Differential antigenic hierarchy associated with spontaneous recovery from hepatitis C virus infection: Implications for vaccine design

Background. Cellular immune responses play a central role in the control of hepatitis C virus (HCV) infection, and in some individuals the adaptive immune response can spontaneously eradicate HCV infection. The development of vaccine candidates to prevent the spread of this infection remains a top priority; however, understanding the correlates of effective immunological containment is an important prerequisite. Methods. Using 750 overlapping peptides, we directly characterized ex vivo total and subgenomic HCV-specific CD4⁺ and CD8⁺ T cell responses in a large cohort of participants with either chronic infection or spontaneously resolved infection. Results. In chronic infection, the frequency of total CD4⁺ T cells specific for HCV averaged 0.06%, compared with 0.38% in resolved infection. Total HCV-specific CD4⁺ and CD8⁺ T cell responses were strongly correlated in the setting of spontaneous resolution but not in the setting of viral persistence. NS3 protein-specific responses comprised a significantly greater proportion of the total response in resolved infection than in chronic infection, whereas responses to different regions comprised a larger proportion of responses in chronic infection. Conclusion. Because these data comprehensively define the breadth, specificity, and threshold of the T cell response associated with spontaneous recovery from HCV infection, they have important implications in the development of multigenic vaccine candidates for this common infection.