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Viruses
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Novel Advances in Vaccines against HCV
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Novel Advances in Vaccines against HCV

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 30813

Special Issue Editor

Prof. Dr. Thomas Fuerst

E-Mail Website
Guest Editor
1. Director, Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA
2. Professor, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
Interests: virology; vaccines; adaptive immunity; immunoadjuvants; delivery systems; virus assembly and maturation; hepatitis C virus; emerging and re-emerging viruses

Special Issue Information

Dear Colleagues,

Hepatitis C virus (HCV) is a major global disease burden, and the leading cause of liver cirrhosis and hepatocellular carcinoma in those infected. Despite the recent approval of antiviral therapeutics, a preventative vaccine is recognized as the most effective means to control HCV globally, particularly in at-risk and developing country populations.

However, there are major challenges in the development of an effective HCV vaccine. These challenges include high sequence variability across the seven major genotypes and subtypes leading to viral evasion of both innate and adaptive immune responses, lack of in vitro systems and immunocompetent small animal models that facilitate determination of protective immunity, and vaccine immunoadjuvant and delivery systems capable of inducing robust humoral and cellular immune responses. It is generally accepted that an effective vaccine will need to produce strong and broadly cross-reactive neutralizing antibodies (bNAbs) and HCV-specific T cell responses (CD4+ and CD8+) to prevent or clear HCV infection. Approaches to elicit humoral immunity have focused on the envelope glycoproteins, E1 and E2, with a principal focus on the E1E2 heterodimer to induce bNAbs. Protective immunity against autologous virus challenge has been demonstrated in chimpanzees immunized with an E1E2-based vaccine, and limited success with heterologous challenge strains. Corresponding human studies have shown moderate immunogenicity with limited cross-neutralization across genotypes. Therefore, the design of the envelope glycoproteins to focus the immune response on conserved domains associated with broadly neutralizing antibodies is an active area of investigation. In addition, the generation of effective cellular and T-cell memory responses will be necessary for protective immunity and control of HCV infection. Therefore, the use of novel adjuvant and delivery systems for the induction of humoral and cellular responses will be of key importance.

This Special Issue will focus on existing vaccines in development, and recent novel advances in developing B and T cell-based vaccines. This, coupled with insights from deep sequencing, surrogate neutralization assays, and animal model systems, and other technological advances, is advancing research toward rationally designed vaccines that preferentially elicit responses toward conserved epitopes of interest that are associated with viral neutralization and clearance.

Prof. Thomas Fuerst
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hepatitis C virus
  • B cell response
  • T cell response
  • neutralization antibodies
  • human monoclonal antibodies
  • viral escape
  • epitope mapping
  • antigenic domains
  • vaccine development
  • immunoadjuvants
  • vector delivery systems.

Published Papers (10 papers)

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Research

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23 pages, 3799 KiB  
Article
Design and Synthesis of HCV-E2 Glycoprotein Epitope Mimics in Molecular Construction of Potential Synthetic Vaccines
by Theodorus J. Meuleman, Vanessa M. Cowton, Arvind H. Patel and Rob M. J. Liskamp
Viruses 2021, 13(2), 326; https://0-doi-org.brum.beds.ac.uk/10.3390/v13020326 - 20 Feb 2021
Cited by 3 | Viewed by 2393
Abstract
Hepatitis C virus remains a global threat, despite the availability of highly effective direct-acting antiviral (DAA) drugs. With thousands of new infections annually, the need for a prophylactic vaccine is evident. However, traditional vaccine design has been unable to provide effective vaccines so [...] Read more.
Hepatitis C virus remains a global threat, despite the availability of highly effective direct-acting antiviral (DAA) drugs. With thousands of new infections annually, the need for a prophylactic vaccine is evident. However, traditional vaccine design has been unable to provide effective vaccines so far. Therefore, alternative strategies need to be investigated. In this work, a chemistry-based approach is explored towards fully synthetic peptide-based vaccines using epitope mimicry, by focusing on highly effective and conserved amino acid sequences in HCV, which, upon antibody binding, inhibit its bio-activity. Continuous and discontinuous epitope mimics were both chemically synthesized based on the HCV-E2 glycoprotein while using designed fully synthetic cyclic peptides. These cyclic epitope mimics were assembled on an orthogonally protected scaffold. The scaffolded epitope mimics have been assessed in immunization experiments to investigate the elicitation of anti-HCV-E2 glycoprotein antibodies. The neutralizing potential of the elicited antibodies was investigated, representing a first step in employing chemically synthesized epitope mimics as a novel strategy towards vaccine design. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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Review

