Several key epitopes associated with broadly neutralizing antibodies (bNAbs) against hepatitis C virus (HCV) and the deleterious effect of mounting a response towards some of these domains on neutralizing breadth were described in a study published in the Journal of Hepatology.

Neutralizing antibodies are known to play a key role in clearance of HCV and have been mapped to several domains of the HCV envelope proteins. Investigators used 168 samples from patients with primary HCV infection to define B-cell immunodominance in primary HCV and its implications on neutralizing breadth and clearance.

Among these 168 patients the antibody responses targeted 2 immunodominant domains, termed domains B and C and genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains. Compared with those who developed chronic infections, no epitopes were uniquely targeted by clearers. Samples with bNAb were enriched for multi-specific responses directed toward the epitopes antigenic region 3, antigenic region 4, and domain D, and did not target non-neutralizing domains.


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Results showed 35% of participants cleared the infection, 41% developed chronic infection, and 41 (24%) had insufficient follow-up to determine the infection outcome. The majority of infections were due to GT1 (32%) and GT3 (34%) viruses. Plasma samples were tested for binding to lectin captured HCV GT1 and GT3 E1E2 antigen. A total of 57% were found to have anti-GT1 E1E2 immunoreactive antibodies, whereas 28% were found with GT3 immunoreactivity and 23% of patients had anti-E1E2 reactive antibodies to both GT1 and GT. Results also found that plasma derived from participants with HCV infection blocked the binding of all monoclonal antibodies in the panel with variability; the binding of the monoclonal antibodies was negatively correlated with the total E1E2 binding for the plasma samples.

A total of 27 samples were examined for bNAb activity using an established panel of 11 pseudoparticles covering 6 HCV genotypes. Of note, samples that exhibited bNAb demonstrated increased epitope mapping score for multiple neutralizing epitopes simultaneously, particularly for AR3, AR4 and domain D. In addition, the induction of AR1 and domain A antibodies showed correlation with narrow antibody responses, despite high epitope mapping score for AR3. Neutralization of GT1 and GT3 HCV displayed the strongest correlation with AR3 epitope mapping score. Increased neutralization potency of GT1 and GT3 HCV was also linked to domain D.

Investigators noted potential confounders in the cross-reactivity of the monoclonal antibodies used in this study. Many of these increased binding of the CBH4G detection antibody leading to the observation of poor competition with this antibody and the inability to observe clearly distinguishable competition results. Moreover, the HC84 cross-competed with AR3A and might have also have led to increased false detection. Furthermore, HC84 increased AR4A binding and AR4A competition may only be detected in high concentrations, meaning samples with low AR4A titers might not be detected. Further limitations included the lack of monoclonal antibodies that target non-GT1 envelope proteins, especially within non-neutralizing domains.

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The results outlined, “a clear immunodominance profile for known HCV neutralizing and non-neutralizing domains.” According to investigators results of the study also suggested that immunodominance is potentially conserved across genotypes and enrichment of certain epitopes might be influenced by variations in the infecting virus’ protein sequences. NAbs will likely be a key component of a protective HCV vaccine and these findings should aid future efforts to design immunogens aimed at generating neutralizing antibodies with a vaccine candidate.

Reference

Brasher NA, Eltahla AA, Underwood A, et al. B cell immunodominance in primary hepatitis C virus infection. J Hepatol. 2020;72:670-679.