title: Chimpanzees as an animal model for human norovirus infection and vaccine development.
abstract: Noroviruses are global agents of acute gastroenteritis, but the development of control strategies has been hampered by the absence of a robust animal model. Studies in chimpanzees have played a key role in the characterization of several fastidious hepatitis viruses, and we investigated the feasibility of such studies for the noroviruses. Seronegative chimpanzees inoculated i.v. with the human norovirus strain Norwalk virus (NV) did not show clinical signs of gastroenteritis, but the onset and duration of virus shedding in stool and serum antibody responses were similar to that observed in humans. NV RNA was detected in intestinal and liver biopsies concurrent with the detection of viral shedding in stool, and NV antigen expression was observed in cells of the small intestinal lamina propria. Two infected chimpanzees rechallenged 4, 10, or 24 mo later with NV were resistant to reinfection, and the presence of NV-specific serum antibodies correlated with protection. We evaluated the immunogenicity and efficacy of virus-like particles (VLPs) derived from NV (genogroup I, GI) and MD145 (genogroup II, GII) noroviruses as vaccines. Chimpanzees vaccinated intramuscularly with GI VLPs were protected from NV infection when challenged 2 and 18 mo after vaccination, whereas chimpanzees that received GII VLPs vaccine or a placebo were not. This study establishes the chimpanzee as a viable animal model for the study of norovirus replication and immunity, and shows that NV VLP vaccines could induce protective homologous immunity even after extended periods of time.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. bokk@niaid.nih.gov
authors.forename: Karin
authors.initials: K
authors.lastname: Bok
authors.forename: Gabriel I
authors.initials: GI
authors.lastname: Parra
authors.forename: Tanaji
authors.initials: T
authors.lastname: Mitra
authors.forename: Eugenio
authors.initials: E
authors.lastname: Abente
authors.forename: Charlene K
authors.initials: CK
authors.lastname: Shaver
authors.forename: Denali
authors.initials: D
authors.lastname: Boon
authors.forename: Ronald
authors.initials: R
authors.lastname: Engle
authors.forename: Claro
authors.initials: C
authors.lastname: Yu
authors.forename: Albert Z
authors.initials: AZ
authors.lastname: Kapikian
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Sosnovtsev
authors.forename: Robert H
authors.initials: RH
authors.lastname: Purcell
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Green
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001483:Base Sequence; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005759:Gastroenteritis / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007421:Intestine, Small / Q000821:virology; D008969:Molecular Sequence Data; D009092:Mucous Membrane / Q000821:virology; D009663:Norwalk virus / Q000235:genetics*; D002679:Pan troglodytes; D017422:Sequence Analysis, DNA; D013997:Time Factors; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D058425:Vaccines, Virus-Like Particle; D014765:Viral Vaccines