Designing an HCV vaccine: a unique convergence of prevention and therapy?

Abstract

Direct acting antivirals can cure chronic hepatitis C virus (HCV) infection but whether they will reduce global liver disease burden is uncertain. Most chronic infections are undiagnosed and transmission has increased in recent years. The first vaccine trial to reduce transmission is now underway in humans at risk for HCV infection. It will test the novel hypothesis that T cell-mediated immunity alone can prevent persistent HCV infection. Another vaccine that elicits neutralizing antibodies is at an advanced stage of development. Attention is turning to the understudied question of whether DAA cure of chronic infection restores HCV immunity. If not, it will be important to determine if preventive vaccines can also act therapeutically to reverse immune dysfunction and protect from re-infection.

Hepatitis C Virus Escape Studies of Human Antibody AR3A Reveal a High Barrier to Resistance and Novel Insights on Viral Antibody Evasion Mechanisms

“…Despite the improvements made in HCV therapy by the advent of DAAs, a prophylactic vaccine remains fundamental to HCV eradication. The high variability among HCV genotypes and the ability of the virus to evade the immune system have so far impeded the development of a pangenotypically protective vaccine (5,(43)(44)(45). The NAb AR3A showed broad neutralization activity across HCV genotypes (14,21,23,46).…”

“…The availability of interferon-free direct-acting antiviral (DAA) therapies offers cure rates of Ͼ95% (2, 3), but the high cost of treatment limits their use, and treatment does not protect against reinfection. Moreover, it is estimated that at least 80% of all HCV infections are undiagnosed (4)(5)(6). Thus, a vaccine is needed to globally eradicate this pervasive human pathogen (7).…”

Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model

“…An IFN‐free regimen of DAAs can achieve sustained virologic response in most HCV‐infected subjects . Considering that persistent antigenic stimulation drives T‐cell exhaustion, DAA cure has the potential to reverse defects and restore protective antiviral functions . However, recovery of T‐cell immunity after antiviral therapy and protection from reinfection are the critical unknowns for translational research in the post‐DAA era.…”

Removal of the C6 vaccinia virus interferon-β inhibitor in the hepatitis C vaccine candidate MVA-HCV elicited in mice high immunogenicity in spite of reduced host gene expression

“…Current efforts in HCV vaccine development are aimed to induce strong T cell and humoral immune responses that are able to target the most conserved viral antigens without producing liver immunopathology. It has been reported the importance of HCV-specific CD4 + and CD8 + T cell responses in clearance of primary infection and reinfection (9–11). Furthermore, recent studies have also proved the key role of antibody response to E1 and E2 HCV glycoproteins in the resolution of HCV infection (reviews in (11, 12).…”

“…It has been reported the importance of HCV-specific CD4 + and CD8 + T cell responses in clearance of primary infection and reinfection (9–11). Furthermore, recent studies have also proved the key role of antibody response to E1 and E2 HCV glycoproteins in the resolution of HCV infection (reviews in (11, 12). To date, several vaccine candidates against HCV have been tested with different rate of success (13).…”