<i>Shigella</i> humoral immunity during the first 2 years of life in children from endemic areas

<i>Shigella</i> is a leading cause of moderate-to-severe diarrhea, primarily affecting children in impoverished regions. Disease incidence is highest in toddlers 1-2 years of age. Acquisition of immunity over time reduces the risk of infection. However, the evolution of childhood immunity resulting from <i>Shigella</i> exposure and the host responses that mediate protection remain poorly understood. Gaining insight into the immunological features that develop over time and prevent subsequent <i>Shigella</i> infection is critical for guiding vaccine design. We examined the antigenic repertoire and magnitude of humoral immunity to <i>Shigella</i> in children < 2 years of age from three endemic areas-Bamako, Mali, and two sites (Afar and Tigray) in Ethiopia-using a qualified multiplex assay. Serum IgG and IgA specific to <i>Shigella</i> proteins (IpaB, IpaC, IpaD, IpaH, and VirG) and lipopolysaccharide (LPS) from <i>S. flexneri</i> 2a, <i>S. flexneri</i> 3a, <i>S. flexneri</i> 6, and <i>S. sonnei</i> were measured in three stratified age groups: 6-8, 12-17, and 18-24 months. The youngest group (6- to 8-month-olds) exhibited similar antibody profiles across all sites. By contrast, antibody levels in the 12- to 17- and 18- to 24-month-old age groups varied by both age and site, reflecting geographical differences in <i>Shigella</i> endemicity and exposure. Notably, most children in the 12- to 17-month-old age group had IgG levels below the adult protective thresholds identified in controlled human infection models, identifying a critical window of vulnerability that would require intervention. Our findings underscore the importance and value of <i>Shigella</i> serosurveillance in children from endemic regions to inform future vaccine rollout decisions.IMPORTANCE<i>Shigella</i> is a major cause of moderate-to-severe diarrhea, the most affected being young children from poor resource countries. <i>Shigella</i> species easily acquire antibiotic resistance, presenting a challenge to infection control. The development of vaccines for young children has been hindered by a lack of understanding of what constitutes protective immunity. Here, for the first time, we investigated the magnitude and specificity of <i>Shigella</i> humoral immunity evoked by natural exposure in children 6 months to 2 years old living in Mali and Ethiopia (<i>Shigella</i>-endemic areas) using a qualified multiplex assay. Antibody profiles varied with age and region, revealing epidemiological trends. Children 12-17 months old were identified as the most vulnerable to infection. Antibodies specific for conserved <i>Shigella</i> proteins were higher in older children, affirming their potential as vaccine candidates. <i>Shigella</i> serosurveillance is useful in guiding public health interventions.