Modeling the Relationship Between Antibody-Dependent Enhancement and Disease Severity in Secondary Dengue Infection

International audienceSequential infections with different dengue serotypes (DENV-1, 4) significantly increase the risk of a severe disease outcome (fever, shock and hemorrhagic disorders). Two hypotheses have been proposed to explain the severity of dengue disease: (1) antibody-dependent enhancement (ADE); (2) original T cell antigenic sin. In this work, we explored the first hypothesis through mathematical modeling. The proposed model reproduces the dynamic of susceptible and infected target cells, and dengue virus in scenarios of infection-neutralizing and-enhancing antibodies competition induced by two distinct serotypes of dengue virus. The enhancement and neutralization functions are derived from basic concepts of chemical reactions and used to mimic binding to the virus by two distinct populations of antibodies. The analytic study of the model showed the existence of two equilibriums, a disease-free equilibrium and an endemic one. We performed the asymptotic stability analysis for these two equilibriums. The local asymptotic stability of the endemic-equilibrium corresponds to the occurrence of dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). We defined the time t DHF at which DHF/DSS occurs as the time when the infected cells (or the virus) population reaches a maximum. This corresponds to the time at which maximum enhancing activity for dengue infection appears. The critical time t DHF was calculated from the model to be few days after the occurrence of the infection, which corresponds to what is observed in the literature. Finally, using as output the basic reproduction number R 0 we were able to rank the contribution of each parameter of the model. In particular, we have highlighted the evidence of the role of enhancing antibodies in cross-reaction and the occurrence of DHF/DSS