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Costa GL, Sautto GA. Towards an HCV vaccine: an overview of the immunization strategies for eliciting an effective B-cell response. Expert Rev Vaccines 2025; 24:96-120. [PMID: 39825640 DOI: 10.1080/14760584.2025.2452955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 10/26/2024] [Accepted: 01/09/2025] [Indexed: 01/20/2025]
Abstract
INTRODUCTION Fifty-eight million people worldwide are chronically infected with hepatitis C virus (HCV) and are at risk of developing cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antivirals are highly effective; however, they are burdened by high costs and the unchanged risk of HCC and reinfection, making prophylactic countermeasures an urgent medical need. HCV high genetic diversity is one of the main obstacles to vaccine development. The protective role of the humoral response directed against the HCV E2 glycoprotein is well established, and broadly neutralizing antibodies play a crucial role in effective viral clearance. AREAS COVERED This review explores the HCV targets and the different vaccination approaches, encompassing different expression systems, antigen selection strategies, and delivery methods, focusing on those aimed at eliciting a broad and effective humoral response. Our search criteria included the keywords 'HCV,' 'Hepatitis C,' and 'vaccine' using publicly available databases. Following the screening, 54 papers were selected. EXPERT OPINION The investigation of novel vaccine platforms beyond traditional approaches is necessary. While progress has been made in this direction, continued investigations on the HCV virology, immunology, and vaccinology are essential to surmount associated obstacles, heling in the development of an HCV vaccine that can benefit the global public health.
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Affiliation(s)
- Gabriel L Costa
- Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, USA
| | - Giuseppe A Sautto
- Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, USA
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Ali AA, Azouz RAM, Hussein NA, El-Shenawy R, Helmy NM, El-Abd YS, Tabll AA. Development of Virus-Like Particles (VLPs) for Hepatitis C Virus genotype 4: a novel approach for vaccine development in Egypt. BMC Biotechnol 2025; 25:8. [PMID: 39827115 PMCID: PMC11742997 DOI: 10.1186/s12896-024-00935-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Egypt has the highest global prevalence of Hepatitis C Virus (HCV) infection, particularly of genotype 4. The development of a prophylactic vaccine remains crucial for HCV eradication, yet no such vaccine currently exists due to the vaccine development challenges. The ability of Virus-Like Particles (VLPs) to mimic the native virus and incorporate neutralizing and conformational epitopes, while effectively engaging both humoral and cellular immune responses, makes them a promising approach to addressing the challenges in HCV vaccine development. METHODS Lentiviral-based vectors were constructed and employed to integrate the full-length sequence of Core, E1, E2, and P7 genes of HCV genotype 4 into the genome of Human Embryonic Kidney cells (HEK293T). Upon the expression, HCV structural proteins can oligomerize and self-assemble into VLPs mimicking the structure of HCV native virus. VLPs were purified and characterized for the development of a potential VLPs-based vaccine. RESULTS In this study, mammalian cells were successfully engineered to stably express HCV structural proteins and generate non-infectious VLPs for HCV genotype 4. The expression of HCV-integrated genes resulted in a successful production of HCV structural proteins, which oligomerized and self-assembled into two layers enveloped VLPs. Electron microscopy analysis of purified VLPs revealed spherical particles with an average diameter of 60-65 nm, closely resembling mature HCV virions. These results highlighted the potential of these VLPs as a vaccine candidate for HCV genotype 4. CONCLUSIONS HCV genotype 4 remains an underexplored target in vaccine development, despite its significant public health burden, especially in Egypt. The successful generation of VLPs for this genotype represents a promising avenue for further vaccine development. The established system provides a robust platform for the production and study of VLP-based vaccines targeting HCV genotype 4.
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Affiliation(s)
- Ahmed A Ali
- Molecular Biology Department, Biotechnology Research Institute, National Research Centre, Cairo, 12622, Egypt.
| | - Rasha A M Azouz
- Molecular Biology Department, Biotechnology Research Institute, National Research Centre, Cairo, 12622, Egypt
| | - Nahla A Hussein
- Molecular Biology Department, Biotechnology Research Institute, National Research Centre, Cairo, 12622, Egypt
| | - Reem El-Shenawy
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, Cairo, 12622, Egypt
| | - Naiera M Helmy
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, Cairo, 12622, Egypt
| | - Yasmine S El-Abd
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, Cairo, 12622, Egypt
| | - Ashraf A Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, Cairo, 12622, Egypt
- Egyptian Centre for Research and Regenerative Medicine (ECRRM), Cairo, 11517, Egypt
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Ali AA, Tabll AA. Unlocking potential: Virus-like particles as a promising strategy for effective HCV vaccine development. Virology 2025; 602:110307. [PMID: 39580887 DOI: 10.1016/j.virol.2024.110307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/01/2024] [Accepted: 11/14/2024] [Indexed: 11/26/2024]
Abstract
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. The development of prophylactic vaccine is essential for HCV global eradication. Despite over three decades of research, no effective vaccine for HCV has been developed, primarily due to the virus's genetic diversity, immune evasion mechanisms, and incomplete understanding of protective immunity. However, Virus-Like Particles (VLPs) offer a promising approach to overcoming these challenges. VLPs mimic the structure of native virus but without the infectious genome, making them safe and non-infectious vaccines candidates. The capability of VLPs to incorporate neutralizing and conformational epitopes, and engage humoral and cellular immune responses, positions them as a promising tool for overcoming challenges associated with the HCV vaccine development. This review examines the challenges and immunological considerations for HCV vaccine development and provides an overview of the VLPs-based vaccines development. It also discusses future directions and public health implications of HCV vaccine development.
