The difference in blockade sensitivity of GII. 4.2006 and GII.4.2009 to NVB 97 provides the first evidence of subtle antigenic divergence between two Minerva variants, each of which caused widespread outbreaks globally [1] . This observation is further supported by Human mAbs NVB 111 and NVB 43.9 reactivity profiles. By single-dilution EIA, NVB 111 specifically reacted to 2006 but minimally with the 2009 variant of Minerva and other tested VLPs (Table 2 and Figure S2 ). Accordingly, NVB 111 required 13-fold more antibody to block GII.4.2009-PGM interaction (EC50 9.953 mg/ml) than it required to block GII.4.2006-PGM interaction (EC50 0.7376 mg/ml) ( Figure 5A and B) (p,0.05). In comparison, NVB 43.9 specifically recognized both the 2006 and 2009 Minerva variants by EIA (Table 2 and Figure S2 ). The interaction of both variants with PGM ligand was efficiently blocked by NVB 43.9 ( Figure 5C (Table 2 and Figure S2 ). Despite broad EIA reactivity, NVB 37.10 Figure 6D ). These three human mAbs indicate the existence of conserved GII.4 epitopes over the past twenty-five years and across three pandemic strains that could serve as targets for broad-based vaccine design. Importantly, NVB 71.4 represents the first potential, broad spectrum immune-therapeutic for any NoV.