Cross-Protective Shigella Whole-Cell Vaccine With a Truncated O-Polysaccharide Chain

Abstract

<i>Shigella</i> is a highly prevalent bacterium causing acute diarrhea and dysentery in developing countries. <i>Shigella</i> infections are treated with antibiotics but Shigellae are increasingly resistant to these drugs. Vaccination can be a countermeasure against emerging antibiotic-resistant shigellosis. Because of the structural variability in Shigellae O-antigen polysaccharides (Oag), cross-protective <i>Shigella</i> vaccines cannot be derived from single serotype-specific Oag. We created an attenuated <i>Shigella flexneri</i> 2a strain with one rather than multiple Oag units by disrupting the Oag polymerase gene (Δ<i>wzy</i>), which broadened protective immunogenicity by exposing conserved surface proteins. Inactivated Δ<i>wzy</i> mutant cells combined with <i>Escherichia coli</i> double mutant LT(R192G/L211A) as adjuvant, induced potent antibody responses to outer membrane protein PSSP-1, and type III secretion system proteins IpaB and IpaC. Intranasal immunization with the vaccine preparation elicited cross-protective immunity against <i>S. flexneri</i> 2a, <i>S. flexneri</i> 3a, <i>S. flexneri</i> 6, and <i>Shigella sonnei</i> in a mouse pneumonia model. Thus, <i>S. flexneri</i> 2a Δ<i>wzy</i> represents a promising candidate strain for a universal <i>Shigella</i> vaccine.