Modelling the mechanisms of antibody mixtures in viral infections: the cases of sequential homologous and heterologous dengue infections.

Antibodies play an essential role in the immune response to viral infections, vaccination or antibody therapy. Nevertheless, they can be either protective or harmful during the immune response. Moreover, competition or cooperation between mixed antibodies can enhance or reduce this protective or harmful effect. Using the laws of chemical reactions, we propose a new approach to modelling the antigen-antibody complex activity. The resulting expression covers not only purely competitive or purely independent binding but also synergistic binding which, depending on the antibodies, can promote either neutralization or enhancement of viral activity. We then integrate this expression of viral activity in a within-host model and investigate the existence of steady-states and their asymptotic stability. We complete our study with numerical simulations to illustrate different scenarios: firstly, where both antibodies are neutralizing and secondly, where one antibody is neutralizing and the other enhancing. The results indicate that efficient viral neutralization is associated with purely independent antibody binding, whereas strong viral activity enhancement is expected in the case of purely competitive antibody binding. Finally, data collected during a secondary dengue infection were used to validate the model. The dataset includes sequential measurements of virus and antibody titres during viremia in patients. Data fitting shows that the two antibodies are in strong competition, as the synergistic binding is low. This contributes to the high levels of virus titres and may explain the antibody-dependent enhancement phenomenon. Besides, the mortality of infected cells is almost twice as high as that of susceptible cells, and the heterogeneity of viral kinetics in patients is associated with variability in antibody responses between individuals. Other applications of the model may be considered, such as the efficacy of vaccines and antibody-based therapies.