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).
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).
Related Pages
Memory B Cell, Plasmablast, Antibody-Dependent Enhancement, Somatic Hypermutation, IgG, Extrafollicular Response