Research Article: A Prospective Nested Case-Control Study of Dengue in Infants: Rethinking and Refining the Antibody-Dependent Enhancement Dengue Hemorrhagic Fever Model

Date Published: October 27, 2009

Publisher: Public Library of Science

Author(s): Daniel H. Libraty, Luz P. Acosta, Veronica Tallo, Edelwisa Segubre-Mercado, Analisa Bautista, James A. Potts, Richard G. Jarman, In-Kyu Yoon, Robert V. Gibbons, Job D. Brion, Rosario Z. Capeding, Jeremy Farrar

Abstract: Analyses of a prospective case-control study of infant dengue by Daniel Libraty and colleagues casts doubt on the antibody-dependent enhancement model for dengue hemorrhagic fever.

Partial Text: Dengue hemorrhagic fever (DHF) is the most severe and sometimes fatal form of illness after infection with any one of the four dengue virus (DENV) serotypes [1]. The global spread of dengue, and the incidence of epidemic DHF, have increased dramatically over the past 50 y and continue on an upward trajectory [2],[3]. An accurate understanding of DHF pathogenesis is important for clinicians, public health officials, and vaccine researchers in dengue affected countries. DHF occurs almost exclusively in two clinical settings: children and adults with secondary heterologous DENV infections and infants with primary DENV infections born to dengue-immune mothers [3]. The most widely accepted and repeatedly cited explanation for the pathogenesis of DHF in these settings is antibody-dependent enhancement (ADE) of DENV infection [4]–[6]. The ability of subneutralizing virus-specific antibodies to enhance DENV as well as other flavivirus infections in vitro was first recognized in the 1960s [7] and has been extensively studied [8]–[11]. The ADE model for DHF proposes that anti-DENV IgG, actively acquired from a previous heterologous DENV infection, or passively acquired in infants from maternal-fetal transfer, enhances DENV infection of Fc receptor-bearing cells under particular conditions in vivo. The ADE of DENV infection increases viral load (infected cell mass) and triggers a host immunological cascade that leads to DHF [3],[12].

This prospective study has captured the entire spectrum of clinical disease severity among infants with primary DENV infections—ranging from inapparent infections, mild outpatient febrile illnesses, hospitalized illnesses without evidence of DHF, and unambiguous hospitalized DHF/DSS. DENV3 was the predominant infecting serotype in the 2007 dengue season covered by this report. We therefore focused on the potential role of maternally derived anti-DENV IgG in shaping DENV3 disease severity. Our data support an initial in vivo protective role for high levels of maternally derived anti-DENV3 IgG at birth. The estimated in vitro anti-DENV3 neutralizing capacity at birth (maternal DENV3 PRNT50 geometric mean titer [GMT] = 413, range 41–5,690) positively correlated with the infant age of symptomatic primary DENV3 illness (all disease severity groups). A similar correlation was previously reported for estimated anti-DENV2 neutralizing capacity at birth in 13 DHF infants with primary DENV2 infections [16]. A more recent study did not report a correlation between estimated serotype-specific neutralizing capacity at birth and the infant age at dengue illness [26]. However, this study combined serotype-specific PRNT50 values for infants with DENV1-3 infections in their analysis and performed a different in vitro neutralization assay.