Hepatitis C virus vaccine design: focus on the humoral immune response

Abstract

Despite the recent development of safe and highly effective direct-acting antivirals, hepatitis C virus (HCV) infection remains a significant health problem. In 2016, the World Health Organization set out to reduce the rate of new HCV infections by 90% by 2030. Still, global control of the virus does not seem to be achievable in the absence of an effective vaccine. Current approaches to the development of a vaccine against HCV include the production of recombinant proteins, synthetic peptides, DNA vaccines, virus-like particles, and viral vectors expressing various antigens. In this review, we focus on the development of vaccines targeting the humoral immune response against HCV based on the cumulative evidence supporting the important role of neutralizing antibodies in protection against HCV infection. The main targets of HCV-specific neutralizing antibodies are the glycoproteins E1 and E2. Recent advances in the knowledge of HCV glycoprotein structure and their epitopes, as well as the possibility of getting detailed information on the human antibody repertoire generated by the infection, will allow rational structure-based antigen design to target specific germline antibodies. Although obtaining a vaccine capable of inducing sterilizing immunity will be a difficult task, a vaccine that prevents chronic hepatitis C infections, a more realistic goal in the short term, would have a considerable health impact.

Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer

“…The challenges posed by HCV sequence diversity (12,13), glycan shielding (14,15), immunodominant nonneutralizing epitopes (16)(17)(18)(19), and preparation of a homogeneous E1E2 antigen all contribute to the difficulty in generating protective B cell immune responses. Although multiple studies in chimpanzees and humans have used E1E2 formulations to induce a humoral immune response, their success in generating high titers of broadly neutralizing antibody (bnAb) responses has been limited (20). Optimization of E1E2 to improve its immunogenicity and elicitation of bnAbs through rational design may lead to an effective B cell-based vaccine (21).…”

Hepatitis C virus DNA vaccines: a systematic review

“…Based on the reviewed literature, the authors suggest that incorporation of multiple viral proteins or their epitopes in a homologous or heterologous prime-boost regimen or using CpG-enriched DNA and recombinant virus vaccines with coexpression of potent adjuvants with high immunogenicity are valid strategies to increase the potency of potential vaccines. Considering the limited efficacy of the results of the registered clinical trials with candidate vaccines [ 73 , 74 ], future studies show focus on maximizing the immunogenicity of their vaccines by incorporating the strategies mentioned throughout this text.…”

From Structural Studies to HCV Vaccine Design

“…HCV applies multiple evasion mechanisms in order to evade the immune system, including high genetic variability, glycan shielding, conformational flexibility, immune decoy epitopes, and the occurrence of escape mutations (reviewed in [ 16 , 42 ]). Most of the escape mutations occur within nAb-binding epitopes; nevertheless, mutation in regions that are not directly involved in the epitopes, but reduce the efficiency of nAbs, can also result in viral escape [ 108 , 109 , 110 ].…”

“…Diverse strategies to induce humoral and/or cell-mediated immunity have been described [ 12 , 15 , 16 , 17 , 18 , 19 ], including viral vectors that express multiple HCV antigens [ 20 , 21 , 22 ], DNA vaccination [ 23 ], recombinant E2 and E1E2 protein vaccination [ 24 , 25 , 26 , 27 ], HCV viruslike particles (VLPs) [ 28 , 29 ], and, recently, antigen-displaying lipid-based nanoparticle vaccines [ 30 ] and self-assembly nanoparticles [ 31 ]. Nevertheless, at present, only three vaccine candidates were proceeded into human preclinical and clinical trials [ 19 , 32 ].…”