About 70 million people worldwide are chronically infected with the hepatitis C virus (HCV). Possible consequences include hepatitis, cirrhosis and liver cancer, but the disease often remains undetected for long periods of time. Thomas Pietschmann of the TWINCORE in Hannover investigates the virus and works on the development of a vaccine that could prevent HCV infections in the future
Mr. Pietschmann, what makes hepatitis C so dangerous?
That the infection with the hepatitis C virus (HCV) often goes unnoticed. The virus is transmitted over blood, nowadays especially in the drug milieu, when people share needles. It causes a chronic infection that can cause severe liver damage over time.
Why does the infection stay unnoticed?
In the beginning, the symptoms are similar to those of influenza common cold. You feel exhausted, feverish, and cannot necessarily associate it with a liver problem right away, because many diseases cause such symptoms.
And why is the hepatitis C virus particularly successful?
In chronic infections, the virus has years or even decades to replicate in a human. That means the period for transmission is very large. Before the discovery of the virus, medical procedures may have also aided in transmission. For if I do not know the virus, I cannot prevent it from being transmitted via blood or organ donations. But generally spoken the virus is successful because it can replicate in humans over long periods of time. The question is: Why is it not neutralised by the immune system? That is due to biological adaptions of the virus that help it escape the immune system.
How does the virus do that?
The virus is able to disrupt crucial signalling cascades that allow the immune system to alert cells to viral infections. Without them, the cells have problems recognising an infection and the initiation of effective immune responses is no longer possible. This allows the virus to permanently settle and start replication. HCV’s high replication rate is another important factor that contributes to its steady hold on the immune system. The virus generates staggeringly high amounts of offspring, that – similar as in humans – all slightly vary from one another. That leads to a huge range of different viruses and further complicates extinction for the immune system.
The virus is only to be found in humans, entailing a drawback in form of high specialisation. But could that same fact also simplify the extinction of HCV?
That is an important point and lastly an advantage for us, when aiming to control global disease burden by treatment, and, in the future, hopefully also by a vaccine. If the pathogen only appears in humans und all of humanity is vaccinated, it cannot proliferate and goes extinct. This was already achieved in the past, the smallpox are an example. On the other hand, the specialisation of the virus is an obstacle, because new vaccines cannot be tested in humans immediately. Experimental evidence is needed to even identify valid vaccine candidates in the first place. Such experiments can be made in cell culture only to a limited extent, for the immune system cannot be wholly transferred into a petri dish. For this reason, we need animal models that mirror the infection. And here lies the problem: If hepatitis C viruses do not proliferate in animals, we have no animal models to test the efficacy of vaccines.
What is your approach to vaccine development?
We concentrate on three main areas. The first one starts in the clinic, where we cooperate with physicians at Hannover Medical School (MHH) who treat patients with HCV infections. Together we investigate which immune responses are formed by patients. Our question is: Are there people with outstanding immune responses among the thousands of patients that are treated at the MHH? The focus here is on antibodies. We want to understand how exceptional antibody responses form in humans and where they attack the virus. This knowledge of natural immunity forms the base for our second research area where we develop and examine own vaccine candidates. Research on HCV’s specialisation forms our third focus area. We aim to learn why the virus cannot proliferate in other animals, mice for example. Not just to decrypt the biology of the virus but also help us to engineer animal models.
Which methods do you use?
There are different possibilities to develop vaccines. One is the administration of individual pathogen components, i. e. proteins. Another one are viral vectors – that are viruses carrying the proteins of another virus. These are then administered as infectious viruses and trigger an immune response. And then there is vaccination via living viruses that are administered as attenuated variants and induce protective immune responses. We pursue mostly protein-based approaches and ultimately want to manipulate these proteins to be more immunogenic, to induce a broader and hopefully more protective immune response. When we know which proteins are most suitable, we will try to insert them in viral vectors, as viral vectors promote a stronger immune response than an individual protein. This is also a joint project at the HZI: Together with the research group of Luca Cicin-Sain we examine vectors based on the cytomegalovirus as transporter for HCV.
Why is the development of a vaccine so important? Is treating existing infections not enough?
That is connected to the global prevalence of HCV. Over 70 Million people carry the virus – sometimes lifelong – and can transmit it. It is impossible to exterminate the virus with drugs overnight. Secondly, many people do not know they are infected due to the initially very unspecific progress. It would be an enormous effort to diagnose and treat all of them. The third point is the prevalence of the virus in populations that are hard to treat. One example are drug addicts, for whom the best medication is not always easily available or who won’t even go see a doctor. Currently there is a new opioid crisis in the USA, more and more people become addicted to drugs. This causes the prevalence of HCV there to increase rather than decrease. The best way to control an infectious agent is to prevent infection from the beginning. Ideally, we would have a combination of treatment and a vaccine to avoid reinfection. For this must also be considered: Even after drug therapy, it is always possible to be infected again.
Interview: Helen Looney