Dynamic changes in circulating T follicular helper cell composition predict neutralising antibody responses after yellow fever vaccination

Objectives T follicular helper (Tfh) cells are the principal T helper cell subset that provides help to B cells for potent antibody responses against various pathogens. In this study, we took advantage of the live‐attenuated yellow fever virus (YFV) vaccine strain, YF‐17D, as a model system for studying human antiviral immune responses in vivo following exposure to an acute primary virus challenge under safe and highly controlled conditions, to comprehensively analyse the dynamics of circulating Tfh (cTfh) cells. Methods We tracked and analysed the response of cTfh and other T and B cell subsets in peripheral blood of healthy volunteers by flow cytometry over the course of 4 weeks after YF‐17D vaccination. Results Using surface staining of cell activation markers to track YFV‐specific T cells, we found increasing cTfh cell frequencies starting at day 3 and peaking around 2 weeks after YF‐17D vaccination. This kinetic was confirmed in a subgroup of donors using MHC multimer staining for four known MHC class II epitopes of YF‐17D. The subset composition of cTfh cells changed dynamically during the course of the immune response and was dominated by the cTfh1‐polarised subpopulation. Importantly, frequencies of cTfh1 cells correlated with the strength of the neutralising antibody response, whereas frequencies of cTfh17 cells were inversely correlated. Conclusion In summary, we describe detailed cTfh kinetics during YF‐17D vaccination. Our results suggest that cTfh expansion and polarisation can serve as a prognostic marker for vaccine success. These insights may be leveraged in the future to improve current vaccine design and strategies. We tracked circulating T follicular helper (cTfh) cells in the blood of healthy individuals who received the yellow fever (YF) vaccine YF‐17D. We found that cTfh1‐polarised cells dominated the cTfh response and that their frequency on day 14 predicted YF virus‐neutralising antibody levels detected on day 28 after vaccination, thus highlighting the prognostic value of cTfh cells for monitoring of vaccine outcomes.