Dynamic immunodominance hierarchy of neutralizing antibody responses to evolving GII.4 noroviruses

A paradigm of RNA viruses is their ability to mutate and escape from herd immunity. Because antibody responses are a major effector for viral immunity, antigenic sites are usually under strong diversifying pressure. Here, we use norovirus as a model to study mechanisms of antigenic diversification of non-enveloped, fast-evolving RNA viruses. We comprehensively characterize all variable antigenic sites involved in virus neutralization and find that single neutralizing monoclonal antibodies (mAbs) map to multiple antigenic sites of GII.4 norovirus. Interactions of multiple epitopes on the viral capsid surface provide a broad mAb-binding repertoire with a remarkable difference in the mAb-binding profiles and immunodominance hierarchy for two distantly related GII.4 variants. Time-ordered mutant viruses confirm a progressive change of antibody immunodominance along with point mutations during the process of norovirus evolution. Thus, in addition to point mutations, switches in immunodominance that redirect immune responses could facilitate immune escape in RNA viruses.