These data indicate that like influenza, a successful norovirus vaccine regimen will require periodic population sampling to identify future strains for inclusion into the next year's vaccine formulation not unlike the strategy employed by the Influenza Virus Global Surveillance Program. Norovirus population sampling has already begun as monitoring systems for detection of NoV infections have been established in the United States, Europe, and Japan. Identification of GII.4 evolving antigenic epitopes furthers our understanding of norovirus pathogenesis and provides target epitopes that may be useful for surveillance and prediction of new strain emergence. Identification of GII.4 conserved epitopes also informs diagnostic and potential therapeutic reagent development and design. Monoclonal antibodies NVB 37.10, 61.3 and 71.4 all recognize epitopes conserved among the GII.4 strains from 1987 through 2009. NVB 37.10 and 61.3 have enhanced GII VLP recognition, binding not only GII.4 VLPs but also other GII VLPs, but are unable to block VLP-PGM interaction. The high conservation of the NVB 37.10 and 61.3 epitopes suggest that these epitopes are highly resistant to antigenic variation within the GII strains, making these mAbs potentially valuable diagnostic reagents as GII strains cause up to 95% of norovirus outbreaks [27, 72] . The unidentified epitope for NVB 71.4 is clearly different from the epitopes recognized by NVB 37.10 and 61.3 and is conserved throughout the GII.4 strains. NVB 71.4 did not recognize any non-GII.4 VLPs but, importantly, it exhibited blockade activity for the entire panel of timeordered GII.4 VLPs with PGM and Bi-HBGAs. Emphasizing the difference between the two quantitative blockade assays and the qualitative HAI assay, GII.4.2002 HA was not inhibited by NVB 71.4. Noting that blockade assays are not true measurements of neutralization, NVB 71.4 has potential as a therapeutic reagent based on its broad GII.4 blockade potential and the fact that it is by nature a human antibody. Clearly, the effectiveness of NVB 71.4 at preventing or treating illness can only be determined empirically. Although one of the blockade-epitope specific mAbs with lower EC50 values/steeper Hill constants may be more effective at select strain neutralization, the breadth of strains neutralized is likely to be limited for these mAbs. There are a number of viral diseases currently being treated with mAbs including RSV, CMV and enterovirus; however, only the anti-RSV humanized mAb palivizumab has FDA approval for prophylactic use in humans [73, 74] . In outbreak settings or in chronically infected patients, an anti-NoV mAb that could be delivered before symptoms begin and protect from illness could be very useful in care facilities, the military and the cruise industry. Given the acute clinical disease window, it is less likely that therapeutic antibodies will provide relief in those individuals experiencing acute infections, however, therapeutic antibodies may offer opportunities for ameliorating symptomatic disease in chronic infections. The discovery of broadly cross reactive and cross blockade human GII.4 mAbs dictates the need for a new approach to map epitopes. Our current experimental approach was designed to identify GII.4 epitopes that change over time and provide insight into broadly conserved epitope locations. Because the identification of the epitopes recognized by NVB 37.10, 61.3, and 71.4 has important implications for successful vaccine design, new panels of mutated VLPs and other approaches will be needed to characterize these epitopes in the future.