Rabbit as a Novel Animal Model for Hepatitis E Virus Infection and Vaccine Evaluation

Abstract

BackgroundThe identification of hepatitis E virus (HEV) from rabbits motivated us to assess the possibility of using rabbits as a non-human primate animal model for HEV infection and vaccine evaluation.Methodology/Principal FindingsFirst, 75 rabbits were inoculated with seven strains of genotypes 1, 3, 4, and rabbit HEV, to determine the appropriate strain, administrative route and viral dosage. Second, 15 rabbits were randomly divided into three groups and vaccinated with 0 µg (placebo), 10 µg and 20 µg of HEV candidate vaccine, HEV p179, respectively. After three doses of the vaccination, the rabbits were challenged with 3.3×105 genome equivalents of genotype 4 HEV strain H4-NJ703. The strain of genotype 1 HEV was not found to be infectious for rabbits. However, approximately 80% of the animals were infected by two rabbit HEV strains. All rabbits inoculated with a genotype 3 strain were seroconverted but did not show viremia or fecal viral shedding. Although two genotype 4 strains, H4-NJ153 and H4-NJ112, only resulted in part of rabbits infected, another strain of genotype 4, H4-NJ703, had an infection rate of 100% (five out of five) when administrated intravenously. However, only two out of fifteen rabbits showed virus excretion and seroconversion when inoculated orally with H4-NJ703 of three different dosages. In the vaccine evaluation study, rabbits vaccinated with 20 µg of the HEV p179 produced anti-HEV with titers of 1∶104–1∶105 and were completely protected from infection. Rabbits vaccinated with 10 µg produced anti-HEV with titers of 1∶103–1∶104 and were protected from hepatitis, but two out of the five rabbits showed virus shedding.Conclusions/SignificanceRabbits may be served as an alternative to the non-human primate models for HEV infection and vaccine evaluation when certain virus strains, appropriate viral dosages, and the intravenous route of inoculation are selected.

Hepatitis E vaccine immunization for rabbits to prevent animal HEV infection and zoonotic transmission

“…Therefore, we selected 6 × 10 4 copies/ml as the low viral load and 6 × 10 6 copies/ml as the high viral load. Moreover, an intravenous challenge was performed in this study, which is more efficient than fecal-oral route [60,61] in natural environment and could ensure all rabbits infected. Thus, if the vaccine could protect rabbits against intravenous challenge with the high viral load of 6 × 10 6 copies/ml, it could also protect rabbits against HEV infection by fecal-oral route in field conditions.…”

Zoonotic Hepatitis E Virus: Classification, Animal Reservoirs and Transmission Routes

“…Infection of SPF rabbits with rabbit HEV induces virus shedding in faeces, viremia and the development of hepatitis, characterised by histopathological changes and an increase in the level of ALT in the serum [95,96,97]. In addition, chronic hepatitis, characterised by liver inflammation and some degree of fibrosis, was observed in rabbits experimentally infected with rabbit HEV [95].…”

Host Immune Status and Response to Hepatitis E Virus Infection

“…Rabbits are susceptible to infection with at least some strains of HEV-3 and HEV-4 but appear to be resistant to infection with HEV-1 (211,212). Conversely, rabbit HEV strains can infect pigs and macaques (213,214), and they can replicate in two human cancer cell lines (96), suggesting the ability to adapt to other mammalian hosts.…”