factor for severe dengue during infancy. In this study, we found that, in healthy Vietnamese infants, there was a strong temporal association between the Fc-dependent, dengue virus infection-enhancing activity of neat plasma and the age-related epidemiology of severe dengue. We then postulated that disease severity in infants with primary infections would be associated with a robust immune response, possibly as a consequence of higher viral burdens in vivo. Accordingly, in infants hospitalized with acute dengue, the activation phenotype of peripheral-blood NK cells and CD8+ and CD4+ T cells correlated with overall disease severity, but HLA-A*1101-restricted NS3(133-142)-specific CD8+ T cells were not measurable until early convalescence. Plasma levels of cytokines/chemokines were generally higher in infants with dengue shock syndrome. Collectively, these data support a model of dengue pathogenesis in infants whereby antibody-dependent enhancement of infection explains the age-related case epidemiology and could account for antigen-driven immune activation and its association with disease severity. These results also highlight potential risks in the use of live attenuated dengue vaccines in infants in countries where dengue is endemic.

The pathogenesis of dengue

“…[48][49][50] These virion-binding, non-neutralising antibodies are thought to enhance the risk of clinically apparent and severe dengue through a process of ADE. [51][52][53][54] In support of this hypothesis, neat plasma from 6-month old healthy Vietnamese infants enhances the infectivity of DENV-2 in Fc receptor bearing cells significantly more than plasma collected at the time of birth or at 1-yr of age. 52 Concerns about ADE have led to fears that a vaccine could contribute to increased disease severity due to re-infection in the presence of incomplete protection to one or more serotypes.…”

“…[51][52][53][54] In support of this hypothesis, neat plasma from 6-month old healthy Vietnamese infants enhances the infectivity of DENV-2 in Fc receptor bearing cells significantly more than plasma collected at the time of birth or at 1-yr of age. 52 Concerns about ADE have led to fears that a vaccine could contribute to increased disease severity due to re-infection in the presence of incomplete protection to one or more serotypes. This hypothetical concern needs to addressed by careful, long-term follow-up of vaccine recipients.…”

“…For example, the kinetics of viremia and NS1 antigenemia in DENV-1 infections is distinctly different (higher) from DENV-2 infections in Vietnamese children. 52,60 Similarly, Vietnamese infants with primary DENV-1 infections have significantly lower plasma NS1 concentrations than DENV-2 infected infants at the time of hospital presentation. Furthermore, a prospective study of hospitalized Thai children suggested DENV-2 and -3 were twice as likely to result in DHF as Collectively, these data are examples that suggest each DEN virus serotype has its own constellation of virological characteristics in human hosts.…”

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…It has been suggested that CD8 ϩ and CD4 ϩ T-lymphocyte activation is associated with severity of dengue infection. 58 We observed a small decrease in the percentage of CD4 ϩ T cells but no changes in the percentage of CD8 ϩ T cells and in the spleen of DENV infected WT and J␣18 Ϫ/Ϫ mice ( Figure 5C). However, although both CD4 ϩ and CD8 ϩ T cells expressed more CD69 in DENV-infected WT mice, this enhancement was less important in infected J␣18 Ϫ/Ϫ mice.…”

“…[57][58][59] Thus, we measured the effect of endogenous iNKT cell activation on the frequency and activation of these other cells. DENV infection was associated with reduced frequency of NK cells ( Figure 5A) and enhanced percentage of neutrophils ( Figure 5B) in the spleen of WT mice.…”