Human monoclonal antibodies against Shigella sonnei for prophylaxis and therapy

Shigellosis, a major cause of childhood morbidity and mortality in Low- and Middle-Income Countries (LMIC), is a growing global health concern, particularly with the increasing prevalence of multidrug-resistant strains of Shigella spp. Among these, S. sonnei has become particularly problematic due to its rising incidence and frequent association with antibiotic-resistant infections. Despite the urgent need for countermeasures, no vaccines have been approved to date. As a promising alternative, monoclonal antibodies (mAbs) offer high specificity, a favorable safety profile, and the possibility to spare the microbiota, making them ideal candidates for therapeutic and prophylactic applications. This thesis reports the identification and characterization of human mAbs targeting S. sonnei (ShimAbs), derived from individuals vaccinated with an experimental Generalized Modules for Membrane Antigens (GMMA)-based S. sonnei vaccine and subsequently exposed to controlled infection with the bacterium. These antibodies were tested for their functionality through different in vitro assays, revealing that our best candidate (mAb1) has a potent bactericidal activity, the ability to block S. sonnei adhesion to and invasion of epithelial cells and of inhibiting biofilm formation. Moreover, it was able to trigger bacterial enchained growth and to enhance the phagocytic activity of THP-1-derived macrophages. mAb1 polyfunctionality correlated with protection against bacterial challenge in a mouse infection model. Additionally, this work pioneers the use of the Organ-on-Chip (OoC) technology to create a relevant in vitro model of S. sonnei infection, thereby offering an innovative platform to assess the functional efficacy of ShimAbs in a physiological microenvironment. In conclusion, this study underscores the potential of mAbs as a new class of antibacterial agents for prevention and treatment of shigellosis. By providing a clear path toward the development of ShimAbs, this work offers a contribution to combating AMR and exemplifies a workflow that can easily be applicable for the discovery of new treatments for other infection diseases.