Maternally Derived Anti-Dengue Antibodies and Risk of DHF in Infants: A Case-Control Study

Abstract

This study proposes to directly test the hypothesis that antibody-dependent enhancement (ADE) is the critical factor in the development of dengue hemorrhagic fever (DHF) in infants. DHF occurs in two distinct clinical settings: a) in children and adults with secondary DENV infection, and b) in infants with primary DENV infection born to mothers with prior DENV infection. The ADE hypothesis proposes that pre-existing serotype-cross-reactive non-neutralizing anti-DENV antibodies bind the heterotypic DENV during secondary infection and enhance its uptake into immune cells, leading to increased viral load and DHF. This model suggests that DHF in DENV-infected infants is caused by the enhancing effect of waning maternal anti-DENV antibodies, thus causing a “physiologic secondary infection” during an infant’s primary infection and thereby increasing the infant’s risk for DHF. The effect of maternal immunity on DHF in infants has been studied exclusively in Southeast Asia. However, the maternal DENV seroprevalence approaches 100% in this part of the world. As a consequence, the ADE model of infant DHF cannot truly be tested in Southeast Asia, because all infants possess anti-DENV antibody at birth. In the Western Hemisphere, by contrast, women may have experienced either a single DENV infection, more than one DENV infection, or no DENV infection at all. The ability to include DENV-seronegative mothers as controls allows for the ADE hypothesis to be directly tested in a clinical study. To our knowledge, no such study has been previously conducted. This thesis presents a case-control study designed to evaluate the influence of positive maternal dengue seroprevalence on the risk of DHF in infants. As the MSCI program provides instruction in study design, this thesis does not present findings. The clinical trial described herein began in May 2010 and enrollment is expected to continue through May 2012 (see Table 4).