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)

OAS T cell mechanism — low-avidity CD8+ expansion and cytolytic loss (Bhatt2020)

Bhatt2020 - Dengue Pathogenesis Review provides the most mechanistically detailed account of OAS in this wiki, consolidating the cellular and functional basis for how the phenomenon drives DHF/DSS pathology:

  • Preferential expansion of low-avidity cross-reactive CD8+ T cells: Memory CD8+ T cells from the primary serotype have a lower activation threshold than naive T cells and are re-expanded preferentially in secondary heterotypic infection. These cross-reactive cells bind heterologous epitopes on the new serotype but with lower affinity than de novo naive T cells would — they are not optimally matched to the secondary serotype.
  • Loss of cytolytic function: Unlike high-avidity serotype-specific T cells that efficiently kill DENV-infected cells via perforin/granzyme, the low-avidity cross-reactive CD8+ T cells lose cytolytic activity against the secondary serotype while retaining cytokine-secreting function. The result is a decoupling of inflammation from killing.
  • High TNF-α and IL-6 without viral clearance: The expanded cross-reactive pool produces elevated levels of TNF-α and IL-6 — both promoters of endothelial activation and vascular permeability — without effectively lysing DENV-infected target cells. Viral clearance is delayed.
  • Positive feedback loop: Delayed viral clearance → higher and more prolonged viraemia → sustained T cell activation → further TNF-α/IL-6 production → amplification of vascular permeability → DHF/DSS. The OAS mechanism thus links impaired T cell quality (avidity mismatch with secondary serotype) to the canonical DHF/DSS phenotype via cytokine excess.

This mechanism is consistent with — and may partly explain — the CD8 TEM exhaustion profile (PRF1, GZMB, PD-1↑, LAG3↑, TIGIT↑) documented in DHF by Sungnak2025: the exhaustion markers may reflect a prolonged activation signal in the absence of efficient killing, precisely what the Bhatt2020 OAS model predicts.

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

  • Guzman2016 - Dengue Infection
  • Bhatt2020 - Dengue Pathogenesis Review (OAS mechanism: low-avidity CD8+ T cells preferentially expanded; heterologous epitope recognition with reduced affinity; cytolytic loss combined with TNF-α/IL-6 excess; delayed viral clearance → DHF/DSS positive feedback loop; review article, India)
  • Pang2017 - DHF Pathogenesis Review (OAS mechanism confirmed: cross-reactive low-affinity memory T cells expand preferentially in secondary infection; inefficient killing of new serotype; IFN-γ/IL-2/TNF-α cytokine excess → DHF; review, China)

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