Abstract
A hepatitis C virus (HCV) vaccine is a critical yet unfulfilled step in addressing the global disease burden of HCV. While decades of research have led to numerous clinical and pre-clinical vaccine candidates, these efforts have been hindered by factors including HCV antigenic variability and immune evasion. Structure-based and rational vaccine design approaches have capitalized on insights regarding the immune response to HCV and the structures of antibody-bound envelope glycoproteins. Despite successes with other viruses, designing an immunogen based on HCV glycoproteins that can elicit broadly protective immunity against HCV infection is an ongoing challenge. Here, we describe HCV vaccine design approaches where immunogens were selected and optimized through analysis of available structures, identification of conserved epitopes targeted by neutralizing antibodies, or both. Several designs have elicited immune responses against HCV in vivo, revealing correlates of HCV antigen immunogenicity and breadth of induced responses. Recent studies have elucidated the functional, dynamic and immunological features of key regions of the viral envelope glycoproteins, which can inform next-generation immunogen design efforts. These insights and design strategies represent promising pathways to HCV vaccine development, which can be further informed by successful immunogen designs generated for other viruses.
Highlights
The ability to conduct rational Hepatitis C virus (HCV) vaccine design would dramatically increase with greater structural information on E1E2 glycoproteins, as demonstrated by immunogens generated using structure-based design for influenza [153,154,155], human immunodeficiency virus (HIV) [39,156], and SARS-CoV-2 [42,69,157,158], which have known glycoprotein complex structures available for reference in design studies
High-resolution structural characterization of the E1E2 heterodimer would be immensely useful in this regard, while useful insights would be gained through the structure of E2 bound to CD81, and any component of the complex interactions between HCV LVPs and multiple lipoprotein receptors [29]
As an alternative to structural characterization of secreted, soluble E1E2 ectodomains, characterization of the native, membrane-bound E1E2 heterodimer can be investigated using methods such as cryogenic electron microscopy with lipid nanodiscs, which has already been used for characterization of full-length HIV glycoprotein assemblies [159]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Different epitope clusters can overlap [31,55], epitope mapping and structural studies have identified the following key E2 regions for bnAb recognition: antigenic domain B (residues 529–535 in H77 isolate numbering), domain D (residues 434–446), and domain E (residues 412–423), all of which contain residues critical for antibody binding that are nearly or fully conserved across genotypes [56,57] Antibodies targeting these three antigenic domains of E2 neutralize the virus through competition with CD81, an HCV co-receptor that is critical for viral entry [58,59,60]. The path to an effective HCV vaccine may include utilization of design strategies that generated promising immunogens for other viruses, including HIV, RSV, and SARS-CoV-2 [38,39,40,41,42], which have led to clinical-stage candidates [65,66,67] and successful vaccines [68,69]
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