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

PROJECT SUMMARY/ABSTRACT This is a competitive renewal application for an ongoing field-immunology Shigella project actively enrolling child participants in Bangladesh. 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 (1) to define antibody functional and biophysical attributes associated with protection against shigellosis, including in young children, using an ongoing and actively enrolling household contact study design approach in an informal settlement area in Dhaka, Bangladesh. We propose to complement this effort with (2) analysis of functional antibody responses correlating with protection from severe disease in children in Bangladesh (continuing our ongoing and actively enrolling index case enrollment study in Dhaka), and we propose (3) to assess antibody-afforded mechanisms of protection involving innate cell activation and functional antibody activity using a library of engineered-Fc antibodies from monoclonal anti-Shigella antibodies cloned from children with shigellosis in Bangladesh. We anticipate that we will identify a profile of antibody attributes that correlate with protection against shigellosis (incident infection and disease severity) and that we will identify mechanisms of protection afforded by such anti-Shigella antibodies. This knowledge will be shared in Open Access fora, will continue building upon our collaborative international capacity building efforts, and will critically guide evaluation efforts for vaccines currently being developed to protect children in resource-limited areas from shigellosis.