If the immune response explanation of the genetic changes discussed above is correct, we could conclude that the stimulation of a potent immune response, which is inferred by the 27 week sequence changes in the animals that recovered from HDV infection, could be achieved by vaccination and that this response could clear the virus. Analysis of antibody responses to HDAg in patients and experimentally infected woodchucks indicated an immun-odominant domain between amino acids 52 and 93 (Bergmann et al. 1989; Wang et al. 1990). A preliminary report (Bergmann et al. 1993) described a vaccine strategy in which woodchucks were vaccinated with three HDAg peptides conjugated individually to keyhole limpet hemocyanin.
Vaccinated woodchucks were challenged with a woodchuck-adapted HDV pool. All animals became infected with HDV, based on the ability to detect HDV RNA in serum (Bergmann et al. 1993). However, preliminary analysis of viral RNA levels suggested that viremia was lower and of shorter duration in the vaccinated animals compared to controls. Further, it was found that antiHD antibody responses were not typical, particularly in the vaccinated animals. Following challenge, none of the three animals that had received the vaccine exhibited increases in antiHD, while four of five unvaccinated control animals produced increasing levels of antiHD following challenge. It was speculated that the lack of a significant increase in antiHD in the vaccinated animals was due to a limited infection that did not elicit a strong antiHD response (Bergmann et al. 1993).
Follow-up analysis of HDV RNA by a sensitive RT-PCR assay has confirmed and extended the original observations (Fig. 3). The three vaccinated animals exhibited low levels of viremia of limited duration. In contrast, all three of the surviving animals in the control group were still viremic 32 weeks post-challenge. Thus, while the peptide vaccine did not prevent HDV infection, it did modulate the course of the viremia. Other studies using different vaccine strategies directed at specifically stimulating cell mediated responses, including infection with recombinant HDAg-vaccinia or injection of DNA constructs designed to express HDAg, have reported similar findings of modulation of the course of HDV superinfection (D'Ugo et al. 2004; Fiedler et al. 2001; Karayiannis et al. 1993; see also the chapter by M. Fiedler and M. Roggendorf, this volume). That these vaccines do not prevent brief viremia should not necessarily be viewed as a failure, because most of the damage done by HDV occurs during chronic infection, which some vaccines appear to have limited.
Frequently, reduced, delayed and shortened periods of viremia correlated with weak or absent humoral antibody responses. That humoral antibody
responses are not protective against HDV infection (Karayiannis et al. 1990) is not particularly surprising given that HDAg is not exposed on the surface of the virion. However, it appears that some form of immunity follows acute, self-limiting infection because hepatitis B carrier chimpanzees superinfected with HDV were resistant to rechallenge with HDV 6 months later (Purcell et al. 1987). Most likely, the alteration of the course of infection by some vaccines is due to the ability to elicit appropriate cell mediated immune responses. However, there appears to be no correlation between vaccine efficacy and antiHD T-cell proliferative responses (Fiedler et al. 2001). Perhaps, cytotoxic T lymphocyte activity is the more important contributor to clearance of virally infected cells. Future vaccine studies may benefit from measurement of cytotoxic T lymphocyte activity induced by vaccines and/or HDV infection.
Most vaccines tested thus far have been closely related, if not identical, to the sequence of HDAg in the inoculum. If minor sequence changes provide an escape mechanism for the virus during the development of chronic infection (see Sect. 2), the occurrence of such sequence differences between vaccines and inocula could be an important factor to consider in the likely success of vaccines. Perhaps the ability to stimulate a potent response to multiple epitopes will be critical for the success of an HDV vaccine outside of the laboratory setting. In future vaccine studies, the relationship between the HDAg sequence used and that of the inoculum may be an additional important consideration. Such studies may benefit from a combined analysis of immune responses to infection/vaccination with inspection of genetic changes occurring on the viral genome.
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