Living on Three Time Scales: The Dynamics of Plasma Cell and Antibody Populations Illustrated for Hepatitis A Virus

Abstract

Understanding the mechanisms involved in long-term persistence of humoral immunity after natural infection or vaccination is challenging and crucial for further research in immunology, vaccine development as well as health policy. Long-lived plasma cells, which have recently been shown to reside in survival niches in the bone marrow, are instrumental in the process of immunity induction and persistence. We developed a mathematical model, assuming two antibody-secreting cell subpopulations (short- and long-lived plasma cells), to analyze the antibody kinetics after HAV-vaccination using data from two long-term follow-up studies. Model parameters were estimated through a hierarchical nonlinear mixed-effects model analysis. Long-term individual predictions were derived from the individual empirical parameters and were used to estimate the mean time to immunity waning. We show that three life spans are essential to explain the observed antibody kinetics: that of the antibodies (around one month), the short-lived plasma cells (several months) and the long-lived plasma cells (decades). Although our model is a simplified representation of the actual mechanisms that govern individual immune responses, the level of agreement between long-term individual predictions and observed kinetics is reassuringly close. The quantitative assessment of the time scales over which plasma cells and antibodies live and interact provides a basis for further quantitative research on immunology, with direct consequences for understanding the epidemiology of infectious diseases, and for timing serum sampling in clinical trials of vaccines.

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…Examples of the mathematical models and their predictions can be found elsewhere (59)(60)(61). A comparative evaluation of the three most current mathematical models for single datasets can be found in a study by Andraud et al (67). The key message is that it is possible to predict zone 3 antibody persistence, within limits, using datasets from zones 1 and 2 and early in zone 3, as shown in Fig.…”

Modeling the long-term antibody response of a hepatitis E vaccine

“…The modified power-law model accounts for both activated and memory B-cells, while the latter are involved in a long-term antibody plateau [28]. The formula of modified power-law model is provided below:…”

“…By considering heterogeneity in the rate of B-cell decay, the model improved to the power-law model [24][25][26]. Furthermore, the modified power-law model, which also accounts for long-term persistence of memory B-cells or long-lived plasma cells, was suggested [24,27,28].…”

Effect of Branched α‐Oligomannoside Structures on Induction of Anti‐Candida Humoral Immune Response

“…Long-lived plasma cells are located in survival niches, especially in bone marrow and to a lesser extent in the spleen. These antibody-secreting cells could be pivotal for the maintenance of humoral immunity [28,29]. Correlation between detected mannan-specific antibody levels in serum and number of mannan-specific antibodysecreting cells (SFCs) in spleen was not observed.…”

“…Plasma cells are terminally differentiated B lymphocytes producing large amounts of antibodies. The immune response gave a rise of short-lived and long-lived plasma cells [28,29]. After antigen stimulation, short-lived plasma cells are rapidly formed in secondary lymphoid organs, where they undergo apoptosis after a few days of intensive antibody secretion.…”