Human Antibody Kills Drug-Resistant Shigella and Prevents Infection in Mice

Shigellosis remains a devastating global health problem, causing diarrheal disease, growth stunting, and death — particularly among children under five in low- and middle-income countries. Shigella sonnei, the dominant species in high-income countries and increasingly prevalent globally, is now routinely multi- and extensively drug-resistant. The WHO has elevated Shigella to high-priority pathogen status, urgently demanding new prophylactic and therapeutic strategies. Monoclonal antibodies represent a promising avenue: they have favorable safety profiles, do not disrupt the gut microbiota, and can be mass-produced.

The research team drew on a unique human sample source — volunteers who participated in a controlled human infection model (CHIM), receiving an experimental S. sonnei vaccine followed by deliberate bacterial challenge. B cells from these individuals were isolated and screened through a high-throughput antibody discovery pipeline. The target antigen of interest was the O-Antigen (OAg), the immunodominant repeating sugar unit on S. sonnei's lipopolysaccharide, composed of the unusual sugars L-AltNAcA and FucNAc4N not found in other Shigella species.

From this screen, one human monoclonal antibody emerged as exceptional. It demonstrated potent serum bactericidal activity (SBA) in vitro, killing S. sonnei at low concentrations. It also significantly inhibited bacterial invasion of epithelial cells in cell culture models, a critical step in Shigella pathogenesis. Structural and binding analyses confirmed the antibody binds specifically to the S. sonnei O-Antigen repeating unit, consistent with the known serotype-specific nature of protective immunity.

Crucially, the antibody conferred full protection in a mouse model of S. sonnei infection — a stringent in vivo test of therapeutic potential. Mice receiving the antibody showed no signs of disease following bacterial challenge. This trifecta of bactericidal killing, anti-invasion activity, and in vivo protection — termed 'multifunctional' by the authors — distinguishes this candidate as particularly robust.

The broader significance lies in the platform itself: by combining CHIM-derived human immune responses with high-throughput antibody screening, the approach could be rapidly applied to generate antibodies against other Shigella species or entirely different pathogens. The authors propose this candidate could advance as a prophylactic for travelers or high-risk groups, a therapeutic for active infection, or a diagnostic reagent — filling a critical gap left by the absence of any approved Shigella vaccine.