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Affiliation(s)
- Ahmed A Ali
- Molecular Biology Department, Biotechnology Research Institute, National Research Centre, (NRC), 12622, Cairo, Egypt.
| | - Ashraf A Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Centre, 12622, Cairo, Egypt; Egyptian Centre for Research and Regenerative Medicine (ECRRM), 11517, Cairo, Egypt.
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Rzymski P, Jibril AT, Rahmah L, Abarikwu SO, Hashem F, Lawati AA, Morrison FMM, Marquez LP, Mohamed K, Khan A, Mushtaq S, Minakova K, Poniedziałek B, Zarębska-Michaluk D, Flisiak R. Is there still hope for the prophylactic hepatitis C vaccine? A review of different approaches. J Med Virol 2024; 96:e29900. [PMID: 39234788 DOI: 10.1002/jmv.29900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/17/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024]
Abstract
Despite remarkable progress in the treatment of hepatitis C virus (HCV) infection, it remains a significant global health burden, necessitating the development of an effective prophylactic vaccine. This review paper presents the current landscape of HCV vaccine candidates and approaches, including more traditional, based on inactivated virus, and more modern, such as subunit protein, vectored, based on nucleic acids (DNA and mRNA) and virus-like particles. The concept of the HCV vaccine is first put in the context of viral genetic diversity and adaptive responses to HCV infection, an understanding of which is crucial in guiding the development of an effective vaccine against such a complex virus. Because ethical dimensions are also significant in vaccine research, development, and potential deployment, we also address them in this paper. The road to a safe and effective vaccine to prevent HCV infection remains bumpy due to the genetic variation of HCV and its ability to evade immune responses. The progress in cell-culture systems allowed for the production of an inactivated HCV vaccine candidate, which can induce cross-neutralizing antibodies in vitro, but whether this could prevent infection in humans is unknown. Subunit protein vaccine candidates that entered clinical trials elicited HCV-specific humoral and cellular responses, though it remains to be shown whether they translate into effective prevention of HCV infection or progression of infection to a chronic state. Such responses were also induced by a clinically tested vector-based vaccine candidate, which decreased the viral HCV load but did not prevent chronic HCV infection. These disappointments were not readily predicted from preclinical animal studies. The vaccine platforms employing virus-like particles, DNA, and mRNA provide opportunities for the HCV vaccine, but their potential in this context has yet to be shown. Ensuring the designed vaccine is based on conserved epitope(s) and elicits broadly neutralizing immune responses is also essential. Given failures in developing a prophylactic HCV vaccine, it is crucial to continue supporting national strategies, including funding for screening and treatment programs. However, these actions are likely insufficient to permanently control the HCV burden, encouraging further mobilization of significant resources for HCV vaccine research as a missing element in the elimination of viral hepatitis as a global public health.
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Affiliation(s)
- Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań, Poland
- Universal Scientific Education and Research Network (USERN)
| | - Aliyu Tijani Jibril
- Universal Scientific Education and Research Network (USERN)
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Laila Rahmah
- Universal Scientific Education and Research Network (USERN)
- Faculty of Medicine, Universitas Muhammadiyah Surabaya, Surabaya, Indonesia
- Department of Digital Health, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sunny O Abarikwu
- Universal Scientific Education and Research Network (USERN)
- Department of Biochemistry, University of Port Harcourt, Choba, PMB, Port Harcourt, Rivers State, Nigeria
| | - Fareeda Hashem
- Universal Scientific Education and Research Network (USERN)
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdullah Al Lawati
- Universal Scientific Education and Research Network (USERN)
- Sultan Qaboos University Hospital, Al Khoud, Muscat, Oman
| | | | - Leander Penaso Marquez
- Universal Scientific Education and Research Network (USERN)
- University of the Philippines Diliman, Quezon City, Philippines
| | - Kawthar Mohamed
- Universal Scientific Education and Research Network (USERN)
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amjad Khan
- Universal Scientific Education and Research Network (USERN)
- Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmacy, Xi'an Jiaotong University, Xi'an, China
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Saima Mushtaq
- Universal Scientific Education and Research Network (USERN)
- Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Kseniia Minakova
- Universal Scientific Education and Research Network (USERN)
- Micro- and Nanoelectronics Department, National Technical University "Kharkiv Polytechnic Institute", Kharkiv, Ukraine
| | - Barbara Poniedziałek
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań, Poland
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
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Garbuglia AR, Pauciullo S, Zulian V, Del Porto P. Update on Hepatitis C Vaccine: Results and Challenges. Viruses 2024; 16:1337. [PMID: 39205311 PMCID: PMC11359353 DOI: 10.3390/v16081337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/15/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Therapy against the Hepatitis C virus (HCV) has significantly improved with the introduction of direct-acting antiviral drugs (DAAs), achieving over 95% sustained virological response (SVR). Despite this, the development of an effective anti-HCV vaccine remains a critical challenge due to the low number of patients treated with DAAs and the occurrence of HCV reinfections in high-risk groups. Current vaccine strategies aim to stimulate either B-cell or T-cell responses. Vaccines based on E1 and E2 proteins can elicit broad cross-neutralizing antibodies against all major HCV genotypes, though with varying efficiencies and without full protection against infection. In humans, the neutralizing antibodies induced by such vaccines mainly target the AR3 region, but their levels are generally insufficient for broad neutralization. Various HCV proteins expressed through different viral vectors have been utilized to elicit T cell immune responses, showing sustained expansion of HCV-specific effector memory T cells and improved proliferation and polyfunctionality of memory T cells over time. However, despite these advancements, the frequency and effectiveness of T-cell responses remain limited.
