Abstract
Shigella infection is the second leading cause of death due to diarrheal disease in young children worldwide. With the rise of antibiotic resistance, initiatives to design and deploy a safe and effective Shigella vaccine are urgently needed. However, efforts to date have been hindered by the limited understanding of immunological correlates of protection against shigellosis. We applied systems serology to perform a comprehensive analysis of Shigella-specific antibody responses in sera obtained from volunteers before and after experimental infection with S. flexneri 2a in a series of controlled human challenge studies. Polysaccharide-specific antibody responses are infrequent prior to infection and evolve concomitantly with disease severity. In contrast, pre-existing antibody responses to type 3 secretion system proteins, particularly IpaB, consistently associate with clinical protection from disease. Linked to particular Fc-receptor binding patterns, IpaB-specific antibodies leverage neutrophils and monocytes, and complement and strongly associate with protective immunity. IpaB antibody-mediated functions improve with a subsequent rechallenge resulting in complete clinical protection. Collectively, our systems serological analyses indicate protein-specific functional correlates of immunity against Shigella in humans.