GII.4 NoVs are significant human pathogens that cause considerable morbidity and mortality, worldwide. The development of mouse mAbs to different time-ordered GII.4 VLPs has greatly facilitated progress towards understanding the complex antigenic relationships between these strains by clearly demonstrating antigenic variation over time and epidemic strain [34] . Here we have expanded these observations using human anti-GII.4 mAbs isolated from a healthy adult donor, who has likely experienced multiple norovirus infections throughout his/her lifetime. The identification of highly significant, varying antigenic epitopes that influence VLP-carbohydrate ligand interaction provides important new insights into vaccine design and the development of therapeutics that target norovirus virions. For example, these antibodies represent the first anti-norovirus human mAbs to be characterized, and they confirm findings from studies using mouse mAbs supporting antigenic drift and its linkage with varying carbohydrate ligand binding profiles within the GII.4 noroviruses. Further, we have demonstrated that the GII.4 NoV varying epitopes can be exchanged between time-ordered VLPs, providing a robust platform for expanding the antigenic and blockade cross reactivity of future vaccine candidates. Using this approach, we have identified two surface-exposed antibody blockade epitopes that vary over time and were differentially recognized by four of the seven human mAbs. We also identified three antibodies which recognize either overlapping or three unique highly conserved epitopes within the GII.4 VLP. These data continue to support the hypothesis that norovirus long-term protective immune responses are elicited following acute infection, a concept essential for effective vaccine design. We anticipate that a full understanding of the varying antigenic and blockade epitopes of GII.4 NoVs may not only help to predict the emergence of new epidemic strains but simultaneously identify key reformulations in vaccine design that will protect public health against contemporary and emerging epidemic strains in the future.