HDV Is a Poor Immunogenic Protein

In several studies immunization of mice or woodchucks with DNA vaccines failed to induce a detectable humoral immune response. In the study of Mauch et al. none of more than 120 mice of different haplotypes that were immunized with plasmids expressing either S- or L-HDAg developed a detectable anti-HDAg response. Failure to detect anti-HDAg was not due to lack of HDV specific T-cell help, as a CD4+ Th-cell immune response was induced by all plasmids. Seizer et al. demonstrated that immunization with low amounts of HDV protein in mice induced no antibody response, which could be significantly enhanced by combination with heterologous antigens such as HBsAg or HBcAg (Seizer et al. 2005). Only DNA constructs expressing another antigen (e.g., GFP) beside HDAg were able to elicit a strong antibody response. The authors demonstrated that the help of specific CD4+ T-cells induced by heterologous proteins was necessary for the induction of an anti-HDAg response. In the woodchuck model vaccination with DNA or vaccinia virus-expressing HDAg was also not able to mount a measurable anti-HDV response in six and four woodchucks, respectively (see Sects. 4.3 and 4.4) (Eckart et al. 1993; Fiedler et al. 2001; Karayiannis et al. 1993a). These data are in contrast with results obtained after intramuscular immunization of mice with a plasmid containing replication competent head-to-tail cDNA dimers of HDV that induced a humoral immune response (Polo et al. 1995). Also Huang et al. were able to detect specific antibodies in mice after DNA immunization (Huang et al. 2000, 2003). Plasmids encoding the small HDAg induced high titer anti-HDAg, whereas plasmids expressing the L-HDAg induced only low antibody titers in 70% of the mice.

The differences in antibody detection in these studies may be partially due to different expression plasmids, protein detection systems and other unknown factors. In conclusion, it could be stated that HDAg itself is a poor B-cell immunogen. HBV/HDV-infected patients develop serum antibody responses to HDAg, presumably because the extracellular forms of HDAg are always associated with immunogenic HBsAg.

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