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T cell responses induced by attenuated flavivirus vaccination are specific and show limited cross-reactivity with other flavivirus species.

By Alba Grifoni, Hannah Voic, Sandeep Kumar Dhanda, Conner K Kidd, James D Brien, Søren Buus, Anette Stryhn, Anna P. Durbin, Stephen Whitehead, Sean A. Diehl, Aruna D. De Silva, Angel Balmaseda, Eva Harris, Daniela Weiskopf, Alessandro Sette

Posted 20 Jan 2020
bioRxiv DOI: 10.1101/2020.01.17.911099 (published DOI: 10.1128/JVI.00089-20)

Members of the flavivirus genus share a high level of sequence similarity and often circulate in the same geographical regions. However, whether T cells induced by one viral species cross-react with other related flaviviruses has not been globally addressed. Here, we tested pools of epitopes derived from dengue (DENV), zika (ZIKV), Japanese Encephalitis (JEV), West Nile (WNV), and yellow fever (YFV) viruses by Intracellular Cytokine Staining (ICS)  using PBMCs of individuals naturally exposed to DENV or immunized with DENV (TV005) or YF17D vaccines. CD8 T cell responses recognized epitopes from multiple flaviviruses, however, the magnitude of cross-reactive responses was consistently several-fold lower than those to the autologous epitope pools, and associated with lower expression of activation markers such as CD40L, CD69, and CD137. Next, we characterized the antigen sensitivity of short-term T cell lines (TCL) representing twenty-nine different individual epitope/donor combinations. TCL derived from DENV monovalent vaccinees induced CD8 and CD4 T cells that cross-reacted within the DENV serocomplex but were consistently associated with more than 100-fold lower antigen sensitivity for most other flaviviruses, with no cross-recognition of YFV derived peptides.  CD8 and CD4 TCL from YF17D vaccinees were associated with very limited cross-reactivity with any other flaviviruses, and in five out of eight cases more than 1000-fold lower antigen sensitivity. Overall, our data suggest limited cross-reactivity for both CD4 and CD8 T cell responses between flaviviruses and has implications for understanding immunity elicited by natural infection, and strategies to develop live attenuated vaccines against flaviviral species.

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