Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies

Abstract

Background and Aims HEV infection can lead to chronicity and rapid progression to liver fibrosis and cirrhosis in immunocompromised organ transplant recipients. Robust animal models are urgently needed to study the pathogenesis and test the efficacy of vaccines and antiviral drugs in immunosuppressed settings. Approach and Results Cyclosporin A was used to induce immunosuppression. Rabbits were challenged with genotype 3 or 4 HEV (i.e., the rabbit‐derived HEV3 and human‐derived HEV3 or HEV4). We assessed HEV markers within 13 weeks post inoculation (wpi) and pathological changes by hematoxylin and eosin and Masson staining at 4, 8, or 13 wpi. Chronic HEV infection was successfully established in immunocompromised rabbits. HEV RNA and/or antigens were detected in the liver, kidney, intestine, urine, and cerebrospinal fluid samples. Chronically infected animals exhibited typical characteristics of liver fibrosis development. Intrahepatic transcriptomic analysis indicated activation of both innate and adaptive immunity. Establishment of HEV chronicity likely contributed to the inhibited T‐cell immune response. Ribavirin is effective in clearing HEV infection in immunocompromised rabbits. Most interestingly, vaccination completed before immunosuppression conferred full protection against both HEV3 and HEV4 infections, but vaccination during immunosuppression was only partially protective, and the efficacy did not improve with increased or additional vaccine doses. Conclusions The immunocompromised rabbit model of both chronic HEV3 and HEV4 infection that was established captured the key features of chronic HEV infection in transplant patients, including liver fibrogenesis, and revealed the distinct effectiveness of vaccination administered before or under immunosuppression. This rabbit model is valuable for understanding the pathogenesis of chronic hepatitis E, as well as for evaluating antiviral agents and vaccines.

Characterization of Chronic Hepatitis E Virus Infection in Immunocompetent Rabbits

“…Serum viral RNA of the infected rabbits persisted for a much shorter period of time when compared to fecal virus shedding. This finding is in line with previous studies of pig and rabbit models of chronic HEV infection [12,14,18] as fecal HEV shedding is more stable and persistent than viraemia. The potential mechanism of this phenomenon warrants future investigation.…”

“…Over the past decade, global interest in chronic hepatitis E has increased. Recent studies have developed several interesting immunocompromised animal models that can mimic human chronic HEV infection, including human liver chimeric mice [9][10][11], pigs [12], cynomolgus macaques [13], and rabbits [14]. Chronic HEV infection in immunocompetent animals has been reported in ferrets [15], rhesus macaques [16] and rabbits [17,18].…”

A small animal model of chronic hepatitis E infection using immunocompromised rats

“…Furthermore, xenotransplanting human hepatocytes into mice at a young age is technically challenging. Rabbits and ferrets also shed species-specific cognate HEV variants for long periods, but chronic infection is not consistently observed in all animals [14][15][16][17].…”

“…As HEV-C1 is a newly recognized cause of chronic hepatitis E, susceptibility to ribavirin is a key question that needs to be addressed. We used a dose of 30 mg/kg/day as per previous publications [17,20]. Ribavirin suppressed viral loads at the second week of treatment although rebound was observed at the third week in 2/5 treated animals.…”

Chronic hepatitis E: Advancing research and patient care

“…65,66 Similarly, vaccination with Hecolin in rabbits prior to administration of immunosuppressive medication fully protected them against genotype 3 and 4 HEV infection, whereas only partial protection was achieved when the animals were already receiving immunosuppressants. 67 From a clinical practice perspective, one could argue in favour of preferentially vaccinating patients on the waiting list for organ transplantation.…”