Het ontwikkelen van effectieve strategieën om infecties met het hepatitis E-virus te beperken of te behandelen

The hepatitis E virus (HEV) is responsible for approximately 20 million infections each year. Usually, the infections with HEV result in a self-limited, acute illness. However, HEV infections can lead to acute hepatitis, which may further develop into chronic hepatitis, especially in solid organ transplant recipients. Moreover, pregnant women are particularly at high risk of developing severe complications resulting from acute hepatitis with a fatal outcome in 30% of the cases. HEV is most prevalent in developing countries with inadequate water supply and environmental sanitation. Large hepatitis E epidemics have been reported in Asia, the Middle East, Africa, and Central America. Drugs with proven safety and effectiveness are lacking, as well as large randomized clinical trials. Based on potential efficacy in small-scale studies, ribavirin is the most obvious drug of choice in HEV-infected patients, but has several side effects and may result in occasional treatment failure. Besides drugs, a vaccine based on recombinant viral proteins was developed, but development was stopped due to low/no profitability in developed countries. Currently, China is the only country where a vaccine (named HEV 239) was approved for the prevention of hepatitis E. The WHO, however, has not issued a recommendation for routine use of the HEV 239 vaccine due to lack of evidence. The lab of Prof. Neyts generated a chimeric JEV/HEV vaccine with the aim to prevent infections caused by HEV as well as Japanese encephalitis virus (JEV); both viruses are highly prevalent in Asia. Studies in mice already showed that antibodies against the backbone of this vaccine (i.e. JEV) are generated. Whether antibodies against HEV are generated remains to be determined because assays for HEV are currently lacking. To be able to evaluate the immunogenicity of the chimeric JEV/HEV vaccine, a toolbox will be developed. Particularly for HEV, reference sera need to be generated and an indirect immunofluorescent assay (IIFA) as well as a serum neutralization assay for the detection of anti-HEV antibodies will be developed. Once these assays have been established, we will evaluate the immunogenicity as well as the efficacy of the chimeric JEV/HEV vaccine candidate. To this end, various animal models can be employed: athymic nude rats (T-cell deficient), interferon (IFN) type 1 receptor knockout (Ifnar-/-) mice, IFN type I and type II receptor knockout (AG129) mice, a humanized mouse liver chimera infection model (in collaboration with Philip Meuleman from UGent) and/or a pig model (Wim van der Poel, Wageningen University, The Netherlands). A screening effort in the lab of Prof Neyts using a library of nucleoside analogues from Janssen Pharmaceutica (JP), lead to the identification of potential hits. Some compounds exhibited antiviral activity in the nanomolar range. Together with JP, we will further optimize and characterize (both in vitro and in vivo) these compounds. The efficacy of the compounds can be evaluated using the rat model. However, since rats have high levels of esterase activity in the gastrointestinal tract and serum, resulting in rapid degradation, an alternative model using zebrafish will be established and employed (a zebrafish model was already established for norovirus). Any other compounds, not being nucleoside inhibitors, that may pop-up in future screens in the lab will be eligible for testing in the rat model.