Abstract
Noroviruses are a leading cause of acute gastroenteritis worldwide, yet no licensed vaccines or antivirals are available. A major barrier to broadly protective vaccine development is the extensive genetic and antigenic diversity of these viruses, leading to immune escape. However, the structural mechanisms underlying this immune escape remain incompletely defined. Here, we analyze a panel of monoclonal antibodies generated against a pandemic GII.4 variant to define the molecular determinants of neutralizing immunity. Guided by immunogenetic features and cross-reactivity patterns spanning four decades of viral evolution, we resolved the atomic structures of two neutralizing antibodies targeting the principal immunodominant antigenic sites, A and G. We show that the spatial positioning of antigenic site G shapes neutralizing responses and that coordinated substitutions within these epitopes drove the rapid antigenic transitions observed between 2004 and 2012.Together, these findings establish a structural framework for GII.4 antigenic evolution and inform rational vaccine design.