Pathobiology of hepatitis E: lessons learned from primate models.

Like the other hepatitis viruses, hepatitis E virus (HEV) has been difficult to study because of limitations in cell culture systems and small animal models. Much of what we know has come from epidemiological studies in developing countries and, more recently, in industrialized countries. However, the epidemiology is very different in these two settings: hepatitis E in developing countries is epidemic as well as sporadic, principally water-borne, most likely to cause disease in older children and young adults and relatively severe, especially in pregnant women; in industrialized countries the disease is sporadic, principally food-borne, most common in the elderly and probably associated with mostly inapparent infections. These differences are believed to be genotypically determined. To examine the biological parameters of hepatitis E, we have studied HEV infections in nonhuman primates, which are surrogates of man. Infections with HEV genotypes 1-3 were compared in rhesus and cynomolgus macaques and chimpanzees. In general, the biological characteristics of the different HEV genotypes mirrored their epidemiological characteristics.

Chimpanzees as an animal model for human norovirus infection and vaccine development.

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.