Weng, X.; Ouyang, Q.; Wang, H.

The timing of vaccine administration during the day significantly affects immunogenicity and efficacy, yet the mechanism governing the time-of-day dependent adaptive immunity and vaccine response remains elusive. Using mathematical modeling, we elucidate that the bistability arising from the self-enhancing homing process of antigen-presenting dendritic cells plays a key role in the time-of-day-dependent adaptive immune response. Modeling analyses of circadian-controlled immune responses to three vaccine types demonstrate 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 reveal 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.