Update on Hepatitis C Vaccine: Results and Challenges

Abstract

Therapy against the Hepatitis C virus (HCV) has significantly improved with the introduction of direct-acting antiviral drugs (DAAs), achieving over 95% sustained virological response (SVR). Despite this, the development of an effective anti-HCV vaccine remains a critical challenge due to the low number of patients treated with DAAs and the occurrence of HCV reinfections in high-risk groups. Current vaccine strategies aim to stimulate either B-cell or T-cell responses. Vaccines based on E1 and E2 proteins can elicit broad cross-neutralizing antibodies against all major HCV genotypes, though with varying efficiencies and without full protection against infection. In humans, the neutralizing antibodies induced by such vaccines mainly target the AR3 region, but their levels are generally insufficient for broad neutralization. Various HCV proteins expressed through different viral vectors have been utilized to elicit T cell immune responses, showing sustained expansion of HCV-specific effector memory T cells and improved proliferation and polyfunctionality of memory T cells over time. However, despite these advancements, the frequency and effectiveness of T-cell responses remain limited.

Keywords: hepatitis C; immune response; immunogenicity; neutralizing antibody; vaccine.

Figure 1

Hepatitis C virus (HCV) structure. Enveloped HCV virion comprises E1/E2 dimers. The viral genome consists of a single positive-sense RNA molecule enclosed in an icosahedral capsid composed of core proteins. Created with BioRender (https://www.biorender.com/, accessed on 19 July 2024).

Figure 2

Schematic representation of the Hepatitis C virus (HCV) genome. (a) The figure shows the organization of genes encoding the structural (Core, E1, and E2) and non-structural (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins of the virus. Structural proteins are indicated in green, and non-structural proteins are indicated in orange. (b) E1 and E2 protein segments are shown in detail, with boxes representing the different functional regions and their respective amino acid residue numbers in black. Additionally, the antigenic domains are mapped on the E2 protein as follows: A (red), B (blue), C (green), D (purple), and E (orange). HVR1, Hypervariable Region 1; VR2, Variable Region 2; VR3, Variable Region 3; Post VR3, Post Variable Region 3; TM, Transmembrane Domain; NTD, N-terminal Domain; pFP, putative Fusion Peptide; CR, Conserved Region.

Figure 3

Adaptive immunity during HCV infection. Immune response involves activation of dendritic cells and other components of innate immunity, whereas B lymphocytes, CD4+ T cells, and CD8+ T cells are effectors of adaptive immunity. Abbreviations: Th1, T helper 1 cell; Th17, T helper 17 cell; Treg, T regulatory cell; Tfh, T follicular helper cell; MBC, memory B cell; CTL, cytotoxic lymphocyte. Created with BioRender.