Comparing reactivity of polyclonal sera collected from immunized mice and infected humans suggested antigenic variation within the GII.4 noroviruses [13, 33] . The development of mouse mAbs to different time-ordered GII.4 VLPs has greatly facilitated progress towards understanding the complex antigenic relations among these strains by clearly demonstrating antigenic variation over time and epidemic strain [34, 42, 43] . However, to maximally define the mechanistic relationships that exist between antigenic variation, immunity, and HBGA binding patterns noted in the GII.4 noroviruses in the context of natural infection history, the cross reactivity patterns, blockade responses, and epitope targets of human anti-GII.4 monoclonal antibodies are needed. Robust approaches exist for the isolation of human monoclonal antibodies that are elicited following virus infection. Using human PBMCs as