Structure-based design of hepatitis C virus E2 glycoprotein improves serum binding and cross-neutralization

Brian G. Pierce; Zhen-Yong Keck; Ruixue Wang; Patrick Lau; Kyle Garagusi; Khadija Elkholy; Eric A. Toth; Richard A. Urbanowicz; Johnathan D. Guest; Pragati Agnihotri; Melissa C. Kerzic; Alexander Marin; Alexander K. Andrianov; Jonathan K. Ball; Roy A. Mariuzza; Thomas R. Fuerst; Steven K.H. Foung

Despite decades of research resulting in several HCV vaccine candidates tested in vivo and in clinical trials (4, 5) , no approved HCV vaccine is available. There are a number of barriers to the development of an effective HCV vaccine, including the high mutation rate of the virus which leads to viral quasi-species in individuals and permits active evasion of T cell and B cell responses (6) . Escape from the antibody response by HCV includes mutations in the envelope glycoproteins, as observed in vivo in humanized mice (7) , studies in chimpanzee models (8) , and through analysis of viral isolates from human chronic infection (9) . This was also clearly demonstrated during clinical trials of a monoclonal antibody, HCV1, which in spite of its targeting a conserved epitope on the viral envelope, failed to eliminate the virus, as viral variants with epitope mutations emerged under immune pressure and dominated the rebounding viral populations in all treated individuals (10, 11) .