Current progress in development of hepatitis C virus vaccines

Abstract

Despite major advances in the understanding and treatment of hepatitis C, a preventive vaccine remains elusive. The marked genetic diversity and multiple mechanisms of persistence of hepatitis C virus, combined with the relatively poor immune response of the infected host against the virus, are major barriers. The lack of robust and convenient model systems further hampers the effort to develop an effective vaccine. Advances in our understanding of virus-host interactions and protective immunity in hepatitis C virus infection provide an important roadmap to develop potent and broadly directed vaccine candidates targeting both humoral and cellular immune responses. Multiple approaches to generating and testing viral immunogens have met with variable success. Several candidates have advanced to clinical trials based on promising results in chimpanzees. The ultimate path to a successful preventive vaccine requires comprehensive evaluations of all aspects of protective immunity, innovative application of state-of-the-art vaccine technology and properly designed vaccine trials that can affirm definitive endpoints of efficacy.

Figure 1

Natural course of HCV infection and types of protective immunity. Top, the course of acute HCV infection and the induced adaptive immune responses to control HCV infection. During the acute phase of HCV infection, replication of the virus is unchecked and attains high-level viremia within a short period of time. Liver enzymes, such as alanine cell aminotransferase (ALT), become elevated. As the host immune response is activated, either viral clearance occurs or viral level drops and persists at a lower level as the viral set point during the chronic phase, which can be associated with elevated ALT. The classical vaccine strategy of inducing sterilizing immunity is to prevent acute infection and has been highly effective in viral infections that cause acute and severe disease. The mechanism of sterilizing protection mediated by vaccine-transient viremia after exposure to HCV that is below the limit of detection (middle).In contrast, cell-mediated immunity is crucial for viral clearance in the case of recovery or control of viral replication during the chronic phase of infection (bottom). Anti-HCV Ab, HCV-specific antibody.

Figure 2

Targets and mechanisms of vaccine-induced immunity in prevention of HCV infection. Various vaccine candidates targeting different aspects of host immune responses are illustrated. Protein-based vaccine targets B cell immunity and, if produced either in unique form or with potent adjuvant, can cross-prime to the T cell pathway. Viral vectors or DNA plasmids induce predominantly T cell responses. They can also prime B cell immunity if the expressed antigens include HCV envelope proteins. VLPs can also target both B and T cell immune responses. B cell immunity, via neutralizing antibodies, can either neutralize circulating virus—usually in complex with lipoprotein—or virus at the entry step.T cell–mediated immunity can either directly eliminate viral-infected cells via cytocidal mechanisms or produce antiviral cytokines such as IFN-γ. IFN-α and IFN-λ can be produced by activated dendritic or other immune cells to inhibit viral replication. Innate immune cells, such as NK or NKT cells, may also be activated by vaccine to produce antiviral cytokines or exert direct cytotoxic effector function. MHC, major histocompatibility complex; TCR, T cell receptor.

Figure 3

Diagram of steps for vaccine trial design and important parameters to monitor during study. PBMCs, peripheral blood mononuclear cells.