UC Santa Cruz

Diarrheal diseases remain a leading cause of death for young children worldwide. However, the reduction of total child deaths from viral sources of diarrhea may be possible through preventative vaccination. Human astroviruses (HAstVs) are a significant cause of viral diarrhea, with young children and immunocompromised populations most at risk. Some evidence indicates that antibodies induced by childhood infection leads to protection in adulthood, suggesting that vaccination against human astrovirus may be possible, but no vaccine or approved therapeutics currently exist. To develop an effective vaccine, it is important to understand how antibodies target critical regions of the virus. However, few studies have explored what regions of the HAstV capsid are responsible for inducing neutralizing antibodies or how these antibodies neutralize HAstV infection. In this thesis research, I have investigated the vulnerable antigenic regions on the HAstV capsid spike by structurally defining the epitopes of three neutralizing monoclonal antibodies, 3B4, 3H4, and 4B6 using X-Ray crystallography or cryogenic electron microscopy. I have discovered three new neutralizing antibody epitopes, with the epitope of antibody 3H4 being an entirely novel and highly conserved antigenic location near the base of the spike. Additionally, all three of these antibodies block virus attachment to cells, and I show using biolayer interferometry that they either fully or partially block HAstV spike binding to the newly discovered HAstV receptor human neonatal Fc receptor (FcRn). Finally, I establish a proof-of-concept system to test a spike-based protein vaccine using the murine astrovirus (MuAstV) infection model in mice. I find that recombinant MuAstV spike folds into a native dimeric structure, and its use as a vaccine immunogen induces anti-spike IgG antibodies in mice, paving the way for future MuAstV challenge and vaccine protection studies. Taken together, my thesis research lays a foundation for HAstV vaccine design and monoclonal antibody therapies to prevent and treat HAstV infection and disease.