These results suggest that the vaccine not only gives some protection against infection but also causes resolution of infection when it does occur. Vaccination achieved a high level of immune response: antibody titers prior to challenge were higher than those usually seen in infected blood donors and patients with chronic hepatitis. Further analysis showed that complete protection against infection was correlated with antibody levels, but not with antibodies to the hypervariable region at the end terminus of gpE2.

However, researchers don’t know how efficient this subunit vaccine, based on HCV subtype 1A, would be against heterologous viral isolates. Initial experiments with a related viral isolate produced rather low levels of antibodies following reboost, and a slight inhibition of the onset of viremia. But it was impossible to conclude from this study that a vaccine based on HCV-1 antigens can prevent chronic infection by heterologous virus. Additional studies are ongoing.

Goals and Problems. The objective for a prophylactic vaccine would be to prime the humeral immune response, using recombinant gpE1 and gpE2 subunits to produce neutralizing antibodies that will restrict viral spread and load and thereby allow cell-mediated immune (CMI) response to clear the infection. In addition, it should also prime the CMI response using antigens to conserved viral proteins—such as the T-cell response to viral NS-3—to enhance its ability to resolve infection.

A constant problem is the knowledge that chimpanzees and humans alike appear to have weak immunity against reinfection. As a result, researchers are hoping to use naked DNA and vector DNA immunizations to broaden the immune response and increase the protective efficacy of the vaccines. At present, however, it seems unlikely that they will be able to achieve a vaccine as effective as those against hepatitis A and B. Still, it will be highly beneficial if they can ameliorate the disease by slowing down or preventing the progression to chronic hepatitis in a significant fraction of subjects.

In response to questions, Dr. Houghton added the following:

• The first population to vaccinate would be high-risk groups such as health care workers, family members of patients, dialysis patients, etc.

• Researchers have not yet identified major differences in the antibody or CTL response of patients who resolve following acute infection compared with those who develop chronic infection. Nor do they understand why they are getting resolution in experimental chimpanzees, although they suspect that the vaccine limits the viral load and spreads sufficiently to allow the host CMI response to deal with the infection.

• The only studies showing resolution have involved HCV subtypes 1-A and 1-B. There seem to be few differences between these two subtypes, but it is impossible to say anything about resolution versus chronicity in the other major strains of HVC.