Epitope A, which likely includes varying amino acid residues 294, 296-298 and 368 and 372 and potentially other undefined nearby residues, has been mapped as a blockade epitope in both GII Figure 9A ). At this time it is unclear how many and which amino acids in Epitope A are needed to mediate an escape mutant phenotype that is completely resistant to GII.4.2006 antibody blockade. However, it is clear that Epitope A varies, and that the site is conserved as a major target for blockade antibody response between 1987 and 2009. Although correlative, comparisons of Epitope A variation along with residues that are proximal to those that appear to be evolving over time suggest that changes at positions 292, 293, 294, 295, 296, 297, 298, 300, 365, 367, 368 and 372 might contribute to an escape phenotype, with residues 294, 296, 297, 298, 300, 368 and 372 playing direct roles in this variation ( Figure 9 ). However, the minor replacements at other positions are likely essential for remodeling the local structural neighborhood such that more profound changes can be tolerated. Supporting the sensitivity of epitopes to the local environment, mAbs that recognized Epitope A differentiated between GII.4.2006 VLPs and GII.4.2006 P dimers. P protein (P dimer) is a dimeric, truncated form of the major capsid protein composed of residues 214-539 [62] . P-dimers have been widely used to determine the crystallographic structure of NoV-HBGA interactions and are considered accurate reflections of the VLP surface topology [16, 21, 63] . P -particles can assemble as higher ordered structures composed of varying copies of the P dimer [46, 64] . These subviral particles are reported to have similar characteristics to VLPs [62, [65] [66] [67] and have been proposed as a candidate vaccine platforms [68] . To our knowledge, this is the first immunologic characterization of P-dimers vs. VLPs using monoclonal antibodies derived from human infections. Here, P-dimers derived from GII.4.2006 lost binding of mAbs NVB 111 and 43.9, the mAbs that recognize Epitope A in GII. 4.2006 . P dimer binding to the Epitope D binding mAb NVB 97 and the broadly cross-blockade mAb NVB 71.4 were retained. Recently, P-particle vaccines were shown to be less robust at inducing strong blockade responses, as compared with intact VLP [69] , perhaps because of the loss of blockade Epitope A in this higher ordered structure. While speculative, it is recognized that virions ''breathe'' suggesting that the possibility that P-dimers and P-particles may become ''locked'' in a slightly less immunologically reactive state that affects some but not all blockade epitopes on the virion surface [70, 71] . These data absolutely underscore the critical importance of determining the structures of several of these human mAbs with their appropriate GII.4 VLP epitopes by either cryoEM or crystallography, for informing targeted mutagenesis to identify the role of key residues in regulating antigenicity and antibody escape.