Multifunctional antibody responses from a primate <i>Shigella</i> outbreak inform vaccine design.

Abstract

There is currently no approved vaccine for <i>Shigella</i> spp., a leading cause of diarrhea with increasing rates of antimicrobial resistance. <i>Shigella</i> vaccine development is complicated in part by an incomplete understanding of the structural and molecular determinants of immunity. To address this, we isolated monoclonal antibodies against candidate <i>Shigella</i> vaccine antigens using samples from a <i>Shigella flexneri</i> outbreak in a nonhuman primate (NHP) research facility. We found that antibodies targeting the <i>Shigella</i> O-antigen can undergo substantial affinity maturation (>10%) to acquire broad cross-reactivity across <i>S. flexneri</i> serotypes. We also found that the virulence-associated type III secretion system (T3SS) proteins IpaD and IpaB elicit moderate T cell and robust antibody responses. T3SS antibodies could either inhibit or enhance bacterial virulence in vitro and differed in vivo depending on their epitope specificity. Collectively, these findings provide insights into protective and deleterious immune responses against <i>Shigella</i> that directly inform vaccine immunogen design.