Evaluation of a Live Attenuated S. sonnei Vaccine Strain in the Human Enteroid Model

Abstract

<i>Shigella</i> is a leading cause of bacillary dysentery worldwide, responsible for high death rates especially among children under five in low-middle income countries. <i>Shigella sonnei</i> prevails in high-income countries and is becoming prevalent in industrializing countries, where multi-drug resistant strains have emerged, as a significant public health concern. One strategy to combat drug resistance in <i>S. sonnei</i> is the development of effective vaccines. There is no licensed vaccine against <i>Shigella,</i> and development has been hindered by the lack of an effective small-animal model. In this work, we used human enteroids, for the first time, as a model system to evaluate a plasmid-stabilized S. <i>sonnei</i> live attenuated vaccine strain, CVD 1233-SP, and a multivalent derivative, CVD 1233-SP::CS2-CS3, which expresses antigens from enterotoxigenic <i>Escherichia coli</i>. The strains were also tested for immunogenicity and protective capacity in the guinea pig model, demonstrating their ability to elicit serum and mucosal antibody responses as well as protection against challenge with wild-type <i>S. sonnei</i>. These promising results highlight the utility of enteroids as an innovative preclinical model to evaluate <i>Shigella</i> vaccine candidates, constituting a significant advance for the development of preventative strategies against this important human pathogen.