Symmetry-breaking antibody binding reveals extensive capsid malleability in pandemic human norovirus.

Virus capsids are metastable assemblies with an exquisite balance between stability and flexibility, obligatory for entry, infectivity, and immune escape. Yet, the extent to which human viruses exploit capsid plasticity and how that consequently shapes antigenic landscapes remains poorly understood. Human noroviruses (HuNoVs) are the leading cause of acute viral gastroenteritis worldwide1. GII.4 HuNoVs have been evolving epochally, driving most global pandemics, and since 2012, GII.4 Sydney has been the dominant variant. The major capsid protein VP1 is central to infectivity and immune recognition, and VP1-based virus-like particles (VLPs) are considered promising vaccine candidates. Yet, how the icosahedral HuNoV capsid responds to antibody pressure at the atomic level is still unclear. Here, we present the first atomic structure of GII.4 Sydney capsid determined by cryo-EM, revealing the structural features that likely contribute to its sustained dominance. Using focused refinement, we uncovered the remarkable capsid plasticity in response to symmetry-breaking binding of neutralizing and non-neutralizing antibodies. VP1 adopts 11 distinct conformational modalities to accommodate asymmetric antibody binding, and antibody-disrupted VLPs reassemble into smaller particles with five additional VP1 states. This previously unrecognized extent of conformational adaptability provides key insights for designing next-generation VLP- or mRNA-based vaccines targeting HuNoV infections.