PROJECT SUMMARY Noroviruses are a top cause of acute gastroenteritis globally, and no approved norovirus vaccine exists. The norovirus capsid protein plays key roles in virus attachment and entry into host cells and is the target of neutralizing antibodies. Recent genomics and serological studies predict the presence of a new antigenic site, named antigenic site G, and suggest that it became immunodominant during the emergence of the most recent GII.4 norovirus variant outbreak, revealing a novel mechanism for virus evolution immune escape. However, the molecular interactions of neutralizing antibodies targeting this immunodominant site on the norovirus capsid have not been described. Our goal is to define the epitopes that are recognized by neutralizing monoclonal antibodies targeting the immunodominant antigenic site G on the norovirus capsid and to directly visualize and map antibody immunodominance in serum antibodies targeting past and current norovirus variants. Using an integrated structural and biophysical approach, we will pursue two specific aims to (1) Define the epitopes of neutralizing monoclonal antibodies targeting the norovirus capsid antigenic site G and (2) Directly visualize the chronological shift in antibody immunodominance towards antigenic site G. Results obtained by this work will provide a molecular roadmap for the development of novel norovirus vaccine immunogens that broadly protect against norovirus infection and disease.

PROJECT NARRATIVE Noroviruses are a top cause of gastroenteritis worldwide. This proposal seeks to understand at the molecular level how antibodies bind to the norovirus capsid and block infectivity, and how virus evolution affects these interactions. These findings will be important for understanding key vulnerabilities of the virus and developing a vaccine to prevent norovirus disease.