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Affiliation(s)
- Anna Rosa Garbuglia
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.)
| | - Silvia Pauciullo
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.)
| | - Verdiana Zulian
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.)
| | - Paola Del Porto
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00100 Rome, Italy;
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Costa GL, Sautto GA. Exploring T-Cell Immunity to Hepatitis C Virus: Insights from Different Vaccine and Antigen Presentation Strategies. Vaccines (Basel) 2024; 12:890. [PMID: 39204016 PMCID: PMC11359689 DOI: 10.3390/vaccines12080890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/25/2024] [Accepted: 08/02/2024] [Indexed: 09/03/2024] Open
Abstract
The hepatitis C virus (HCV) is responsible for approximately 50 million infections worldwide. Effective drug treatments while available face access barriers, and vaccine development is hampered by viral hypervariability and immune evasion mechanisms. The CD4+ and CD8+ T-cell responses targeting HCV non-structural (NS) proteins have shown a role in the viral clearance. In this paper, we reviewed the studies exploring the relationship between HCV structural and NS proteins and their effects in contributing to the elicitation of an effective T-cell immune response. The use of different vaccine platforms, such as viral vectors and virus-like particles, underscores their versability and efficacy for vaccine development. Diverse HCV antigens demonstrated immunogenicity, eliciting a robust immune response, positioning them as promising vaccine candidates for protein/peptide-, DNA-, or RNA-based vaccines. Moreover, adjuvant selection plays a pivotal role in modulating the immune response. This review emphasizes the importance of HCV proteins and vaccination strategies in vaccine development. In particular, the NS proteins are the main focus, given their pivotal role in T-cell-mediated immunity and their sequence conservation, making them valuable vaccine targets.
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Affiliation(s)
| | - Giuseppe A. Sautto
- Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA;
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Liu S, Hu M, Liu X, Liu X, Chen T, Zhu Y, Liang T, Xiao S, Li P, Ma X. Nanoparticles and Antiviral Vaccines. Vaccines (Basel) 2023; 12:30. [PMID: 38250843 PMCID: PMC10819235 DOI: 10.3390/vaccines12010030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/23/2024] Open
Abstract
Viruses have threatened human lives for decades, causing both chronic and acute infections accompanied by mild to severe symptoms. During the long journey of confrontation, humans have developed intricate immune systems to combat viral infections. In parallel, vaccines are invented and administrated to induce strong protective immunity while generating few adverse effects. With advancements in biochemistry and biophysics, different kinds of vaccines in versatile forms have been utilized to prevent virus infections, although the safety and effectiveness of these vaccines are diverse from each other. In this review, we first listed and described major pathogenic viruses and their pandemics that emerged in the past two centuries. Furthermore, we summarized the distinctive characteristics of different antiviral vaccines and adjuvants. Subsequently, in the main body, we reviewed recent advances of nanoparticles in the development of next-generation vaccines against influenza viruses, coronaviruses, HIV, hepatitis viruses, and many others. Specifically, we described applications of self-assembling protein polymers, virus-like particles, nano-carriers, and nano-adjuvants in antiviral vaccines. We also discussed the therapeutic potential of nanoparticles in developing safe and effective mucosal vaccines. Nanoparticle techniques could be promising platforms for developing broad-spectrum, preventive, or therapeutic antiviral vaccines.
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Affiliation(s)
- Sen Liu
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
| | - Meilin Hu
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
- State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511400, China
| | - Xiaoqing Liu
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Xingyu Liu
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
| | - Tao Chen
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
- State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511400, China
| | - Yiqiang Zhu
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
| | - Taizhen Liang
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
- State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511400, China
| | - Shiqi Xiao
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
| | - Peiwen Li
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
| | - Xiancai Ma
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou 510005, China; (S.L.); (M.H.); (X.L.); (X.L.); (T.C.); (Y.Z.); (T.L.); (S.X.); (P.L.)
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
- State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511400, China
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
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Charoenkwan P, Waramit S, Chumnanpuen P, Schaduangrat N, Shoombuatong W. TROLLOPE: A novel sequence-based stacked approach for the accelerated discovery of linear T-cell epitopes of hepatitis C virus. PLoS One 2023; 18:e0290538. [PMID: 37624802 PMCID: PMC10456195 DOI: 10.1371/journal.pone.0290538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a concerning health issue that causes chronic liver diseases. Despite many successful therapeutic outcomes, no effective HCV vaccines are currently available. Focusing on T cell activity, the primary effector for HCV clearance, T cell epitopes of HCV (TCE-HCV) are considered promising elements to accelerate HCV vaccine efficacy. Thus, accurate and rapid identification of TCE-HCVs is recommended to obtain more efficient therapy for chronic HCV infection. In this study, a novel sequence-based stacked approach, termed TROLLOPE, is proposed to accurately identify TCE-HCVs from sequence information. Specifically, we employed 12 different sequence-based feature descriptors from heterogeneous perspectives, such as physicochemical properties, composition-transition-distribution information and composition information. These descriptors were used in cooperation with 12 popular machine learning (ML) algorithms to create 144 base-classifiers. To maximize the utility of these base-classifiers, we used a feature selection strategy to determine a collection of potential base-classifiers and integrated them to develop the meta-classifier. Comprehensive experiments based on both cross-validation and independent tests demonstrated the superior predictive performance of TROLLOPE compared with conventional ML classifiers, with cross-validation and independent test accuracies of 0.745 and 0.747, respectively. Finally, a user-friendly online web server of TROLLOPE (http://pmlabqsar.pythonanywhere.com/TROLLOPE) has been developed to serve research efforts in the large-scale identification of potential TCE-HCVs for follow-up experimental verification.
