In the battle against hepatitis C virus (HCV), reinfections pose a significant challenge, underscoring the difficulty in achieving sterilizing immunity in highly exposed individuals. Memory B cell MBC quality, but not necessarily the range of nAb responses, is crucial for protection against antigenically diverse variants, which is promising for HCV vaccine development.
Broad neutralizing antibodies (BnAb) responses correlated with MBC recall, but not with clearing reinfection. Significant evidence of antigen imprinting emerged, and the B cell receptor repertoire exhibited substantial clonality along with continued somatic hypermutation in many clones across multiple reinfection events. Single-cell transcriptomic analyses revealed that cleared reinfections were characterized by an activated transcriptomic profile in HCV-specific B cells that rapidly expanded upon reinfection.
“In this study, 15 subjects that had naturally resolved a primary HCV infection were followed through multiple reinfection events, with natural disease outcomes and the associated immune responses compared,” explains investigators. “Surprisingly, neither the neutralizing breadth in plasma nor the epitope specificities, were associated with clearance of HCV reinfection. However, the HCV E2-specific B cell responses did correlate with outcome.”
3 Key Takeaways
- The study highlights the difficulty in naturally developing sterilizing immunity against HCV, as reinfection is frequent in those highly exposed to the virus. This underscores the need for effective vaccines and therapeutics against HCV.
- The quality of memory B cell (MBC) responses, rather than the breadth of nAb responses, is crucial for protection against antigenically diverse variants of HCV.
- The study suggests that B cell functionality may be a key factor in successful protection against highly diverse RNA viruses like HCV.
This study provides insights into immune responses associated with HCV reinfection but has limitations. The small sample size may limit the generalizability of the findings and affect the statistical power. Due to the costs and complexity of antigen-specific single-cell research, only a limited number of HCV E2-specific B cells and BCRs were analyzed. The study focused only on responses to the core E2 region, potentially overlooking other critical viral regions such as the E1E2 heterodimer. Technical challenges in cloning and expressing autologous E1/E2 proteins from reinfecting viruses also limited the characterization of the immune response. These factors should be considered in the interpretation of the results and in planning future research.
“An additional finding of interest in this study was the observation of boosting of primary autologous virus neutralization titres, and highly conserved epitope specificities between primary and subsequent reinfections, which indicated that HCV may induce ‘antigen imprinting’ in a similar fashion to SARS-CoV-2 and influenza,” according to the investigators. “Overall, this study suggested that B cell functionality may be a key consideration for successful protection against highly diverse RNA viruses.”
Overall, this study showed that humoral responses play a key role in protection and suggests that for viruses with high genetic diversity, such as HCV, exploring beyond antibodies might be useful for identifying correlates of protection. B cell signatures linked with unfavorable reinfection outcomes could apply to other viral infections. Understanding these B cell signatures is crucial for developing effective vaccines.
Reference
1. Underwood A, Gupta M, Wu B, et. al. B cell Characteristics Define HCV Reinfection Outcome. Journal of Hepatology. Published April 9, 2024. Accessed April 24, 2024. doi: https://doi.org/10.1016/j.jhep.2024.04.004
