B cell immunodominance in primary hepatitis C virus infection

Abstract

B cell immunodominance in primary hepatitis C virus infectionGraphical abstract Immunodominance of anti-HCV E1E2 antibodies measured in 168 patientsHighlights Neutralising antibodies will likely form a key component of an HCV vaccine.We characterise the immunodominance of neutralising and non-neutralising epitopes in primary HCV infection.We identify that virus genotype might influence the epitopes targeted.We also identify that certain epitope target combinations are associated with greater breadth.Background & Aims: Neutralising antibodies (NAbs) play a key role in clearance of HCV. NAbs have been isolated and mapped to several domains on the HCV envelope proteins. However, the immunodominance of these epitopes in HCV infection remains unknown, hindering efforts to elicit optimal epitope-specific responses. Furthermore, it remains unclear which epitopespecific responses are associated with broad NAb (bNAb) activity in primary HCV infection. The aim of this study was to define B cell immunodominance in primary HCV, and its implications on neutralisation breadth and clearance. Methods: Using samples from 168 patients with primary HCV infection, the antibody responses targeted 2 immunodominant domains, termed domains B and C. Genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains.Results: No epitopes were uniquely targeted by clearers compared to those who developed chronic infection. Samples with bNAb activity were enriched for multi-specific responses directed towards the epitopes antigenic region 3, antigenic region 4, and domain D, and did not target non-neutralising domains.Conclusions: This study outlines for the first time a clear NAb immunodominance profile in primary HCV infection, and indicates that it is influenced by the infecting virus. It also highlights the need for a vaccination strategy to induce multi-specific responses that do not target non-neutralising domains. Lay summary: Neutralising antibodies will likely form a key component of a protective hepatitis C virus vaccine. In this work we characterise the predominant neutralising and nonneutralising antibody (epitope) targets in acute hepatitis C virus infection. We have defined the natural hierarchy of epitope immunodominance, and demonstrated that viral genotype can impact on this hierarchy. Our findings highlight key epitopes that are associated with broadly neutralising antibodies, and the deleterious impact of mounting a response towards some of these domains on neutralising breadth. These findings should guide future efforts to design immunogens aimed at generating neutralising antibodies with a vaccine candidate.

Adaptive Immune Response against Hepatitis C Virus

“…The exact binding epitopes of many bnAbs were identified by global alanine scanning of the E1E2 protein, followed by antibody binding assays [28,29]. The immunodominance of bnAbs were analyzed very recently in natural acute infection [30], as well as in samples from a (historic) E1E2 vaccination study in healthy volunteers [31].…”

Hepatitis C Virus Epitope Immunodominance and B Cell Repertoire Diversity

“…For example, it has been shown that epitope II-specific Abs can interfere with the neutralisation ability of epitope I-specific Abs [28]. More recent studies have analysed these combinatorial effects of several NAbs, identifying a wide range of synergies and interferences [29,30]. These findings suggest it may be beneficial to have a vaccine that can facilitate the induction of certain Ab specificities over others, with a focus on inducing multiple synergistic Abs with enhanced neutralisation breadth and potency.…”

“…By characterising the immunodominance of the response to epitopes associated with effective bNAbs, it becomes possible to understand which bNAbs are more readily induced by a wider population, which is critical information in the context of vaccine design. This is a research area that is only just beginning to be explored, with two very recent studies addressing the topic of Ab immunodominance in HCV [30,38]. By defining the unique specificities within the polyclonal Ab responses in patients with acute HCV infection, the relationship between these specificities and the potency and breadth of neutralisation can be resolved.…”

“…By defining the unique specificities within the polyclonal Ab responses in patients with acute HCV infection, the relationship between these specificities and the potency and breadth of neutralisation can be resolved. Although different panels of pseudoparticles and reference mAbs were used in these two studies, both reported that strong bNAb responses were enriched with broadly specific bNAbs directed towards AR3, AR4 and domain D. Moreover, there was no particular epitope associated with viral clearance, but rather Kinchen et al indicated that viral clearance was associated with the presence of multiple NAbs targeting unique neutralising epitopes and reduced activity against non-neutralising domains [30,38]. The other of these two studies also suggested that the immunodominance profile may be influenced by the genotype of the virus (Figure 2) [30].…”

“…Figure 2. Relative immunodominance of Abs specific to antigenic regions (ARs) 1-5 and domainsA-E of a GT1 viral envelope (H77)[30].…”