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Affiliation(s)
- Phasit Charoenkwan
- Modern Management and Information Technology, College of Arts, Media and Technology, Chiang Mai University, Chiang Mai, Thailand
| | - Sajee Waramit
- Department of Zoology, Faculty of Science, Kasetsart University, Bangkok, Thailand
| | - Pramote Chumnanpuen
- Department of Zoology, Faculty of Science, Kasetsart University, Bangkok, Thailand
- Omics Center for Agriculture, Bioresources, Food, and Health, Kasetsart University (OmiKU), Bangkok, Thailand
| | - Nalini Schaduangrat
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand
| | - Watshara Shoombuatong
- Center for Research Innovation and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand
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Collett S, Earnest L, Carrera Montoya J, Edeling MA, Yap A, Wong CY, Christiansen D, Roberts J, Mumford J, Lecouturier V, Pavot V, Marco S, Loi JK, Simmons C, Gulab SA, Mackenzie JM, Elbourne A, Ramsland PA, Cameron G, Hans D, Godfrey DI, Torresi J. Development of virus-like particles with inbuilt immunostimulatory properties as vaccine candidates. Front Microbiol 2023; 14:1065609. [PMID: 37350788 PMCID: PMC10282183 DOI: 10.3389/fmicb.2023.1065609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 05/17/2023] [Indexed: 06/24/2023] Open
Abstract
The development of virus-like particle (VLP) based vaccines for human papillomavirus, hepatitis B and hepatitis E viruses represented a breakthrough in vaccine development. However, for dengue and COVID-19, technical complications, such as an incomplete understanding of the requirements for protective immunity, but also limitations in processes to manufacture VLP vaccines for enveloped viruses to large scale, have hampered VLP vaccine development. Selecting the right adjuvant is also an important consideration to ensure that a VLP vaccine induces protective antibody and T cell responses. For diseases like COVID-19 and dengue fever caused by RNA viruses that exist as families of viral variants with the potential to escape vaccine-induced immunity, the development of more efficacious vaccines is also necessary. Here, we describe the development and characterisation of novel VLP vaccine candidates using SARS-CoV-2 and dengue virus (DENV), containing the major viral structural proteins, as protypes for a novel approach to produce VLP vaccines. The VLPs were characterised by Western immunoblot, enzyme immunoassay, electron and atomic force microscopy, and in vitro and in vivo immunogenicity studies. Microscopy techniques showed proteins self-assemble to form VLPs authentic to native viruses. The inclusion of the glycolipid adjuvant, α-galactosylceramide (α-GalCer) in the vaccine formulation led to high levels of natural killer T (NKT) cell stimulation in vitro, and strong antibody and memory CD8+ T cell responses in vivo, demonstrated with SARS-CoV-2, hepatitis C virus (HCV) and DEN VLPs. This study shows our unique vaccine formulation presents a promising, and much needed, new vaccine platform in the fight against infections caused by enveloped RNA viruses.
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Affiliation(s)
- Simon Collett
- School of Science, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, Australia
| | - Linda Earnest
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Julio Carrera Montoya
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Melissa A. Edeling
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Ashley Yap
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Chinn Yi Wong
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Dale Christiansen
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Jason Roberts
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Department of Infectious Diseases, The University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Jamie Mumford
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | | | | | | | - Joon Keit Loi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Cameron Simmons
- Institute of Vector-Borne Disease, Monash University, Clayton, VIC, Australia
| | - Shivali A. Gulab
- Avalia Immunotherapies Limited, Wellington, New Zealand
- Vaccine Alliance Aotearoa New Zealand, Wellington, New Zealand
| | - Jason M. Mackenzie
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Aaron Elbourne
- School of Science, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, Australia
| | - Paul A. Ramsland
- School of Science, College of Science, Engineering and Health, RMIT University, Melbourne, VIC, Australia
- Department of Surgery Austin Health, University of Melbourne, Heidelberg, VIC, Australia
- Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Garth Cameron
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Dhiraj Hans
- Research, Innovation and Commercialisation, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Dale I. Godfrey
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
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10
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Gomez-Escobar E, Roingeard P, Beaumont E. Current Hepatitis C Vaccine Candidates Based on the Induction of Neutralizing Antibodies. Viruses 2023; 15:1151. [PMID: 37243237 PMCID: PMC10220683 DOI: 10.3390/v15051151] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
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.
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Affiliation(s)
| | - Philippe Roingeard
- Inserm U1259 MAVIVH, Université de Tours and CHRU de Tours, 37000 Tours, France;
| | - Elodie Beaumont
- Inserm U1259 MAVIVH, Université de Tours and CHRU de Tours, 37000 Tours, France;
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11
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Sliepen K, Radić L, Capella-Pujol J, Watanabe Y, Zon I, Chumbe A, Lee WH, de Gast M, Koopsen J, Koekkoek S, Del Moral-Sánchez I, Brouwer PJM, Ravichandran R, Ozorowski G, King NP, Ward AB, van Gils MJ, Crispin M, Schinkel J, Sanders RW. Induction of cross-neutralizing antibodies by a permuted hepatitis C virus glycoprotein nanoparticle vaccine candidate. Nat Commun 2022; 13:7271. [PMID: 36434005 PMCID: PMC9700739 DOI: 10.1038/s41467-022-34961-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 11/14/2022] [Indexed: 11/27/2022] Open
Abstract
Hepatitis C virus (HCV) infection affects approximately 58 million people and causes ~300,000 deaths yearly. The only target for HCV neutralizing antibodies is the highly sequence diverse E1E2 glycoprotein. Eliciting broadly neutralizing antibodies that recognize conserved cross-neutralizing epitopes is important for an effective HCV vaccine. However, most recombinant HCV glycoprotein vaccines, which usually include only E2, induce only weak neutralizing antibody responses. Here, we describe recombinant soluble E1E2 immunogens that were generated by permutation of the E1 and E2 subunits. We displayed the E2E1 immunogens on two-component nanoparticles and these nanoparticles induce significantly more potent neutralizing antibody responses than E2. Next, we generated mosaic nanoparticles co-displaying six different E2E1 immunogens. These mosaic E2E1 nanoparticles elicit significantly improved neutralization compared to monovalent E2E1 nanoparticles. These results provide a roadmap for the generation of an HCV vaccine that induces potent and broad neutralization.
