Despite improved treatment methods, hepatitis C virus infection still leads to approximately 400,000 deaths worldwide each year. The development of a vaccine is urgently needed, but efforts have so far failed due to the virus’s genetic diversity and high mutation rate. A team led by scientists from the University Hospital of Cologne and the German Center for Infection Research (DZIF)
investigated the immune response in greater detail and was able to isolate broad-spectrum antibodies from a group of patients that, as “elite neutralizers,” can attack an extremely large number of virus variants simultaneously. Now, scientists have been able to identify the specific properties of these antibodies. The discovery could be an important step toward a vaccine.
The hepatitis C virus (HCV) is a genetically highly variable virus that mutates significantly. Therefore, an effective vaccine must elicit broadly neutralizing antibodies that neutralize not just a single HCV strain, but as many genotypes as possible that are prevalent worldwide. To date, all attempts to develop a vaccine have failed. A better understanding of the antibody response to HCV is needed to give new impetus to vaccine development. Thus, the initial research question was: what specific properties of antibodies against HCV lead to broad neutralization of the virus?
Lead authors Timm Weber and Julian Potthoff from the University Hospital of Cologne explained that “For this work, we drew on our experience from our HIV research. We studied a large group of patients in our laboratory to identify so-called ‘elite neutralizers.’ These are individuals whose antibodies can neutralize various HCV genotypes.” To carry out this work, the scientists collaborated at the German Center for Infection Research with the team of Prof. Thomas Pichmann and Prof. Thomas Krey, two experts in the field of HCV research. “We have been working in Hanover for a long time on methods to measure antibody-mediated neutralization of globally circulating HCV strains in the laboratory under conditions as close as possible to physiological ones,” says Pichman. In a cohort of 435 patients with hepatitis C, up to five percent exhibited exceptional HCV neutralizing activity. The team isolated more than 300 antibodies from the blood of four of these elite neutralizers, including some that neutralized the hepatitis C virus with particular effectiveness. Using structural and mutational analyses, the researchers characterized these unique antibodies and were able, for example, to identify which amino acid sequences influence neutralizing ability. A laboratory at the renowned California Institute of Technology in Pasadena conducted structural biological analysis and identified exactly where the antibodies bind to the virus.
After characterizing the antibodies, the scientists went even further. Computer scientists working with Professor Nico Pfeiffer in Tübingen developed a computer program that was fed the amino acid sequences of highly and poorly neutralizing antibodies against HCV, and was then able to predict whether an antibody could effectively neutralize the virus. This machine learning method allowed researchers to artificially assemble a synthetic, broadly neutralizing antibody against HCV. “This artificially assembled antibody against hepatitis C could be an important basis for vaccine development,” said study leader Professor Florian Klein, a researcher at the German Center for Infection Research at Cologne University Hospital. As a next step, the scientists plan to test the most potent antibodies in animal models. The German Center for Infection Research, coordinated by Thomas Pichmann and Thomas Kre, is also already investigating new vaccination strategies against HCV; new findings are already being implemented for this purpose.
