Abstract
Dengue virus (DENV) is a serious mosquito-borne pathogen causing significant global disease burden, either as classic dengue fever (DF) or in its most severe manifestation dengue hemorrhagic fever (DHF). Nearly half of the world's population is at risk of dengue disease and there are estimated to be millions of infections annually; a situation which will continue to worsen with increasing expansion of the mosquito vectors and epidemic DF/DHF. Currently there are no available licensed vaccines or antivirals for dengue, although significant effort has been directed toward the development of safe and efficacious dengue vaccines for over 30 years. Promising vaccine candidates are in development and testing phases, but a better understanding of immune responses to DENV infection and vaccination is needed. Humoral immune responses to DENV infection are complex and may exacerbate pathogenicity, yet are essential for immune protection. In this report, we develop DENV-2 envelope (E) protein epitope-specific antigens and measure immunoglobulin responses to three distinct epitopes in DENV-2 infected human serum samples. Immunoglobulin responses to DENV-2 infection exhibited significant levels of individual variation. Antibody populations targeting broadly cross-reactive epitopes centered on the fusion peptide in structural domain II were large, highly variable, and greater in primary than in secondary DENV-2 infected sera. E protein domain III cross-reactive immunoglobulin populations were similarly variable and much larger in IgM than in IgG. DENV-2 specific domain III IgG formed a very small proportion of the antibody response yet was significantly correlated with DENV-2 neutralization, suggesting that the highly protective IgG recognizing this epitope in murine studies plays a role in humans as well. This report begins to tease apart complex humoral immune responses to DENV infection and is thus important for improving our understanding of dengue disease and immunological correlates of protection, relevant to DENV vaccine development and testing.
Highlights
Dengue virus (DENV) is the quintessential 21st century re-emerging infectious disease
Human infections with DENV range from asymptomatic to an acute self-limiting febrile illness known as dengue fever (DF) or with increasing frequency, a life-threatening hemorrhagic fever and circulatory shock known as dengue hemorrhagic fever/ dengue shock syndrome (DHF/DSS) [2]
An important research agenda necessary to successfully address the DENV global public health challenge is to improve our understanding of humoral immune responses to DENV infection; the E-protein epitope-targeting of the immunoglobulin response and the relative quantities of epitope-specific antibody populations after viral exposure and vaccination in humans, the infection neutralizing and/or enhancing capabilities of these immunoglobulin populations and their role as correlates of protection in vaccine efficacy studies [4,22,34,39,40,41,42]
Summary
Dengue virus (DENV) is the quintessential 21st century re-emerging infectious disease. An important research agenda necessary to successfully address the DENV global public health challenge is to improve our understanding of humoral immune responses to DENV infection; the E-protein epitope-targeting of the immunoglobulin response and the relative quantities of epitope-specific antibody populations after viral exposure and vaccination in humans, the infection neutralizing and/or enhancing capabilities of these immunoglobulin populations and their role as correlates of protection in vaccine efficacy studies [4,22,34,39,40,41,42]. Immunoglobulin populations recognizing dominant cross reactive epitopes centered on the EDII fusion peptide were large and highly variable, averaging approximately 50% and 30% in primary and secondary DENV-2 infected sera respectively. The results presented in this report extend our understanding of the diverse nature of humoral immune responses to human DENV infection and we discuss their relevance in the context of understanding DENV disease and the development of safe and efficacious DENV vaccine candidates
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