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Affiliation(s)
- Kwinten Sliepen
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands.
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands.
| | - Laura Radić
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Joan Capella-Pujol
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Yasunori Watanabe
- School of Biological Sciences, University of Southampton, Southampton, UK
| | - Ian Zon
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Ana Chumbe
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Wen-Hsin Lee
- Department of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Marlon de Gast
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Jelle Koopsen
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Sylvie Koekkoek
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Iván Del Moral-Sánchez
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Philip J M Brouwer
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Rashmi Ravichandran
- Department of Biochemistry, University of Washington, Seattle, USA
- Institute for Protein Design, University of Washington, Seattle, USA
| | - Gabriel Ozorowski
- Department of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Neil P King
- Department of Biochemistry, University of Washington, Seattle, USA
- Institute for Protein Design, University of Washington, Seattle, USA
| | - Andrew B Ward
- Department of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Marit J van Gils
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Max Crispin
- School of Biological Sciences, University of Southampton, Southampton, UK
| | - Janke Schinkel
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands
| | - Rogier W Sanders
- Amsterdam UMC, location University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam, The Netherlands.
- Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, The Netherlands.
- Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, USA.
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12
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Lin T, Chi X, Liu X, Pan S, Chen W, Duan H, Zhang X, Yang W. Recombinant Full-Length Hepatitis C Virus E1E2 Dimer Elicits Pangenotypic Neutralizing Antibodies. Front Immunol 2022; 13:831285. [PMID: 35837406 PMCID: PMC9273934 DOI: 10.3389/fimmu.2022.831285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 06/02/2022] [Indexed: 11/13/2022] Open
Abstract
An effective prophylactic vaccine would be beneficial for controlling and eradicating hepatitis C virus (HCV) infections. However, the high diversity across HCV genotypes is a major challenge for vaccine development. Selection of the appropriate immunogen is critical to elicit broad HCV neutralizing antibodies (NAbs). To increase the antigenic coverage of heterodimer glycoproteins, we designed and produced recombinant E1E2 antigens for genotypes 1a/1b/2a/3a/6a from an IgG Fc-tagged precursor protein in FreeStyle 293-F cells. The recombinant E1 and E2 antigens were localized and associated with the endoplasmic reticulum and co-purified from membrane extracts. By examining the interactions with HCV entry co-receptors and the blockade of HCV infection, we found that these purified Fc-E1E2 proteins displayed correct folding and function. Mouse immunization results showed that each recombinant E1E2 antigen could elicit a pangenotypic antibody response to itself and other genotypes. We also found that the pentavalent formula triggered a relatively higher and more uniform NAb titer and T cell response than monovalent antigens. Taken together, our findings may provide a useful strategy for the vaccine development of HCV and other viruses with highly heterogeneous surface glycoproteins.
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13
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Liu T, Li L, Cheng C, He B, Jiang T. Emerging prospects of protein/peptide-based nanoassemblies for drug delivery and vaccine development. NANO RESEARCH 2022; 15:7267-7285. [PMID: 35692441 PMCID: PMC9166156 DOI: 10.1007/s12274-022-4385-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 05/09/2023]
Abstract
Proteins have been widely used in the biomedical field because of their well-defined architecture, accurate molecular weight, excellent biocompatibility and biodegradability, and easy-to-functionalization. Inspired by the wisdom of nature, increasing proteins/peptides that possess self-assembling capabilities have been explored and designed to generate nanoassemblies with unique structure and function, including spatially organized conformation, passive and active targeting, stimuli-responsiveness, and high stability. These characteristics make protein/peptide-based nanoassembly an ideal platform for drug delivery and vaccine development. In this review, we focus on recent advances in subsistent protein/peptide-based nanoassemblies, including protein nanocages, virus-like particles, self-assemblable natural proteins, and self-assemblable artificial peptides. The origin and characteristics of various protein/peptide-based assemblies and their applications in drug delivery and vaccine development are summarized. In the end, the prospects and challenges are discussed for the further development of protein/peptide-based nanoassemblies.
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Affiliation(s)
- Taiyu Liu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816 China
| | - Lu Li
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816 China
| | - Cheng Cheng
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816 China
| | - Bingfang He
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816 China
| | - Tianyue Jiang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816 China
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14
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Yato K, Matsuda M, Watanabe N, Watashi K, Aizaki H, Kato T, Tamura K, Wakita T, Muramatsu M, Suzuki R. Induction of neutralizing antibodies against hepatitis C virus by a subviral particle-based DNA vaccine. Antiviral Res 2022; 199:105266. [DOI: 10.1016/j.antiviral.2022.105266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 02/09/2022] [Accepted: 02/17/2022] [Indexed: 12/26/2022]
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15
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Bankwitz D, Krey T, Pietschmann T. [Development approaches for vaccines against hepatitis C virus infections]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2022; 65:183-191. [PMID: 35015104 PMCID: PMC8749110 DOI: 10.1007/s00103-021-03477-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/07/2021] [Indexed: 11/04/2022]
Abstract
Mehr als 10 Jahre nach der Zulassung der ersten direkt wirkenden antiviralen Wirkstoffe zur Behandlung der Hepatitis C bleibt die Inzidenz der Hepatitis-C-Virus-(HCV-)Infektion ungebrochen hoch. In manchen Ländern stecken sich mehr Menschen neu mit dem Virus an, als Patienten durch eine erfolgreiche Therapie geheilt werden. Die Entwicklung eines prophylaktischen Impfstoffes könnte die Transmission des Virus unterbinden und dadurch einen wesentlichen Beitrag zur Kontrolle dieser weltweit verbreiteten Infektion leisten. In diesem Artikel werden die besonderen Herausforderungen und die aktuellen Ansätze der HCV-Impfstoffentwicklung dargestellt. HCV ist ein hochgradig diverses und wandlungsfähiges Virus, das zumeist dem Immunsystem entkommt und chronische Infektionen etabliert. Andererseits heilt die HCV-Infektion bei bis zu einem Drittel der exponierten Individuen aus, sodass eine schützende Immunität erreichbar ist. Zahlreiche Untersuchungen zu den Determinanten einer schützenden Immunität gegen HCV zeichnen ein immer kompletteres Bild davon, welche Ziele ein Impfstoff erreichen muss. Sehr wahrscheinlich werden sowohl starke neutralisierende Antikörper als auch wirkungsvolle zytotoxische T‑Zellen gebraucht, um sicher vor einer chronischen Infektion zu schützen. Die Schlüsselfrage ist, welche Ansätze besonders breit wirksame Antikörper und T‑Zellen heranreifen lassen. Dies wird erforderlich sein, um vor der großen Fülle unterschiedlicher HCV-Varianten zu schützen. Die jüngsten Erfolge von mRNA-Impfstoffen öffnen neue Türen auch für die HCV-Impfstoffforschung. Kombiniert mit einem tieferen Verständnis der Struktur und Funktion der viralen Hüllproteine, der Identifizierung kreuzprotektiver Antikörper- und T‑Zellepitope sowie der Nutzung standardisierter Verfahren zur Quantifizierung der Wirksamkeit von Impfkandidaten ergeben sich neue Perspektiven für die Entwicklung eines Impfstoffes.
