Better fight against hepatitis E

Infections with the hepatitis E virus often go unnoticed because they cause no symptoms. However, in patients with weakened immune system or existing liver damage and also in pregnant women, the virus can cause severe liver inflammation, which can be fatal. Despite existing therapeutic approaches, there are currently no authorised specific treatment options. Researchers at TWINCORE, Centre for Experimental and Clinical Infection Research in Hannover, and the University of Lübeck have now identified neutralising antibodies that could be used therapeutically to prevent severe courses. They have now published their results in the journal Nature Communications.

The World Health Organization (WHO) estimates that around 20 million people worldwide are infected with HEV every year. Most cases are asymptomatic, but around 3.3 million develop symptomatic hepatitis that can lead to severe chronic inflammation of the liver, including fibrosis or cirrhosis. 44,000 people died as a result in 2015. In Germany, an estimated 400,000 people are infected each year, with some risk groups such as organ transplant recipients or people with liver damage at increased risk of a severe course of the disease.

”In our search for new therapeutic options, we examined which antibodies against the hepatitis E virus are formed in people who have survived the infection,“ says Dr Patrick Behrendt, Head of the Clinical Junior Research Group “Translational Virology” at TWINCORE and Senior Physician at the Department of Gastroenterology at the Hannover Medical School. To do this, they isolated so-called memory B cells from the blood of the cured patients. These are immune cells that produce antibodies. “During the more detailed characterisation, we initially found that many of the antibodies were directed against the HEV capsid.” This protein is a structural component of the virus that encloses its genetic information in infectious particles. However, it is also present as a soluble protein freely circulating in the blood of patients. “In this way, HEV directs the immune response away from the infectious virus particles, thus escaping the immune response,” says Behrendt.

This soluble capsid protein differs from the protein embedded in infectious viral particles due to a certain modification that can potentially be used for new therapeutic approaches. “We then focused on the antibodies that specifically recognize infectious particles,” says Dr. Katja Dinkelborg, a physician and researcher in Behrendt’s group and one of the first authors of the publication.

Researchers at the University of Lübeck were able to decipher the exact structure and mode of action of these antibodies. The team led by Prof. Thomas Krey from the Institute of Biochemistry investigated the antibodies in more detail and was able to show how they bind and neutralise the virus. ”Antibodies targeting infectious particles bind differently than antibodies that recognise soluble capsid protein,“ says Dr. George Ssebyatika, the first author from Krey's research group. "Using high-resolution X-ray structure analyses, we were able to visualise the precise binding of the antibodies to the virus for the first time." Thomas Krey adds: "Our findings show that specifically developed antibodies are a promising approach to better treat hepatitis E infections."

Behrendt and Krey now want to further develop the neutralising antibodies with an antiviral effect in order to optimise them for clinical use. To this end, they are receiving further funding from the German Centre for Infection Research (DZIF), which has also supported the previous work. The study was also funded by the Lower Saxony Cluster of Excellence RESIST and the Volkswagen Foundation.