Functional profiling of OSP-specific and other antibodies during shigella infection

PROJECT SUMMARY/ABSTRACT Shigella infection is a leading cause of diarrheal illness in young children in resource-limited settings, and results in tens of thousands of deaths each year. Protection against shigellosis is associated with antibodies targeting O-specific polysaccharide (OSP), but immune responses against other antigens have also been noted to correlate with protection. Functional attributes of anti-shigella antibodies have also been noted to correlate with protection, including complement activation and ability to induce host cell phagocytic activity. Despite this, a shigella OSP-conjugate vaccine failed to protect young children in a field trial, despite providing protection in older children and adults. We propose that such issues may reflect differences not only in antibody magnitude (titer) following vaccination, but also differences in antibody functional effector attributes, including Fc interactions with the innate immune system. Such differences have been noted to correlate with protection against a range of infectious pathogens. To address this, we propose to define antibody functional and biophysical attributes associated with protection against shigella infection, including in young children, using a household contact study design approach in an informal settlement area in Dhaka, Bangladesh. We propose to complement this analysis with data from North American vaccine and Controlled Human Infection Models (CHIMs) and related studies. We anticipate that we will identify a profile of antibody attributes that correlates with protection against shigellosis, that this knowledge will critically guide vaccine development and evaluation efforts, and that this knowledge will focus future mechanistic studies.