a source of memory B cells, we created a panel of human mAbs directed against GII.4 strains and compared the reactivity of these mAbs to a panel of time-ordered GII.4 VLPs using EIAs and surrogate neutralization assays. We identified one novel, broadly cross reactive antibody that differentially blocks GII.4.1987 through 2009 VLP interactions with carbohydrate ligands, a potential immunotherapeutic for the treatment of acute or chronic GII.4 disease. We also defined unique antibody interactions with two different surface exposed epitopes that evolve over time. Importantly, antigenic variation in one of these epitopes correlated with changing carbohydrate ligand binding patterns over time, supporting the proposed relationship between epitope escape from human herd immunity and changing HBGA usage for virus docking [13] . In addition to defining the first human monoclonal antibodies with therapeutic potential for treating acute and chronic NoV GII.4 infections, these data support the hypothesis that GII.4 norovirus evolution results in antigenic drift of neutralizing epitopes and consequently, antibody-driven HBGA receptor switching; thus, protective herd immunity is a driving force in norovirus evolution.