Dynamic mechanisms of time-of-day-dependent adaptive immunity and vaccination responses

The timing of vaccine administration during the day significantly affects immunogenicity and vaccine efficacy, yet the mechanism governing the time-of-day-dependent adaptive immunity and vaccine response remains elusive. In this study, we developed a comprehensive model for circadian-regulated adaptive immune responses that integrates recent findings on clock-immune interaction. The model was first benchmarked with experimental observations. We elucidated that the bistability arising from the self-enhancing homing process of antigen-presenting dendritic cells, combined with downstream rapid cell proliferation and the stability of memory T and B cells and antibodies, underlies the sustained differences observed in long-term vaccine efficacy. Modeling analyses of circadian-controlled immune responses to three vaccine types demonstrated that vaccine-specific differences in time-of-day-dependent immunity originate from distinctions in the circadian-regulated activation of antigen-presenting dendritic cells. This divergence is amplified by bistability in the dendritic cell homing process, resulting in long-term distinctions in adaptive immunity across vaccine types. The model results revealed a dynamic mechanism by which adaptive immune responses maintain circadian variations over extended time periods, suggesting that the timing of vaccine administration within the day is a promising strategy for effective disease prevention.