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bioRxiv · 10.1101/2025.04.16.649113

Pre-existing YFV-17D immunity mediates T cell cross-protection against DENV-2 infection

Tonto, P. B.·Gallon, S.·Alatrash, R.·Wang, W.-K.·Herrera, B. B.
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Abstract

Widespread yellow fever virus (YFV) immunity in Sub-Saharan Africa may mitigate orthoflavivirus outbreaks. Here, we investigate whether pre-existing YFV-17D immunity confers cross-protection against dengue virus serotype 2 (DENV-2) in a murine model. IFNAR1-/- mice immunized with YFV-17D exhibited significantly reduced DENV-2 viremia, weight loss, and disease severity, with improved survival compared to YFV-naive controls. Mechanistic studies revealed that cross-protection was mediated by heterologous T cell responses rather than cross-neutralizing antibodies. Depletion of T cells in YFV-17D-immune mice prior to DENV-2 challenge resulted in increased viremia, weight loss, and disease severity, underscoring the protective role of YFV-17D-elicited T cell immunity. Furthermore, YFV-17D-specific T cells displayed cytotoxicity against DENV NS3- and NS5-pulsed cells, demonstrating their functional role in viral control. These findings highlight the critical contribution of heterologous T cell immunity in YFV-17D-mediated protection against DENV-2 and suggest that vaccines designed to elicit T cell responses could enhance cross-protection against orthoflavivirus infections.

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Tonto, P. B., Gallon, S., Alatrash, R., Wang, W.-K., Herrera, B. B.. 2025-04-20. Pre-existing YFV-17D immunity mediates T cell cross-protection against DENV-2 infection. https://doi.org/10.1101/2025.04.16.649113

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