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Affiliation(s)
- Dorothea Bankwitz
- Twincore Zentrum für Experimentelle und Klinische Infektionsforschung, Institut für Experimentelle Virologie, Feodor-Lynen-Str. 7, 30625, Hannover, Deutschland
| | - Thomas Krey
- Medizinische Hochschule Hannover, RESIST Exzellenzcluster EXC2155, Hannover, Deutschland.,Zentrum für Strukturbiologie und Zellbiologie in der Medizin, Institut für Biochemie, Universität Lübeck, Lübeck, Deutschland.,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Hamburg-Lübeck-Borstel-Riems, Braunschweig, Deutschland.,Institut für Virologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Thomas Pietschmann
- Twincore Zentrum für Experimentelle und Klinische Infektionsforschung, Institut für Experimentelle Virologie, Feodor-Lynen-Str. 7, 30625, Hannover, Deutschland. .,Medizinische Hochschule Hannover, RESIST Exzellenzcluster EXC2155, Hannover, Deutschland. .,Deutsches Zentrum für Infektionsforschung (DZIF), Partnerstandort Hannover-Braunschweig, Braunschweig, Deutschland.
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16
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Virus-Like Particles Containing the E2 Core Domain of Hepatitis C Virus Generate Broadly Neutralizing Antibodies in Guinea Pigs. J Virol 2022; 96:e0167521. [PMID: 34986001 PMCID: PMC8906423 DOI: 10.1128/jvi.01675-21] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
A vaccine to prevent hepatitis C virus (HCV) infection is urgently needed for use alongside direct-acting antiviral drugs to achieve elimination targets. We have previously shown that a soluble recombinant form of the glycoprotein E2 ectodomain (residues 384 to 661) that lacks three variable regions (Δ123) is able to elicit a higher titer of broadly neutralizing antibodies (bNAbs) than the parental form (receptor-binding domain [RBD]). In this study, we engineered a viral nanoparticle that displays HCV glycoprotein E2 on a duck hepatitis B virus (DHBV) small surface antigen (S) scaffold. Four variants of E2-S virus-like particles (VLPs) were constructed: Δ123-S, RBD-S, Δ123A7-S, and RBDA7-S; in the last two, 7 cysteines were replaced with alanines. While all four E2-S variant VLPs display E2 as a surface antigen, the Δ123A7-S and RBDA7-S VLPs were the most efficiently secreted from transfected mammalian cells and displayed epitopes recognized by cross-genotype broadly neutralizing monoclonal antibodies (bNMAbs). Both Δ123A7-S and RBDA7-S VLPs were immunogenic in guinea pigs, generating high titers of antibodies reactive to native E2 and able to prevent the interaction between E2 and the cellular receptor CD81. Four out of eight animals immunized with Δ123A7-S elicited neutralizing antibodies (NAbs), with three of those animals generating bNAbs against 7 genotypes. Immune serum generated by animals with NAbs mapped to major neutralization epitopes located at residues 412 to 420 (epitope I) and antigenic region 3. VLPs that display E2 glycoproteins represent a promising vaccine platform for HCV and could be adapted to large-scale manufacturing in yeast systems. IMPORTANCE There is currently no vaccine to prevent hepatitis C virus infection, which affects more than 71 million people globally and is a leading cause of progressive liver disease, including cirrhosis and cancer. Broadly neutralizing antibodies that recognize the E2 envelope glycoprotein can protect against heterologous viral infection and correlate with viral clearance in humans. However, broadly neutralizing antibodies are difficult to generate due to conformational flexibility of the E2 protein and epitope occlusion. Here, we show that a VLP vaccine using the duck hepatitis B virus S antigen fused to HCV glycoprotein E2 assembles into virus-like particles that display epitopes recognized by broadly neutralizing antibodies and elicit such antibodies in guinea pigs. This platform represents a novel HCV vaccine candidate amenable to large-scale manufacture at low cost.
