Prime/Boost Immunization with DNA and Adenoviral Vectors Protects from Hepatitis D Virus (HDV) Infection after Simultaneous Infection with HDV and Woodchuck Hepatitis Virus

Abstract

Hepatitis D virus (HDV) superinfection of hepatitis B virus (HBV) carriers causes severe liver disease and a high rate of chronicity. Therefore, a vaccine protecting HBV carriers from HDV superinfection is needed. To protect from HDV infection an induction of virus-specific T cells is required, as antibodies to the two proteins of HDV, p24 and p27, do not neutralize the HBV-derived envelope of HDV. In mice, HDV-specific CD8 ؉ and CD4 ؉ T cell responses were induced by a DNA vaccine expressing HDV p27. In subsequent experiments, seven naive woodchucks were immunized with a DNA prime and adenoviral boost regimen prior to simultaneous woodchuck hepatitis virus (WHV) and HDV infection. Five of seven HDV-immunized woodchucks were protected against HDV infection, while acute self-limiting WHV infection occurred as expected. The two animals with the breakthrough had a shorter HDV viremia than the unvaccinated controls. The DNA prime and adenoviral vector boost vaccination protected woodchucks against HDV infection in the setting of simultaneous infection with WHV and HDV. In future experiments, the efficacy of this protocol to protect from HDV infection in the setting of HDV superinfection will need to be proven. H epatitis delta virus (HDV) superinfection of hepatitis B virus (HBV) carriers causes the most severe hepatitis in humans.Nearly all patients develop chronic HDV infection that has a high probability of progressing to liver cirrhosis and hepatocellular carcinoma (1, 2). Worldwide, approximately 15 million patients are affected with HDV. About 8% of HBV surface antigen (HBsAg)-positive patients in several European countries have tested positive for antibodies against HDV (2). Therapeutic options for HBV/HDV carriers are limited. Only in about 25% of the patients does alpha interferon therapy result in sustained viral clearance (3).HBV carriers are at risk of being superinfected with HDV. Therefore, a vaccine protecting HBV carriers from HDV superinfection would be eligible. A main obstacle for the design of a vaccine against HDV infection is the fact that antibodies to the two proteins of HDV, p24 and p27, do not neutralize the HDV particle. The HDV protein/RNA complex is covered by the envelope protein of HBV (HBsAg). Therefore, classical vaccines which induce neutralizing antibodies cannot be expected to prevent HDV infection.Immunizations with nucleoproteins of, e.g., influenza A virus-, HBV-, or woodchuck hepatitis virus (WHV) induced virus-specific T cells and were able to suppress replication, e.g., by cytokine secretion. In a second step, these virus-specific T cells are able to eliminate infected cells by their cytolytic activity and thus prevent the spread of the virus (4-7). T cell vaccines may not provide sterile immunity, because they do not induce neutralizing antibodies. However, T cell vaccines may stop infection via the cellular immune response at a very early phase of infection. Most conventional vaccines for humans induce sufficient amounts of neutralizing antibodies which prevent infection. ...

Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options

“…In vitro results were promising as stimulation of CD8 T cells with HDV peptides led to an increase on IFN gamma production and cytotoxic activity (206). However, in woodchucks, vaccination (either by HDV proteins, DNA or recombinant viruses) was only effective in preventing HDV infection of naïve animals but not in WHV chronic carriers and, although the course of infection was modified, its utility is still to be proven (207,208).…”

Amino Acid Substitutions within HLA-B*27-Restricted T Cell Epitopes Prevent Recognition by Hepatitis Delta Virus-Specific CD8+T Cells

“…These T cells prevented the development of L-HDAg-expressing tumors in 80 to 100% of immunized mice (9). Moreover, a DNA prime and adenoviral vector boost vaccination with L-HDAg protected woodchucks from HDV in the setting of simultaneous infection with woodchuck hepatitis virus (WHV) and HDV (10). Nisini et al demonstrated a polyspecific but weak CD4 T cell response to HDAg in patients that was related to the resolution of HDV-induced disease activity (11).…”

Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen

“…When co-infected with the Woodchuck Hepatitis Virus (WHV), a relative of HBV within the genus orthohepadnaviruses , the replicating HDV RNP can be packaged into the WHV envelope and secreted into the serum, where it infects neighboring hepatocytes with much higher efficiency than the initial HDV. Although this model is suitable to address some specific questions, e.g., related to the development of HDAg-specific therapeutic vaccines [ 59 ], it relies on WHV and not HBV. One major difference between both viruses is that the WHV envelope proteins probably recognize a receptor different from hNTCP and therefore the model cannot be applied to study the natural infection/co-infection of HBV and HDV.…”