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Multiple, but not isolated, yellow fever virus-associated orthoflavivirus immune histories drive antibody-dependent enhancement of Zika and dengue viruses

Gallon, S.; Baffour Tonto, P.; Ding, Y.; Chen, G.-H.; Naito-Keoho, K.; Brites, C.; Netto, E. M.; Wang, W.-K.; Herrera, B. B.

2026-06-01 infectious diseases
10.64898/2026.05.22.26353817 medRxiv
Show abstract

Antibody-dependent enhancement (ADE) is a major concern across orthoflavivirus infections, yet how multiple viral exposures shape enhancement risk remains incompletely understood. Here, we integrated serosurveillance from Saude, Brazil with functional immunologic analyses to define how yellow fever virus (YFV)-associated orthoflavivirus immune histories influence ADE phenotypes. Using serocomplex-specific anti-premembrane antibody profiling validated by microneutralization assays, plasma samples were stratified into YFV-only, YFV+DENV, and YFV+DENV+ZIKV exposure groups. In Fc gamma receptor-bearing U937 cells, YFV-only plasma demonstrated minimal enhancement activity, whereas cumulative orthoflavivirus exposure generated broader ADE phenotypes across heterologous viruses. In IFNAR1-/- passive-transfer models, YFV-only plasma did not enhance ZIKV or DENV2 infection in vivo. In contrast, YFV+DENV plasma increased ZIKV viremia and accelerated mortality kinetics, while YFV+DENV+ZIKV plasma demonstrated concentration-dependent enhancement phenotypes. Collectively, these findings indicate that isolated YFV immunity does not predispose to ADE, whereas cumulative orthoflavivirus exposure generates antibody repertoires capable of producing concentration-dependent enhancement in vivo.

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