Future Prospects, Approaches, and the Government's Role in the Development of a Hepatitis C Virus Vaccine

Abstract

Developing a safe and effective vaccine against the hepatitis C virus (HCV) remains a top priority for global health. Despite recent advances in antiviral therapies, the high cost and limited accessibility of these treatments impede their widespread application, particularly in resource-limited settings. Therefore, the development of the HCV vaccine remains a necessity. This review article analyzes the current technologies, future prospects, strategies, HCV genomic targets, and the governmental role in HCV vaccine development. We discuss the current epidemiological landscape of HCV infection and the potential of HCV structural and non-structural protein antigens as vaccine targets. In addition, the involvement of government agencies and policymakers in supporting and facilitating the development of HCV vaccines is emphasized. We explore how vaccine development regulatory channels and frameworks affect research goals, funding, and public health policy. The significance of international and public-private partnerships in accelerating the development of an HCV vaccine is examined. Finally, the future directions for developing an HCV vaccine are discussed. In conclusion, the review highlights the urgent need for a preventive vaccine to fight the global HCV disease and the significance of collaborative efforts between scientists, politicians, and public health organizations to reach this important public health goal.

Keywords: COVID-19; SARS-CoV-2; government agencies; hepatitis C virus; prevalence; vaccine.

Figure 1

Genome organization of HCV. HCV contains a single-stranded positive-sense RNA genome of about 9.6 kb in size. The genome has a single open reading frame (ORF) flanked by two untranslated regions (UTR) at both ends. The ORF encodes a single polyprotein of approximately 3030 amino acids, which is processed co- and post-translationally by various cellular and viral proteases into three structural proteins (Core, E1, and E2) at the N-terminus and seven non-structural proteins (P7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) at the C-terminus. Structural proteins oligomerize and self-assemble to form the viral particle, while non-structural proteins are involved in viral assembly and genome replication.

Figure 2

Schematic diagram of HCV- E1 envelope protein. E1 contains N-terminal domain (NTD, 192–383). The size of the E1 protein is 190 aa and is divided into ectodomain (160aa) and transmembrane domain (TMD) (30aa). Four N-glycosylation sites (N196, N209, N234, and N305) are conserved in all genotypes; N250 is found in genotypes 1b and 6, but N325 is absent when a proline residue is present at Asn-X-Ser/Thr. 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. Antibody 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.

Figure 3

Structure of HCV E2 protein. The E2 consists of 360 aa, which is divided into 30 aa for the transmembrane domain (TMD), and consists of 3 variable regions (HVR1, HVR2, and igVR), including front layer, a back layer, CD81-binding loop (CD81bl), as well as STEM region, TMD regions start at 718 and end at 746, and 11 N-glycosylation sites. The epitope 1 (aa412–423) can adopt three conformations: beta hairpin, semi-open, and open. The epitope II (aa434–446) was co-crystallized with human monoclonal antibodies (mAbs) (H-84-27) and HC-84-1. The crystal structure of epitope III (523–535) was also obtained by co-crystallization with the mouse mAb DAO5 and targeted by the mAbs 1:7 and A8.

Figure 4

HCV Attachment and Cell Entry. This figure summarizes the main steps of HCV particle cell entry and genome release. (1, 2) The attachment, binding, and internalization are facilitated by the interaction of the viral envelope glycoproteins (E1 and E2) with cell membrane receptors, co-receptors, and host factors. The main cell receptors and factors that mediate the virus attachment and cell entry include glycosaminoglycan (GAG), low-density lipoprotein (LDL-R), scavenger receptor class B type I (SR-BI), cluster of differentiation 81 (CD81), claudin-1 (CLDN1), and occludin (OCLN). (3) Endocytosis: the interaction of viral envelop proteins with the cell receptors and co-receptors triggers the internalization of the virus into an endosome via endocytosis. (4, 5) Fusion, uncoating, and genome release: once inside the endosome, the virus undergoes fusion with the endosome membrane, leading to the uncoating of the nucleocapsid and the release of the viral genetic material into the cytoplasm. This diagram was created with BioRender.com.