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16 pages, 1240 KiB  
Review
Towards a Systems Immunology Approach to Understanding Correlates of Protective Immunity against HCV
by Naglaa H. Shoukry
Viruses 2021, 13(9), 1871; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091871 - 18 Sep 2021
Cited by 5 | Viewed by 2696
Abstract
Over the past decade, tremendous progress has been made in systems biology-based approaches to studying immunity to viral infections and responses to vaccines. These approaches that integrate multiple facets of the immune response, including transcriptomics, serology and immune functions, are now being applied [...] Read more.
Over the past decade, tremendous progress has been made in systems biology-based approaches to studying immunity to viral infections and responses to vaccines. These approaches that integrate multiple facets of the immune response, including transcriptomics, serology and immune functions, are now being applied to understand correlates of protective immunity against hepatitis C virus (HCV) infection and to inform vaccine development. This review focuses on recent progress in understanding immunity to HCV using systems biology, specifically transcriptomic and epigenetic studies. It also examines proposed strategies moving forward towards an integrated systems immunology approach for predicting and evaluating the efficacy of the next generation of HCV vaccines. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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17 pages, 530 KiB  
Review
Hepatitis C Virus Vaccine Research: Time to Put Up or Shut Up
by Alex S. Hartlage and Amit Kapoor
Viruses 2021, 13(8), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081596 - 12 Aug 2021
Cited by 13 | Viewed by 3568
Abstract
Unless urgently needed to prevent a pandemic, the development of a viral vaccine should follow a rigorous scientific approach. Each vaccine candidate should be designed considering the in-depth knowledge of protective immunity, followed by preclinical studies to assess immunogenicity and safety, and lastly, [...] Read more.
Unless urgently needed to prevent a pandemic, the development of a viral vaccine should follow a rigorous scientific approach. Each vaccine candidate should be designed considering the in-depth knowledge of protective immunity, followed by preclinical studies to assess immunogenicity and safety, and lastly, the evaluation of selected vaccines in human clinical trials. The recently concluded first phase II clinical trial of a human hepatitis C virus (HCV) vaccine followed this approach. Still, despite promising preclinical results, it failed to protect against chronic infection, raising grave concerns about our understanding of protective immunity. This setback, combined with the lack of HCV animal models and availability of new highly effective antivirals, has fueled ongoing discussions of using a controlled human infection model (CHIM) to test new HCV vaccine candidates. Before taking on such an approach, however, we must carefully weigh all the ethical and health consequences of human infection in the absence of a complete understanding of HCV immunity and pathogenesis. We know that there are significant gaps in our knowledge of adaptive immunity necessary to prevent chronic HCV infection. This review discusses our current understanding of HCV immunity and the critical gaps that should be filled before embarking upon new HCV vaccine trials. We discuss the importance of T cells, neutralizing antibodies, and HCV genetic diversity. We address if and how the animal HCV-like viruses can be used for conceptualizing effective HCV vaccines and what we have learned so far from these HCV surrogates. Finally, we propose a logical but narrow path forward for HCV vaccine development. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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22 pages, 406 KiB  
Review
Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial
by Christopher C. Phelps, Christopher M. Walker and Jonathan R. Honegger
Viruses 2021, 13(7), 1351; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071351 - 13 Jul 2021
Cited by 1 | Viewed by 3009
Abstract
Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical [...] Read more.
Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
29 pages, 3740 KiB  
Review
Structural and Biophysical Characterization of the HCV E1E2 Heterodimer for Vaccine Development
by Eric A. Toth, Andrezza Chagas, Brian G. Pierce and Thomas R. Fuerst
Viruses 2021, 13(6), 1027; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061027 - 29 May 2021
Cited by 5 | Viewed by 3109
Abstract
An effective vaccine for the hepatitis C virus (HCV) is a major unmet medical and public health need, and it requires an antigen that elicits immune responses to multiple key conserved epitopes. Decades of research have generated a number of vaccine candidates; based [...] Read more.
An effective vaccine for the hepatitis C virus (HCV) is a major unmet medical and public health need, and it requires an antigen that elicits immune responses to multiple key conserved epitopes. Decades of research have generated a number of vaccine candidates; based on these data and research through clinical development, a vaccine antigen based on the E1E2 glycoprotein complex appears to be the best choice. One bottleneck in the development of an E1E2-based vaccine is that the antigen is challenging to produce in large quantities and at high levels of purity and antigenic/functional integrity. This review describes the production and characterization of E1E2-based vaccine antigens, both membrane-associated and a novel secreted form of E1E2, with a particular emphasis on the major challenges facing the field and how those challenges can be addressed. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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11 pages, 646 KiB  
Review
Hepatitis C Virus Epitope Immunodominance and B Cell Repertoire Diversity
by Nicholas A. Brasher, Anurag Adhikari, Andrew R. Lloyd, Nicodemus Tedla and Rowena A. Bull
Viruses 2021, 13(6), 983; https://0-doi-org.brum.beds.ac.uk/10.3390/v13060983 - 25 May 2021
Cited by 5 | Viewed by 2696
Abstract
Despite the advent of effective, curative treatments for hepatitis C virus (HCV), a preventative vaccine remains essential for the global elimination of HCV. It is now clear that the induction of broadly neutralising antibodies (bNAbs) is essential for the rational design of such [...] Read more.
