Abstract
Dengue viruses (DENV) are the causative agents of dengue fever (DF) and dengue hemorrhagic fever (DHF). Here we review the current state of knowledge about the human antibody response to dengue and identify important knowledge gaps. A large body of work has demonstrated that antibodies can neutralize or enhance DENV infection. Investigators have mainly used mouse monoclonal antibodies (MAbs) to study interactions between DENV and antibodies. These studies indicate that antibody neutralization of DENVs is a “multi-hit” phenomenon that requires the binding of multiple antibodies to neutralize a virion. The most potently neutralizing mouse MAbs bind to surface exposed epitopes on domain III of the dengue envelope (E) protein. One challenge facing the dengue field now is to extend these studies with mouse MAbs to better understand the human antibody response. The human antibody response is complex as it involves a polyclonal response to primary and secondary infections with 4 different DENV serotypes. Here we review studies conducted with immune sera and MAbs isolated from people exposed to dengue infections. Most dengue-specific antibodies in human immune sera are weakly neutralizing and bind to multiple DENV serotypes. The human antibodies that potently and type specifically neutralize DENV represent a small fraction of the total DENV-specific antibody response. Moreover, these neutralizing antibodies appear to bind to novel epitopes including complex, quaternary epitopes that are only preserved on the intact virion. These studies establish that human and mouse antibodies recognize distinct epitopes on the dengue virion. The leading theory proposed to explain the increased risk of severe disease in secondary cases is antibody dependent enhancement (ADE), which postulates that weakly neutralizing antibodies from the first infection bind to the second serotype and enhance infection of FcγR bearing myeloid cells such as monocytes and macrophages. Here we review results from human, animal and cell culture studies relevant to the ADE hypothesis. By understanding how human antibodies neutralize or enhance DENV, it will be possible to better evaluate existing vaccines and develop the next generation of novel vaccines.
Highlights
Dengue viruses (DENV) are emerging, mosquito-borne flaviviruses and are the causative agents of dengue fever (DF) and dengue hemorrhagic fever (DHF)
Serum antibodies against DENV E protein have been the focus of several studies as this is the main antigen on the virion surface and the target of neutralizing antibody [39,40,42,43,44,47]
Much remains to be learned about DENV pathogenesis, antibodies have emerged as important host molecules that reduce or exacerbate disease severity
Summary
Dengue viruses (DENV) are emerging, mosquito-borne flaviviruses and are the causative agents of dengue fever (DF) and dengue hemorrhagic fever (DHF). People who have recovered from primary DENV infections develop robust antibody responses that cross react with the 4 serotypes. People experiencing a secondary dengue infection with a new serotype face a much greater risk of developing DHF indicating that pre-existing immunity to DENV can exacerbate disease. Antibody dependent enhancement (ADE) of DENV is the most widely supported theory explaining the higher risk of DHF associated with secondary infection [4]. The antibody response to DENV infection is complex, with potential to benefit or harm the host. An in-depth understanding of the human antibody response to DENV is highly relevant to evaluating vaccines already in the pipeline and for developing new vaccines. We review the current state of knowledge about the human antibody response to DENV infection and identify important gaps in our knowledge
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