Modeling Dengue Immune Responses Mediated by Antibodies: A Qualitative Study.

Abstract

Simple SummaryWith more than one-third of the world population at risk of acquiring the disease, dengue fever is a major public health problem. Caused by four antigenically distinct but related serotypes, disease severity is associated with the immunological status of the individual, seronegative or seropositive, prior to a natural dengue infection. While a primary natural dengue infection is often asymptomatic or mild, individuals experiencing a secondary dengue infection with a heterologous serotype have higher risk of developing the severe form of the disease, linked to the antibody-dependent enhancement (ADE) process. We develop a modeling framework to describe the dengue immune responses mediated by antibodies. Our model framework can describe qualitatively the dynamic of the viral load and antibodies production for scenarios of primary and secondary infections, as found in the empirical immunology literature. Studies such as the one described here serve as a baseline to further model extensions. Future refinements of our framework will be of use to evaluate the impact of imperfect dengue vaccines.Dengue fever is a viral mosquito-borne infection and a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called antibody-dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: (i) primary dengue infection, (ii) secondary dengue infection with the same (homologous) dengue virus and (iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights into the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines.