Up to 170 million people worldwide are infected with hepatitis C virus (HCV), a major cause of liver cirrhosis, liver failure and hepatocellular carcinoma (HCC). HCC is the second leading case of cancer death world-wide. The World Health Organization estimates an increase in the global burden by 2 million new infections per year, mainly due to injection drug use (IDU). Infection is increasing in young adults in the U.S. because of IDU. For patients, the development of many promising HCV-specific direct acting antivirals (DAA) has improved treatment and disease outcome. However, the high costs of DAA limit their access to patients with low income and in countries with limited resources. In addition, health care workers with occupational risk for blood-borne pathogens and injection drug users (IDUs) will remain at risk for repeated exposure to HCV, even after successful treatment. Finally, recent clinical evidence suggests that treatment-induced cure in patients with established cirrhosis does not eliminate the risk of HCC. Taken together, there is a significant need for an effective preventive HCV vaccine to be developed.

A first step in a “rational vaccine design” approach for HCV is to identify relevant mechanisms of immune protection. Multiple lines of evidence suggest that CD4+ and CD8+ T cell responses are needed to control acute infection but are insufficient for preventing long-term persistence. At the same time, cumulative evidence supports the importance of virus neutralizing antibodies to protect against HCV infection and to facilitate clearance. A significant challenge for a B cell based HCV vaccine is defining conserved epitopes that are capable of eliciting protective antibodies unassociated with viral escape. While the hypervariable region 1 in the HCV E2 glycoprotein, HVR1, is an immunodominant region associated with neutralization, viral escape occurs rapidly and without compromising viral fitness. Substantial efforts have shown that the majority of antibodies with broad neutralizing activities to diverse HCV isolates recognize conformational epitopes in the HCV E2 glycoprotein. However, only some of these conserved epitopes are not associated with viral escape.

Current efforts at B cell-based vaccine development have focused on the preservation of native HCV E1E2 tertiary structures to induce broadly reactive neutralizing antibodies, but without regard to the induction of these antibodies associated with viral escape or non-neutralizing antibodies. While these approaches are promising, improvements leading to the induction of broadly neutralizing antibodies not associated with viral escape are necessary. This will require a greater understanding of (i) the specificities of protective B cell responses; (ii) the role of immunologic decoys and the potential of interfering antibodies, (iii) the molecular locations of these domains on E1E2 and (iv) on how to modulate the immune responses to these regions.

In this Research Topic, we welcome the submission of Reviews, Mini-Reviews and Perspective articles on the status and challenges to be considered in the development of an effective preventative HCV vaccine. We welcome the submission of manuscripts covering, but not limited to, the following topics:

1. Perspectives on a HCV vaccine.
2. Mapping determinants of Heptatitis C virus neutralization and viral escape.
3. Defining breadth of protection within a HCV genotype.
4. Role of HCV envelope glycoprotein E1 in viral entry and fusion.
5. Role of HCV HVR1 in immune escape and shielding.
6. Apolipoproteins and viral evasion from neutralizing antibodies.
7. Glycan shielding and modulation of neutralizing antibodies.
8. Structural stability and instability in regions of HCV envelope glycoproteins.
9. Importance of extrahepatic sites of HCV infection.
10. Animal models of HCV infection.
11. Induction of B and T cell responses with inactivated infectious cell-cultured HCV.

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