Dengue Literature Review

Original Antigenic Sin

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Original Antigenic Sin

Overview

Original antigenic sin (OAS) — also called the Hoskins effect in the context of influenza — describes the phenomenon whereby the immune memory established by a first antigen exposure dominates and shapes subsequent responses to related but distinct antigens. In dengue, the term is most commonly applied to T cell responses: upon secondary infection with a heterotypic DENV serotype, cross-reactive memory T cells from the primary serotype are preferentially re-expanded (because they have a lower activation threshold as memory cells), even if their affinity for the new serotype is lower than naive T cells specific for the new serotype would have. The resulting T cell response may be poorly tuned to the new infecting serotype and may contribute to immunopathology via excessive cytokine production and suboptimal viral clearance.

Key Points from Literature

  • OAS is listed as one of three hypotheses to explain dengue vascular permeability syndrome (alongside cytokine storm from overactive T cells, and immune complex-mediated complement activation), situating it within the context of the broader DHF pathogenesis debate (see Guzman2016 - Dengue Infection)
  • The original antigenic sin model predicts that cross-reactive T cell responses are directed preferentially against the original infecting serotype’s NS protein epitopes, potentially producing lower-affinity responses against the secondary serotype while generating excessive cytokine production — contributing to cytokine storm without effective viral clearance
  • Sungnak2025 offers single-cell evidence that CD8 TEM cells in symptomatic dengue (particularly DHF) show exhaustion markers (PD-1, LAG3, TIGIT) and a different effector profile (PRF1, GZMB) compared to the functional non-exhausted profile in asymptomatic dengue (IFNG, TNF, GZMH, GNLY) — which is consistent with, though not definitive evidence for, OAS-driven T cell dysfunction in severe disease (see T Cell Responses in Dengue)

Contradictions & Debates

  • OAS is a long-standing hypothesis but has not been definitively proven to drive DHF pathogenesis in humans; it is difficult to distinguish OAS-driven T cell dysfunction from exhaustion due to high antigen load or cytokine-mediated suppression in severe disease
  • The implication that cross-reactive T cells are immunopathological in secondary dengue is in tension with evidence that T cells are also protective: effective CD8+ T cell immunity against NS protein epitopes is associated with protection, and Sungnak2025 found functional CD8 TEM enrichment in asymptomatic dengue

Sources

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