Current Hepatitis C Vaccine Candidates Based on the Induction of Neutralizing Antibodies

Abstract

The introduction of direct-acting antivirals (DAAs) has revolutionized hepatitis C treatment. Short courses of treatment with these drugs are highly beneficial to patients, eliminating hepatitis C virus (HCV) without adverse effects. However, this outstanding success is tempered by the continuing difficulty of eradicating the virus worldwide. Thus, access to an effective vaccine against HCV is strongly needed to reduce the burden of the disease and contribute to the elimination of viral hepatitis. The recent failure of a T-cell vaccine based on the use of viral vectors expressing the HCV non-structural protein sequences to prevent chronic hepatitis C in drug users has pointed out that the induction of neutralizing antibodies (NAbs) will be essential in future vaccine candidates. To induce NAbs, vaccines must contain the main target of this type of antibody, the HCV envelope glycoproteins (E1 and E2). In this review, we summarize the structural regions in E1 and E2 proteins that are targeted by NAbs and how these proteins are presented in the vaccine candidates currently under development.

Keywords: envelope glycoproteins; hepatitis C virus; neutralizing antibodies; vaccine development.

Figure 2

Structure of the HCV envelope glycoprotein E2. E2 is a 360 aa protein (including 30 aa for the transmembrane domain (TMD)) that contains 3 variable regions (hypervariable region (HVR)1, HVR2, and intergenotypic variable region (igVR)), a front layer, a back layer, a CD81-binding loop (CD81bl), a stem region and 11 N-glycosylation sites (in magenta). The crystal structure of the core of E2 considered individually (aa 421–645/656) was obtained by two groups (PDB: 4MWF and 4WEB). Three epitopes for neutralizing antibodies were identified (I, II, and III). The epitope I (aa 412–423) can adopt 3 conformations: β-hairpin (PDB: 4DGY), semi-open (PDB: 4XVJ), and open (PDB: 4WHY). The epitope II (aa 434–446) was co-crystallized with the human monoclonal antibodies (mAbs) HC84-27 (PDB: 4JZO) and HC84-1 (PDB: 4JZN), but also targeted by the 2A5 mAb. The crystal structure of the epitope III (aa 523–535), inside the CD81bl, (PDB: 5NPJ) was also obtained by co-crystallization with the mouse mAb DAO5, and targeted by the mAbs 1:7 and A8. Antibodies targeting each epitope are indicated in dark blue. Cysteines (and disulfide bonds) are represented in yellow and asparagines in magenta [70,71,75,86,87,88,89]. Molecular graphics were performed using Chimera UCSF [59]. PDB: Protein Data Bank (https://www.rcsb.org/ accessed on 26 February 2023).

Figure 1

Structure of the HCV envelope glycoprotein E1. The E1 protein contains 190 aa (160 aa for the ectodomain and 30 aa for the transmembrane domain (TMD)), 5 or 6 N-glycosylation sites (including 4 which are highly conserved in all genotypes, represented in magenta; N250 exclusively found in genotypes 1b and 6, and N325 absent when a Proline residue is present immediately following the sequon (Asn-X-Ser/Thr), both represented in gray) and a putative fusion peptide (FP). The crystal structure of the N-terminal domain of E1 considered individually was determined (PDB: 4UOI), as well as the region 314–324 (PDB: 4N0Y) by co-crystallization with the human antibody IGH526. Antibodies (in dark blue) binding sites: aa 192–202 for the human monoclonal antibody (mAb) H-111, aa 215–299 for the human mAb HEPC112, and aa 313–324 for the human mAbs IGH505 and IGH526 [49,58]. Cysteines (and disulfide bonds) are represented in yellow and asparagines in magenta. Molecular graphics were performed using Chimera UCSF [59]. PDB: Protein Data Bank (https://www.rcsb.org/ accessed on 26 February 2023).

Figure 3

Structure of the E1E2 heterodimer. (A) Representation of the E1E2 complex (PDB: 7T6X), E1 in blue and E2 in red, with N-glycans in purple and disulfide bonds in yellow [51]. (B) In the “Stem-in-hand” model, the stem of E2 (aa 701–717) is held by E1, which represents the “hand”. The epitopes of antibodies used to solve the structure of the heterodimer are encircled in blue. AT1209 targets the CD81 binding loop in E2, AR4A is directed against the back layer of E2 but requires the presence of E1, and IGH505 binds amino acids in the stem region of E1. Molecular graphics were performed using Chimera UCSF [59]. PDB: Protein Data Bank (https://www.rcsb.org/ accessed on 26 February 2023).