Protective immunity against <i>Shigella sonnei</i> in vaccinated and challenged adult Thai volunteers

ABSTRACT A safe, effective, and affordable vaccine that can prevent Shigella -induced diarrhea could have a significant impact on reducing morbidity and mortality in populations at risk. WRSS1, a live attenuated Shigella sonnei vaccine candidate, was well tolerated and immunogenic in adult Thai volunteers, achieving 40% efficacy against wild-type (WT) S. sonnei . We performed an in-depth analysis of mucosal and systemic antibodies in these individuals following WRSS1 vaccination and S. sonnei challenge, including a broader analysis of antibody specificity, functional features, and associations with clinical protection. IgG and IgA against Shigella proteins IpaB, IpaC, IpaD, IpaH, VirG, and LPS from multiple strains, as well as complement-mediated bactericidal and opsonophagocytic killing activity, were assessed in serum, fecal extracts, and antibodies in lymphocyte supernatants. Shigella- specific serum and ALS IgG and IgA increased after WRSS1 vaccination and S. sonnei challenge, particularly in naïve individuals, and most robustly post-challenge. Shedding the vaccine or infecting strain was associated with ALS responses. Fecal IgA was broadly reactive to most antigens, while fecal IgG was specific for S. sonnei LPS. Functional antibodies were detected prominently in fecal extracts; the highest responders were naïve individuals post-challenge. Notably, higher protein-specific serum IgA titers before challenge were associated with clinical protection against disease. Our results highlight the nuanced immunity to Shigella in endemic regions and the importance of understanding the elements that mediate protection in these settings to inform effective vaccine implementation. IMPORTANCE Understanding the immune response in Shigella -endemic regions is critical for the design and implementation of vaccines for the target population. We characterized the breadth of systemic and mucosal antibody responses to WRSS1 vaccination and WT S. sonnei challenge in Thai adult volunteers. Antigen-specific IgG and IgA in ALS were elevated only in individuals who shed the vaccine or challenge strain, indicating exposure. Serum IgA responses to Shigella proteins were associated with clinical protection. Our findings underscore the value of serosurveillance in guiding public health interventions and support the concept of protein-based vaccines to prevent disease in high-burden settings.