Combination of DNA Prime – Adenovirus Boost Immunization with Entecavir Elicits Sustained Control of Chronic Hepatitis B in the Woodchuck Model

Abstract

A potent therapeutic T-cell vaccine may be an alternative treatment of chronic hepatitis B virus (HBV) infection. Previously, we developed a DNA prime-adenovirus (AdV) boost vaccination protocol that could elicit strong and specific CD8+ T-cell responses to woodchuck hepatitis virus (WHV) core antigen (WHcAg) in mice. In the present study, we first examined whether this new prime-boost immunization could induce WHcAg-specific T-cell responses and effectively control WHV replication in the WHV-transgenic mouse model. Secondly, we evaluated the therapeutic effect of this new vaccination strategy in chronically WHV-infected woodchucks in combination with a potent antiviral treatment. Immunization of WHV-transgenic mice by DNA prime-AdV boost regimen elicited potent and functional WHcAg-specific CD8+ T-cell response that consequently resulted in the reduction of the WHV load below the detection limit in more than 70% of animals. The combination therapy of entecavir (ETV) treatment and DNA prime-AdV boost immunization in chronic WHV carriers resulted in WHsAg- and WHcAg-specific CD4+ and CD8+ T-cell responses, which were not detectable in ETV-only treated controls. Woodchucks receiving the combination therapy showed a prolonged suppression of WHV replication and lower WHsAg levels compared to controls. Moreover, two of four immunized carriers remained WHV negative after the end of ETV treatment and developed anti-WHs antibodies. These results demonstrate that the combined antiviral and vaccination approach efficiently elicited sustained immunological control of chronic hepadnaviral infection in woodchucks and may be a new promising therapeutic strategy in patients.

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

“…This is in line with recent therapeutic vaccination attempts in chronically infected woodchucks, in which antiviral therapy promoted T-cell responses to a DNA prime/adenovirus boost vaccine regimen. 11 Therefore, appropriately adjuvanted vaccines have the potential to effectively activate DCs in chronic HBV infection and stimulate T-cell immunity.…”

“…Based on the results of these trials, therapeutic vaccines in development have expanded to incorporate new adjuvants 10 and multiple components in combination with antiviral therapy. 11 T cell-inducing vaccines rely on the network of professional antigen-presenting cells to take up and present vaccine antigens in a context that is capable of reversing T-cell exhaustion. This job primarily falls on dendritic cells, but whether DCs in chronic HBV patients are phenotypically and functionally equal to DCs from healthy donors has been a longstanding point of debate.…”

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

“…Chronically infected individuals usually exhibit the immune tolerance to targeted antigens. 5 In short, HBV-specific CTL activity has the key role in controlling the outcome of HBV infection because the magnitude of the T-cell response is a critical factor in determining viral control. [6][7][8][9] CD8 þ T cells recognize antigenic peptides presented by MHC I molecules on the surface of APCs or target cells.…”

Novel Woodchuck Hepatitis Virus (WHV) Transgene Mouse Models Show Sex-Dependent WHV Replicative Activity and Development of Spontaneous Immune Responses to WHV Proteins

“…The possibility of breaking immune tolerance to WHcAg in Tg mice allows the testing of different therapeutic vaccines and vaccination regimens. Recently, an immunization protocol including priming with DNA vaccines and boosts with adenoviral vectors was shown to elicit robust and effective humoral and cellular immune responses against WHV in woodchucks (25,38). This protocol was also evaluated in Tg mice and was superior to DNA vaccination alone (A. D. Kosinska, M. Lu, and M.…”