EFB Dengue Literature Review

Antibody-Dependent Enhancement

3 min read

Antibody-Dependent Enhancement

Overview

Antibody-dependent enhancement (ADE) is a mechanism by which pre-existing cross-reactive antibodies, at sub-neutralising concentrations, bind to virus particles and facilitate their uptake into Fcγ receptor (FcγR)-bearing cells (monocytes, macrophages), thereby enhancing viral replication rather than preventing it. In dengue, ADE is one of the leading hypotheses to explain why secondary heterotypic infections are associated with increased disease severity (DHF/DSS). The model posits that cross-reactive antibodies generated during a primary infection bind the secondary serotype with insufficient avidity to neutralise it but sufficient affinity to promote FcγR-mediated entry into myeloid cells.

Key Points from Literature

  • Near-universal ADE activity of dengue plasmablast-derived mAbs: 45/53 mAbs generated from sorted acute-phase plasmablasts in secondary DENV2 infection enhanced DENV infection of U937 cells (FcγR⁺ monocytic cell line) at 1 µg/ml. Enhancement ranged from 5-fold to 161-fold across DENV1–4. ADE was independent of neutralisation potency — even potently neutralising mAbs caused enhancement. Cross-reactive neutralising mAbs caused greater average fold-enhancement than mono-neutralising mAbs. Only 2/53 DENV-reactive mAbs (32.2F04 and 39.3G03) did not enhance infection (see Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue, n=4 secondary DHF, FcγR-bearing U937 ADE assay).
  • ADE and neutralisation are not mutually exclusive: The most potently neutralising mAb that was also DENV2-specific (31.3F03) exhibited the highest cross-serotypic ADE in the entire panel — demonstrating that ADE is a property of the antibody at sub-neutralising concentrations or against heterotypic serotypes, not a marker of poor neutralisation capacity per se (see Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue).
  • ADE is more relevant for future exposures than current infection: The authors note that viremia in dengue patients subsides before the peak plasmablast response (days 6–7), making it unlikely that acutely produced ADE-competent antibodies enhance the current infection. Rather, these antibodies enter the serum pool and may enhance subsequent heterotypic infections — connecting the acute plasmablast wave to long-term susceptibility to severe dengue (see Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue).

Contradictions & Debates

  • The in vitro ADE assay (U937 cells, single mAb concentration) does not capture the concentration-dependent balance between neutralisation and enhancement that exists in vivo. At sufficiently high concentrations, most antibodies neutralise; at sub-neutralising dilutions, they enhance. Whether the plasmablast-derived antibody concentrations achieved in patient serum fall within the enhancing or neutralising range is unknown.
  • The Extrafollicular Response produces non-neutralising IgG that correlates with disease severity but not with neutralising titres (the “neutralizing Ab paradox” from Ansari2025 and Woodruff2020). Whether this non-neutralising fraction is specifically the ADE-mediating subset has not been tested — it is a plausible but undemonstrated connection.

Original Antigenic Sin, Plasmablast, IgG, Memory B Cell, Extrafollicular Response

Sources

Graph View

Backlinks