EFB Dengue Literature Review

Original Antigenic Sin

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Original Antigenic Sin

Overview

Original antigenic sin (OAS), also termed “immune imprinting,” describes the phenomenon whereby the immune system preferentially recalls memory B cells specific for a previously encountered antigen variant when exposed to a related but distinct antigen. In the context of dengue, OAS manifests as the preferential expansion of memory B cells and plasmablasts specific for a prior serotype during secondary heterotypic infection. This can result in antibodies that bind and neutralise the prior serotype more potently than the currently infecting serotype — a potentially maladaptive response if the recalled antibodies cross-react at sub-neutralising concentrations with the current serotype, creating conditions favourable for Antibody-Dependent Enhancement.

Key Points from Literature

  • Direct evidence of OAS in secondary dengue plasmablast response: In 2/4 patients with secondary DENV2 infection, sorted plasmablast-derived mAbs preferentially neutralised DENV1 over the infecting DENV2. DENV1-specific mAbs were more potent (median FRNT₅₀ = 0.16 µg/ml) than DENV2-specific mAbs (median FRNT₅₀ = 1.2 µg/ml). The DENV1 bias was reflected at the serum level (FRNT₅₀) and at the mAb level in both binding (capture virus ELISA) and neutralisation. DENV1-specific mAbs did not bind monomeric rE but showed clear DENV1 preference on intact virions, with low-level DENV2 cross-reactivity sufficient to trigger their activation during DENV2 infection (see Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue, n=4 secondary DHF, 53 mAbs).
  • OAS is consistent with memory origin of the plasmablast response: The high SHM (mean 18.1 VH mutations), CDR R:S >2.9 (antigenic selection), and 23% clonal relatedness in these plasmablasts all support recall of affinity-matured memory B cells from prior DENV exposure. The OAS-biased neutralisation pattern is the functional consequence of this memory recall — the strongest evidence that secondary dengue plasmablasts are memory-derived (see Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue, n=4 secondary DHF, single-cell VH sequencing of sorted PBs, 53 mAbs).
  • Lower SHM in secondary dengue IgG consistent with OAS-driven recall of pre-existing clones: Secondary dengue IgG sequences had significantly lower somatic hypermutation rates than primary dengue (p<0.001), contrary to the expectation that repeated antigen exposure drives higher SHM through iterative GC re-entry. This is consistent with OAS: recalled memory B cells may have been generated during primary infection and reactivated without extensive further GC maturation, preserving their original (lower) SHM levels. The bias toward IGHV1-2 and IGHV1-69 gene usage in dengue further suggests selection of germline-encoded cross-reactive specificities during recall (see GodoyLozano2016 - Lower IgG SHM Rates in Acute Dengue, n=5 primary + 6 secondary dengue, bulk IgG NGS — small sample, single timepoint).
  • Higher clonal convergence in secondary dengue implies shared memory recall: Convergent CDR-H3 amino acid sequences were more prevalent in secondary (52%) than primary dengue patients, and secondary infections showed higher overall clonality (p=0.04). Convergent clonotypes across patients suggest that OAS-driven recall selects from a shared pool of cross-reactive memory B cells initially primed by the primary serotype, producing stereotyped responses dominated by previously expanded clones (see Parameswaran2013 - Convergent Antibody Signatures in Dengue, n=8 primary + 11 secondary dengue, IgG NGS of sorted PBs — observational, no serotype-specificity mapping).
  • Selective recruitment of E-specific IgG⁺ memory into the plasmablast pool: In secondary dengue, circulating plasmablasts were 85% E-specific while memory B cells had broader specificities (56% complex epitope, 24% prM, 18% E), with minimal clonal overlap between the two compartments. This selective recruitment is consistent with OAS: only the E-specific IgG⁺ memory subset — likely the subset most cross-reactive with the secondary serotype — is activated into the plasmablast response, while prM-specific and complex-epitope memory B cells maintain memory identity (see Appanna2016 - Plasmablasts as Subset of Memory B Cell Pool, n=6 secondary dengue, single-cell mAb cloning + flow cytometry).
  • Isotype-fate segregation as a mechanistic basis for selective OAS recall: IgG⁺ memory B cells are predisposed to plasmablast differentiation, while IgM⁺ memory B cells tend to re-initiate germinal center reactions (Seifert et al. 2015 model, cited by Bhattacharya2016). This provides a mechanistic explanation for OAS in secondary dengue: the IgG⁺ E-specific memory subset generated during primary infection is inherently biased toward PB fate upon re-encounter, producing the massive cross-reactive PB wave, while IgM⁺ memory cells with potentially novel specificities are shunted toward GC re-entry and do not contribute to the acute antibody response (see Bhattacharya2016 - Memory B Cell Subset Selection in Secondary Dengue, commentary — no original data, cites Seifert2015 and Appanna2016).
  • Tph-driven memory B cell activation as the cellular engine of OAS recall: CXCR5⁻PD-1⁺ peripheral helper T cells (Tph), expanded in secondary dengue, preferentially activate memory B cells (not naive B cells) via IL-21 in coculture, driving their differentiation into plasmablasts. This Tph→memory B cell→PB axis provides a T cell-dependent mechanism for the selective recall of pre-existing memory clones that underlies OAS. However, the coculture system used seropositive donor memory T cells rather than acute patient T cells (which died in culture), and the memory B cell preference may partly reflect the experimental system (see Ansari2025 - Peripheral T Helper Subset Drives B Cell Response in Dengue, n=60 dengue cohort, in vitro coculture — coculture caveat applies).

Contradictions & Debates

  • OAS was observed in only 2/4 patients (Pt. 32 and Pt. 33). The other two patients (Pt. 31, Pt. 39) showed DENV2-biased neutralisation — the expected pattern if the response were driven by the current infection. The variation likely reflects differences in prior serotype exposure history, which was not formally determined in this study. OAS in dengue may thus be exposure-history-dependent rather than universal.
  • The low SHM reported by GodoyLozano2016 - Lower IgG SHM Rates in Acute Dengue in secondary dengue (lower than primary) is consistent with an alternative interpretation: that OAS activates germline-coded cross-reactive B cells that bypass GC maturation, rather than recalling heavily mutated GC-derived memory. Priyamvada2016 and GodoyLozano2016 may be capturing different subsets — high-SHM memory-derived PBs (sorted by Priyamvada) vs. the global IgG pool including low-SHM de novo PBs (bulk sequencing by GodoyLozano).
  • Counter-evidence: infecting-serotype dominance in a Brazilian cohort. In secondary DENV3-infected Brazilian adults, serum PRNT₅₀ showed a 3-fold preference for the infecting serotype (DENV-3) over heterologous serotypes — the opposite of the OAS pattern. This suggests that OAS is not universal in secondary dengue and may depend on prior exposure history, serotype combination, geographic/genetic background, or time since primary infection. The Thai DHF cohort (Priyamvada2016) showed OAS in 2/4 patients; the Brazilian cohort (GarciaBates2013) showed infecting-serotype dominance. Whether these reflect genuine population differences or methodological differences (mAb-level vs. serum-level neutralisation, DENV2 vs. DENV3 secondary infection) remains unresolved (see GarciaBates2013 - Plasmablast Response and Dengue Severity, n=41 secondary dengue, serum PRNT₅₀).

Memory B Cell, Plasmablast, Antibody-Dependent Enhancement, Somatic Hypermutation, IgG, Extrafollicular Response, Germinal Center, Class Switch Recombination, Peripheral Helper T Cell

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