Despite the advent of effective, curative treatments for hepatitis C virus (HCV), a preventative vaccine remains essential for the global elimination of HCV. It is now clear that the induction of broadly neutralising antibodies (bNAbs) is essential for the rational design of such a vaccine. This review details the current understanding of epitopes on the HCV envelope, characterising the potency, breadth and immunodominance of antibodies induced against these epitopes, as well as describing the interactions between B-cell receptors and HCV infection, with a particular focus on bNAb heavy and light chain variable gene usage. Additionally, we consider the importance of a public repertoire for antibodies against HCV, compiling current knowledge and suggesting that further research in this area may be critical to the rational design of an effective HCV vaccine. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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16 pages, 929 KiB  
Review
Immunopotentiating and Delivery Systems for HCV Vaccines
by Alexander K. Andrianov and Thomas R. Fuerst
Viruses 2021, 13(6), 981; https://0-doi-org.brum.beds.ac.uk/10.3390/v13060981 - 25 May 2021
Cited by 7 | Viewed by 3189
Abstract
Development of preventive vaccines against hepatitis C virus (HCV) remains one of the main strategies in achieving global elimination of the disease. The effort is focused on the quest for vaccines capable of inducing protective cross-neutralizing humoral and cellular immune responses, which in [...] Read more.
Development of preventive vaccines against hepatitis C virus (HCV) remains one of the main strategies in achieving global elimination of the disease. The effort is focused on the quest for vaccines capable of inducing protective cross-neutralizing humoral and cellular immune responses, which in turn dictate the need for rationally designed cross-genotype vaccine antigens and potent immunoadjuvants systems. This review provides an assessment of the current state of knowledge on immunopotentiating compounds and vaccine delivery systems capable of enhancing HCV antigen-specific immune responses, while focusing on the synergy and interplay of two modalities. Structural, physico-chemical, and biophysical features of these systems are discussed in conjunction with the analysis of their in vivo performance. Extreme genetic diversity of HCV-a well-known hurdle in the development of an HCV vaccine, may also present a challenge in a search for an effective immunoadjuvant, as the effort necessitates systematic and comparative screening of rationally designed antigenic constructs. The progress may be accelerated if the preference is given to well-defined molecular immunoadjuvants with greater formulation flexibility and adaptability, including those capable of spontaneous self-assembly behavior, while maintaining their robust immunopotentiating and delivery capabilities. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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16 pages, 736 KiB  
Review
Structure-Based and Rational Design of a Hepatitis C Virus Vaccine
by Johnathan D. Guest and Brian G. Pierce
Viruses 2021, 13(5), 837; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050837 - 05 May 2021
Cited by 7 | Viewed by 3217
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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23 pages, 3024 KiB  
Review
From Structural Studies to HCV Vaccine Design
by Itai Yechezkel, Mansun Law and Netanel Tzarum
Viruses 2021, 13(5), 833; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050833 - 04 May 2021
Cited by 7 | Viewed by 3222
Abstract
Hepatitis C virus (HCV) is a serious and growing public health problem despite recent developments of antiviral therapeutics. To achieve global elimination of HCV, an effective cross-genotype vaccine is needed. The failure of previous vaccination trials to elicit an effective cross-reactive immune response [...] Read more.
Hepatitis C virus (HCV) is a serious and growing public health problem despite recent developments of antiviral therapeutics. To achieve global elimination of HCV, an effective cross-genotype vaccine is needed. The failure of previous vaccination trials to elicit an effective cross-reactive immune response demands better vaccine antigens to induce a potent cross-neutralizing response to improve vaccine efficacy. HCV E1 and E2 envelope (Env) glycoproteins are the main targets for neutralizing antibodies (nAbs), which aid in HCV clearance and protection. Therefore, a molecular-level understanding of the nAb responses against HCV is imperative for the rational design of cross-genotype vaccine antigens. Here we summarize the recent advances in structural studies of HCV Env and Env-nAb complexes and how they improve our understanding of immune recognition of HCV. We review the structural data defining HCV neutralization epitopes and conformational plasticity of the Env proteins, and the knowledge applicable to rational vaccine design. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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26 pages, 1087 KiB  
Review
To Include or Occlude: Rational Engineering of HCV Vaccines for Humoral Immunity
by Felicia Schlotthauer, Joey McGregor and Heidi E Drummer
Viruses 2021, 13(5), 805; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050805 - 30 Apr 2021
Cited by 5 | Viewed by 2555
Abstract
Direct-acting antiviral agents have proven highly effective at treating existing hepatitis C infections but despite their availability most countries will not reach the World Health Organization targets for elimination of HCV by 2030. A prophylactic vaccine remains a high priority. Whilst early vaccines [...] Read more.
Direct-acting antiviral agents have proven highly effective at treating existing hepatitis C infections but despite their availability most countries will not reach the World Health Organization targets for elimination of HCV by 2030. A prophylactic vaccine remains a high priority. Whilst early vaccines focused largely on generating T cell immunity, attention is now aimed at vaccines that generate humoral immunity, either alone or in combination with T cell-based vaccines. High-resolution structures of hepatitis C viral glycoproteins and their interaction with monoclonal antibodies isolated from both cleared and chronically infected people, together with advances in vaccine technologies, provide new avenues for vaccine development. Full article
(This article belongs to the Special Issue Novel Advances in Vaccines against HCV)
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