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17
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Manne V, Ryan J, Wong J, Vengayil G, Basit SA, Gish RG. Hepatitis C Vaccination: Where We Are and Where We Need to Be. Pathogens 2021; 10:pathogens10121619. [PMID: 34959574 PMCID: PMC8705661 DOI: 10.3390/pathogens10121619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open
Abstract
The hepatitis C virus (HCV) is a common cause of chronic liver disease and liver cancer worldwide. Despite advances in curative therapies for HCV, the incidence of new infections is not decreasing at the expected rate to hit the World Health Organization (WHO) target for the elimination of HCV by 2030. In fact, there are still more new cases of infection in the United States and worldwide than are being cured. The reasons for the rise in new cases include poor access to care and the opioid epidemic. The clinical burden of HCV requires a multimodal approach to eradicating the infection. Vaccination would be an excellent tool to prevent incidence of new infections; however, the genetic diversity of HCV and its ability to generate quasispecies within an infected host make creating a broadly reactive vaccine difficult. Multiple vaccine candidates have been identified, but to date, there has not been a target that has led to a broadly reactive vaccine, though several of the candidates are promising. Additionally, the virus is very difficult to culture and testing candidates in humans or chimpanzees is ethically challenging. Despite the multiple barriers to creating a vaccine, vaccination still represents an important tool in the fight against HCV.
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Affiliation(s)
- Vignan Manne
- HCA Healthcare Graduate Medical Education, Las Vegas, NV 89148, USA; (V.M.); (J.W.); (G.V.)
| | - John Ryan
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA; (J.R.); (S.A.B.)
| | - Jonathan Wong
- HCA Healthcare Graduate Medical Education, Las Vegas, NV 89148, USA; (V.M.); (J.W.); (G.V.)
| | - Gayatri Vengayil
- HCA Healthcare Graduate Medical Education, Las Vegas, NV 89148, USA; (V.M.); (J.W.); (G.V.)
| | - Syed Abdul Basit
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA; (J.R.); (S.A.B.)
| | - Robert G. Gish
- Liver Transplant Clinic, Loma Linda University, Loma Linda, CA 92350, USA
- Correspondence: ; Tel.: +1-866-873-8877
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18
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Zhu M, Yang H, Lu Y, Yang H, Tang Y, Li L, Zhu Y, Yuan J. Cardiac ectopic lymphoid follicle formation in viral myocarditis involving the regulation of podoplanin in Th17 cell differentiation. FASEB J 2021; 35:e21975. [PMID: 34618980 DOI: 10.1096/fj.202101050rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 11/11/2022]
Abstract
Autoimmunity contributes to the pathogenesis of viral myocarditis (VMC), which is characterized by the production of anti-heart autoantibodies (AHA) from lymphoid follicles. Recently, the formation of ectopic lymphoid follicles (ELFs) was reported in heart grafts. However, the existence and role of ELFs in myocardial tissues of VMC remain unclear. This study aimed to explore whether and how cardiac ELFs with germinal centers (GCs) could be generated during the development of VMC. We identified the existence of ELFs and explored the underlying mechanism. In a BALB/c mouse model of VMC, the dynamic myocardial infiltrations of lymphocytic aggregates and expressions of associated lymphorganogenic factors were investigated, accompanied by the detection of the production and location of myocardial AHA. The data indicated ELFs formation in myocardial tissues of VMC, and the number of ELFs was in accordance with the severity of VMC. Moreover, the functional ELFs with GCs were capable of facilitating the production of local AHA. Blocking IL-17 or podoplanin (PDPN) could inhibit cardiac ELFs generation, perhaps due to the negative regulation of PDPN neutralization in Th17 cell proliferation and differentiation. The presence of cardiac ELFs and AHA might offer new opportunities for stratification and early identification of VMC patients.
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Affiliation(s)
- Mingxin Zhu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Lu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongmin Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaohan Tang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lixia Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaoxi Zhu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Yuan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Pisano MB, Giadans CG, Flichman DM, Ré VE, Preciado MV, Valva P. Viral hepatitis update: Progress and perspectives. World J Gastroenterol 2021; 27:4018-4044. [PMID: 34326611 PMCID: PMC8311538 DOI: 10.3748/wjg.v27.i26.4018] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis, secondary to infection with hepatitis A, B, C, D, and E viruses, are a major public health problem and an important cause of morbidity and mortality. Despite the huge medical advances achieved in recent years, there are still points of conflict concerning the pathogenesis, immune response, development of new and more effective vaccines, therapies, and treatment. This review focuses on the most important research topics that deal with issues that are currently being solved, those that remain to be solved, and future research directions. For hepatitis A virus we will address epidemiology, molecular surveillance, new susceptible populations as well as environmental and food detections. In the case of hepatitis B virus, we will discuss host factors related to disease, diagnosis, therapy, and vaccine improvement. On hepatitis C virus, we will focus on pathogenesis, immune response, direct action antivirals treatment in the context of solid organ transplantation, issues related to hepatocellular carcinoma development, direct action antivirals resistance due to selection of resistance-associated variants, and vaccination. Regarding hepatitis D virus, we describe diagnostic methodology, pathogenesis, and therapy. Finally, for hepatitis E virus, we will address epidemiology (including new emerging species), diagnosis, clinical aspects, treatment, the development of a vaccine, and environmental surveillance.
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Affiliation(s)
- María B Pisano
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - Cecilia G Giadans
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Diego M Flichman
- Institute of Biomedical Investigations in Retrovirus and AIDS (INBIRS), School of Medicine, University of Buenos Aires, CONICET, CABA C1121ABG, Buenos Aires, Argentina
| | - Viviana E Ré
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - María V Preciado
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Pamela Valva
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
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20
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Andrianov AK, Fuerst TR. Immunopotentiating and Delivery Systems for HCV Vaccines. Viruses 2021; 13:v13060981. [PMID: 34070543 PMCID: PMC8227888 DOI: 10.3390/v13060981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/16/2021] [Accepted: 05/19/2021] [Indexed: 12/13/2022] Open
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 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.
