Vaccine Development for Hepatitis C

Martin Lechmann, PhD and T. Jake Liang, MD, Liver Diseases Section, NIDDK, National Institutes of Health, Bethesda, Maryland

Semin Liver Dis. 2000;20(2) 

In This Article

Humoral Immunity

B cells play an important role in protection against viral infections. During primary infection, antibodies, cell-mediated immunity, or both are crucial. However, during secondary infections, antibodies are the critical mediators and are often essential for the control of viral spread. This observation is reflected by the fact that many successful antiviral vaccines are based on the induction of neutralizing antibodies. In infections with other flaviviruses such as yellow fever,[2] dengue,[3] and tickborne encephalitis virus,[4] antibodies against the envelope glycoproteins have neutralizing capacity and protect against lethal flavivirus challenge. In addition, it has been reported that antibodies against a nonstructural protein of the tickborne encephalitis virus are also able to protect against virus challenge.[5] The complete identification of neutralizing or protective epitopes in HCV has not yet been accomplished. The envelope protein E2 of HCV has been of particular interest because it contains highly variable sequences within the N-terminal region (HVR1) that encodes neutralizing B-cell epitopes. [6] In addition, the E2 protein binds to CD81, which is thought to be a receptor for HCV,[7] although the CD81 binding region of E2 is probably not located within the HVR1 site.[8] The hypervariability of this region has been suggested as a possible mechanism through which the virus evades the immune response.[6,9,10]

Mutations within the N-terminus of HVR1 have been shown to occur rapidly in infected individuals and coincide with the disappearance of preexisting anti-HVR1 antibodies.[11] Farci et al.[9] reported in vitro neutralization of HCV with a rabbit hyperimmune serum raised against a homologous synthetic peptide derived from the HVR1 region. The anti-HVR1 serum induced protection against the homologous HCV strain in chimpanzees but not against the mutants that cannot be neutralized by the antiserum. However, the antibody response against E2 and its role in viral clearance is still controversial. Early development of anti-E2 or anti-HVR1 has been suggested to be associated with recovery from acute HCV infection in humans.[12,13] However, other studies found no correlation between anti-E2 and self-limited infection by HCV in humans and in chimpanzees. [14,15,16,17] Because protection against HCV infection did not correlate with anti-HVR1 levels in a chimpanzee immunization experiment,[18] neutralization determinants other than the HVR1 site likely exist. Finally, antibody responses to the envelope proteins develop slowly and achieve only modest titers during primary infection.[19] Therefore, neutralizing antibodies may emerge too late to prevent chronic infection. In addition, antienvelope antibodies tend to be short-lived and disappear gradually after viral clearance.[19]

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