Human astrovirus is an important cause of viral
gastroenteritis worldwide. Young children, the elderly, and the immunocompromised are especially at risk for contracting severe disease. However, no
vaccines exist to combat human astrovirus
infection. Evidence points to the importance of
antibodies in protecting healthy adults from
reinfection. To develop an effective
subunit vaccine that broadly protects against diverse astrovirus serotypes, we must understand how
neutralizing antibodies target the capsid surface at the molecular level. Here, we report the structures of the human astrovirus capsid spike domain bound to two neutralizing
monoclonal antibodies. These
antibodies bind two distinct conformational
epitopes on the spike surface. We add to existing evidence that the human astrovirus capsid spike contains a receptor-binding domain and demonstrate that both
antibodies neutralize human astrovirus by blocking virus attachment to host cells. We identify patches of conserved
amino acids which overlap or border the antibody
epitopes and may constitute a receptor-binding site. Our findings provide a basis for developing
therapies to prevent and treat human astrovirus
gastroenteritis. IMPORTANCE Human astroviruses infect nearly every person in the world during childhood and cause
diarrhea,
vomiting, and
fever. Despite the prevalence of this virus, little is known about how
antibodies block astrovirus
infection. Here, we determined the crystal structures of the astrovirus
capsid protein in complex with two virus-
neutralizing antibodies. We show that the
antibodies bind to two distinct sites on the capsid spike domain, however, both
antibodies block virus attachment to human cells. Importantly, our findings support the use of the human astrovirus capsid spike as an
antigen in a subunit-based
vaccine to prevent astrovirus disease.