Which immune response is particularly efficient and can contribute to the development of a new vaccine?
What is this research project about?
Hepatitis C virus (HCV) has chronically infected ca. 71 million people worldwide. These patients are at risk of severe liver disease including hepatocellular carcinoma. The WHO has reported approximately 400.000 HCV-associated deaths for 2015. Novel HCV combination therapies cure more than 95% of treated patients. However, many people are unaware of their infection, and high treatment costs limit access to therapy. In addition, successful therapy does not protect from viral re-infection, which occurs readily in populations with frequent virus exposure (e.g. people who inject drugs). For these reasons HCV transmission remains high and consequently development of a prophylactic HCV vaccine is an unmet medical need. In fact, recent studies suggest that global control of HCV will only be possible with a prophylactic HCV vaccine combined with antiviral treatment.
What’s the current status?
The quality of the cellular immunity has an important influence on the clinical outcome of HCV infection. Moreover, accumulating evidence underpins the key role of broadly neutralizing antibodies (bnAbs) in the control of acute and chronic HCV infection. Notably, 20-30% of exposed individuals naturally clear the infection and immunization with recombinant glycoproteins elicits neutralizing antibodies in animal models. These findings raise hopes that development of a prophylactic HCV vaccine is possible.
The HCV surface proteins E1 and E2 are the major targets for bnAbs and therefore in the focus of vaccine research. However, HCV has evolved a number of evasion mechanisms, which complicate development of E1-E2-directed vaccines: Extensive sugar modifications of E1 and E2, and flexibility of key antibody target sites reduce immunogenicity. Moreover, most antibodies are directed against highly variable viral “decoy” target sites, which readily mutate, rendering these antibodies ineffective.
How do we get there?
A paramount step in this project will be the identification of such “elite” neutralizers from the patients treated in the MHH hepatitis outpatient clinic by performing a large-scale neutralization screening. In order to identify these patients with a particularly efficient immune response, the project uses the hepatitis C cohort of the MHH. This screening will identify elite neutralizers as well as patients with moderate or weak antibody responses. Consequently, it will enable molecular analyses of the determinants that control evolution of powerful antibodies. To this end, we will use single cell-resolved B cell profiling in these different patient groups to investigate differences in the B cell repertoires that correlate with evolution of phenotypically distinct antibody responses. To identify potent HCV-specific bnAbs, we will isolate B cells from elite neutralizers. Subsequently, we will sequence and clone B cell receptor genes. We will measure neutralization potency and will functionally and structurally analyze antibody-antigen complexes for the most powerful antibodies. This work should provide detailed structural information on neutralization epitopes and antigen recognition by potent bnAbs. It will pave the way for the use of novel computational methods for immunogen design using structure-based strategies with the primary goal to optimize immunogenic epitope presentation for enhanced induction of epitope-specific antibodies.