Up to 170 million people worldwide are chronically infected with Hepatitis C Virus (HCV), with many at significant risk for cirrhosis, liver failure and hepatocellular carcinoma. The World Health Organization estimates an annual increase in the global burden by 2 million new infections. Efforts at vaccine development have yet to succeed despite two decades of work. A key step towards t his goal is to identify and exploit relevant mechanisms of immune protection. The challenge is to overcome the huge diversity of the virus, and its potential for escape from host immune responses. There is an increasing body of evidence that supports the importance of virus-neutralizing (Vn) antibodies, and the ability of B cell responses to modify the course of infection leading to protective immunity. The challenge for vaccine development is defining conserved epitopes that i) are capable of eliciting protective antibodies in this highly diverse virus and ii) are resistant to development of escape mutants. Such an approach involves refocusing the immune response from the immunodominant variable regions from which the virus can escape to the conserved neutralizing domains of the virus to achieve protective immunity. This embodies the fundamental principles of structural vaccinology, i.e., understand the nature of principal neutralizing determinants at the atomic level and refocus the immune response.
The ultimate goal of structural vaccinology is to control antigenicity at the atomic level.
For site-specific vaccine design strategies to succeed, it is critical to choose an appropriate antigenic site as the target (see Figure 1). Antigenic sites that comprise multiple overlapping epitopes recognized by multiple antibodies (“supersites”) appear to be the most suitable targets. IBBR researchers are working closely with Stanford University in the identification, molecular characterization, and stabilization of antigenic domains on the E2 envelope glycoprotein of HCV. This supersite, which was defined by a panel of human monoclonal antibodies (HMAbs) isolated using yeast display technology, consists of multiple overlapping epitopes that elicit diverse high potency neutralizing antibodies. In particular, anti-domain D HMAbs are broadly neutralizing against virtually all HCV genotypes and subtypes (see Figure 2). Moreover, in an assay that mimics the evolution of HCV antigenic determinants under immune pressure in humans, HCV escape was not observed with anti-domain D HMAbs. Therefore, the domain D supersite, in addition other HCV E2 antigenic sites, represent an excellent candidate for structure-guided vaccine design aimed at augmenting protective immune responses to this highly diverse virus.