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

Abstract

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. Author SummaryInfection with the same pathogen in the morning or afternoon, or receiving the same vaccine at different times of the day, often leads to significantly different consequences in terms of infection severity or vaccine efficacy. This phenomenon is known as the time-of-day-dependent immune response. Although it is relatively common, the underlying dynamic mechanisms remain mostly unclear. In this paper, we employ mathematical modeling to investigate in detail the dynamics of adaptive immune responses following vaccination. We reveal that the kinetic origin of the time-of-day-dependent immune response lies in the positive feedback process during the homing of antigen-presenting cells, particularly dendritic cells. The bistability induced by self-activation, under the regulation of the circadian clock, plays a decisive role in generating this diurnal time dependency. The discovery of this mechanism suggests that time-of-day-specific vaccination is an effective strategy to optimize vaccine efficacy.