scholarly journals Afucosylated maternal anti-dengue IgGs are a biomarker for susceptibility to dengue disease in their infants

2019 ◽  
Author(s):  
Natalie K. Thulin ◽  
R. Camille Brewer ◽  
Robert Sherwood ◽  
Stylianos Bournazos ◽  
Karlie G. Edwards ◽  
...  
Keyword(s):  
Infant Mortality ◽  
Global Health ◽  
Dengue Virus ◽  
Virus Replication ◽  
Severe Disease ◽  
Antibody Dependent Enhancement ◽  
Dengue Disease ◽  
Health Burden ◽  
Post Entry ◽  
Activating Receptor

SummaryInfant mortality from dengue disease is a devastating global health burden that could be minimized with the ability to identify susceptibility for severe disease prior to infection. While most primary infant dengue infections are asymptomatic, maternally derived anti-dengue IgGs present during infection can trigger progression to severe disease through antibody-dependent enhancement mechanisms. Importantly, specific characteristics of maternal IgGs that herald progression to severe infant dengue are unknown. Here, we define ≥10% afucosylation of maternal anti-dengue IgGs as a biomarker for susceptibility of infants to symptomatic dengue infections. Mechanistic experiments show that anti-dengue afucosylation, a modification that enhances Fc affinity for the activating receptor FcγRIIIa, promotes infection of FcγRIIIa+ monocytes. FcγRIIIa signaling, in turn, enhances a post-entry step of dengue virus replication. These studies identify a biomarker that can be applied to reduce mortality associated with dengue viruses and define a mechanism by which afucosylated antibodies and FcγRIIIa enhance dengue infections.

scholarly journals Antibody-dependent enhancement of severe dengue disease in humans

Science ◽  
2017 ◽  
Vol 358 (6365) ◽  
pp. 929-932 ◽  
Author(s):  
Leah C. Katzelnick ◽  
Lionel Gresh ◽  
M. Elizabeth Halloran ◽  
Juan Carlos Mercado ◽  
Guillermina Kuan ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Severe Disease ◽  
Severe Dengue ◽  
Antibody Dependent Enhancement ◽  
Dengue Disease ◽  
Symptomatic Disease ◽  
Immune Correlates ◽  
Antibody Titers ◽  
Approaches To Study

For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.

scholarly journals Adaptive Immunity to Dengue Virus: Slippery Slope or Solid Ground for Rational Vaccine Design?

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 470 ◽  
Author(s):  
Lucas Wilken ◽  
Guus F. Rimmelzwaan
Keyword(s):  
Dengue Virus ◽  
Vaccine Development ◽  
Secondary Infection ◽  
Severe Disease ◽  
Structural Protein ◽  
Dengue Vaccine ◽  
Dengue Disease ◽  
Generation Vaccine ◽  
Virus Serotype ◽  
Rational Vaccine Design

The four serotypes of dengue virus are the most widespread causes of arboviral disease, currently placing half of the human population at risk of infection. Pre-existing immunity to one dengue virus serotype can predispose to severe disease following secondary infection with a different serotype. The phenomenon of immune enhancement has complicated vaccine development and likely explains the poor long-term safety profile of a recently licenced dengue vaccine. Therefore, alternative vaccine strategies should be considered. This review summarises studies dissecting the adaptive immune responses to dengue virus infection and (experimental) vaccination. In particular, we discuss the roles of (i) neutralising antibodies, (ii) antibodies to non-structural protein 1, and (iii) T cells in protection and pathogenesis. We also address how these findings could translate into next-generation vaccine approaches that mitigate the risk of enhanced dengue disease. Finally, we argue that the development of a safe and efficacious dengue vaccine is an attainable goal.

scholarly journals Changes in complement alternative pathway components, factor B and factor H during dengue virus infection in the AG129 mouse

2021 ◽  
Author(s):  
Sheila Cabezas-Falcon ◽  
Aidan J. Norbury ◽  
Jarrod Hulme-Jones ◽  
Sonja Klebe ◽  
Penelope Adamson ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Alternative Pathway ◽  
Severe Disease ◽  
Denv Infection ◽  
Factor H ◽  
Severe Dengue ◽  
Complement Alternative Pathway ◽  
Factor B ◽  
Dengue Disease

The complement alternative pathway (AP) is tightly regulated and changes in two important AP components, factor B (FB) and factor H (FH) are linked to severe dengue in humans. Here, a mouse model of dengue was investigated to define the changes in FB and FH and assess the utility of this model to study the role of the AP in severe dengue. Throughout the period of viremia in the AG129 IFN signalling-deficient mouse, an increase in FB and a decrease in FH was observed following dengue virus (DENV) infection, with the former only seen in a model of more severe disease associated with antibody-dependent enhancement (ADE). Terminal disease was associated with a decrease in FB and FH, with greater changes during ADE, and accompanied by increased C3 degradation consistent with complement activation. In silico analysis of NFκΒ, signal transducer and activator of transcription (STAT) and IFN-driven FB and FH promoter elements to reflect the likely impact of the lack of IFN-responses in AG129 mice, demonstrated that these elements differed markedly between human and mouse, notably with mouse FH lacking NFκΒ and key IFN-stimulated response elements (ISRE), and FB with many more NFκΒ and STAT-responsive elements than human FB. Thus, the AG129 mouse offers utility in demonstrating changes in FB and FH that, similar to humans, are associated with severe disease, but lack predicted important human-specific and IFN-dependent responses of FB and FH to DENV-infection that are likely to regulate the subtleties of the overall AP response during dengue disease in humans.

scholarly journals Antibody-Dependent Enhancement of Severe Disease Is Mediated by Serum Viral Load in Pediatric Dengue Virus Infections

2020 ◽  
Vol 221 (11) ◽  
pp. 1846-1854 ◽  
Author(s):  
Jesse J Waggoner ◽  
Leah C Katzelnick ◽  
Raquel Burger-Calderon ◽  
Julia Gallini ◽  
Renee H Moore ◽  
...  
Keyword(s):  
Viral Load ◽  
Dengue Virus ◽  
Disease Severity ◽  
Antibody Titer ◽  
Severe Disease ◽  
Severe Dengue ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antibody Dependent Enhancement ◽  
Serum Viral Load ◽  
Antibody Titers

Abstract Background Low preexisting anti-dengue virus (DENV) antibody levels are associated with elevated disease severity. While antibody-dependent enhancement of dengue is thought to be driven by viral load, this has not been conclusively shown. We evaluated the association between preinfection anti-DENV antibody titers, viral load, and disease severity among 133 dengue cases in a Nicaraguan pediatric cohort study. Methods Viral load was quantified in acute-phase serum by real-time reverse transcription polymerase chain reaction and analyzed in relation to preinfection antibody titer (measured by inhibition enzyme-linked immunosorbent assay) and dengue severity, categorized using 3 definitions. Results Higher viral load was significantly associated with dengue severity; for each increase of 1.0 log10 copies/mL, the odds of severe dengue increased approximately 50%, regardless of severity definition. Viral load at presentation and the odds of severe disease were highest among patients with low to intermediate preinfection antibody titers and lowest among those with the highest antibody titers. We showed the effect of preinfection antibody titer on disease severity was mediated by viral load for each of 3 dengue severity outcomes. Conclusions This study demonstrates the association between preinfection anti-DENV antibody titer, serum viral load, and disease severity, and provides evidence for the mechanism of antibody-dependent enhancement in dengue cases.

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