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Affiliation(s)
- Alexander K. Andrianov
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA;
- Correspondence:
| | - Thomas R. Fuerst
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA;
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
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To Include or Occlude: Rational Engineering of HCV Vaccines for Humoral Immunity. Viruses 2021; 13:v13050805. [PMID: 33946211 PMCID: PMC8146105 DOI: 10.3390/v13050805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/16/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
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 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.
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Abstract
PURPOSE OF REVIEW The WHO has set ambitious targets for hepatitis C virus (HCV) elimination by 2030. In this review, we explore the possibility of HCV micro-elimination in HIV-positive (+) MSM, discussing strategies for reducing acute HCV incidence and the likely interventions required to meet these targets. RECENT FINDINGS With wider availability of directly acting antivirals (DAAs) in recent years, reductions in acute HCV incidence have been reported in some cohorts of HIV+ MSM. Recent evidence demonstrates that treatment in early infection is well tolerated, cost effective and may reduce the risk of onward transmission. Modelling studies suggest that to reduce incidence, a combination approach including behavioural interventions and access to early treatment, targeting both HIV+ and negative high-risk groups, will be required. HCV vaccine trials have not yet demonstrated efficacy in human studies, however phase one and two studies are ongoing. SUMMARY Some progress towards the WHO HCV elimination targets has been reported. Achieving sustained HCV elimination is likely to require a combination approach including early access to DAAs in acute infection and reinfection, validated and reproducible behavioural interventions and an efficacious HCV vaccine.
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer-related death worldwide.
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Kardani K, Basimi P, Fekri M, Bolhassani A. Antiviral therapy for the sexually transmitted viruses: recent updates on vaccine development. Expert Rev Clin Pharmacol 2020; 13:1001-1046. [PMID: 32838584 DOI: 10.1080/17512433.2020.1814743] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The sexually transmitted infections (STIs) caused by viruses including human T cell leukemia virus type-1 (HTLV-1), human immunodeficiency virus-1 (HIV-1), human simplex virus-2 (HSV-2), hepatitis C virus (HCV), hepatitis B virus (HBV), and human papillomavirus (HPV) are major public health issues. These infections can cause cancer or result in long-term health problems. Due to high prevalence of STIs, a safe and effective vaccine is required to overcome these fatal viruses. AREAS COVERED This review includes a comprehensive overview of the literatures relevant to vaccine development against the sexually transmitted viruses (STVs) using PubMed and Sciencedirect electronic search engines. Herein, we discuss the efforts directed toward development of effective vaccines using different laboratory animal models including mice, guinea pig or non-human primates in preclinical trials, and human in clinical trials with different phases. EXPERT OPINION There is no effective FDA approved vaccine against the sexually transmitted viruses (STVs) except for HBV and HPV as prophylactic vaccines. Many attempts are underway to develop vaccines against these viruses. There are several approaches for improving prophylactic or therapeutic vaccines such as heterologous prime/boost immunization, delivery system, administration route, adjuvants, etc. In this line, further studies can be helpful for understanding the immunobiology of STVs in human. Moreover, development of more relevant animal models is a worthy goal to induce effective immune responses in humans.
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Affiliation(s)
- Kimia Kardani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Parya Basimi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Mehrshad Fekri
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
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25
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Hepatitis C virus vaccine design: focus on the humoral immune response. J Biomed Sci 2020; 27:78. [PMID: 32631318 PMCID: PMC7338099 DOI: 10.1186/s12929-020-00669-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023] Open
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.
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26
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Duncan JD, Urbanowicz RA, Tarr AW, Ball JK. Hepatitis C Virus Vaccine: Challenges and Prospects. Vaccines (Basel) 2020; 8:vaccines8010090. [PMID: 32079254 PMCID: PMC7157504 DOI: 10.3390/vaccines8010090] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/25/2020] [Accepted: 02/04/2020] [Indexed: 02/07/2023] Open
Abstract
The hepatitis C virus (HCV) causes both acute and chronic infection and continues to be a global problem despite advances in antiviral therapeutics. Current treatments fail to prevent reinfection and remain expensive, limiting their use to developed countries, and the asymptomatic nature of acute infection can result in individuals not receiving treatment and unknowingly spreading HCV. A prophylactic vaccine is therefore needed to control this virus. Thirty years since the discovery of HCV, there have been major gains in understanding the molecular biology and elucidating the immunological mechanisms that underpin spontaneous viral clearance, aiding rational vaccine design. This review discusses the challenges facing HCV vaccine design and the most recent and promising candidates being investigated.
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Affiliation(s)
- Joshua D. Duncan
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
- Correspondence:
| | - Richard A. Urbanowicz
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Alexander W. Tarr
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Jonathan K. Ball
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
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27
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Cox AL. Challenges and Promise of a Hepatitis C Virus Vaccine. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036947. [PMID: 31548228 DOI: 10.1101/cshperspect.a036947] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
An estimated 1.5-2 million new hepatitis C virus (HCV) infections occur globally each year. Critical to the World Health Organization's (WHO) HCV elimination strategy is an 80% reduction in incidence of HCV infections by 2030. However, even among high-income countries, few are on target to achieve the WHO's incident infection-reduction goal. A preventative vaccine could have a major impact in achieving incidence-reduction targets globally. However, barriers to HCV vaccine development are significant and include at-risk populations that are often marginalized: viral diversity, limited options for testing HCV vaccines, and an incomplete understanding of protective immune responses. In part because of those factors, testing of only one vaccine strategy has been completed in at-risk individuals as of 2019. Despite challenges, immunity against HCV protects against chronic infection in some repeated HCV exposures and an effective HCV vaccine could prevent transmission regardless of risk factors. Ultimately, prophylactic vaccines will likely be necessary to achieve global HCV elimination.
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Affiliation(s)
- Andrea L Cox
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland 21205, USA
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28
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Quasispecies dynamics in disease prevention and control. VIRUS AS POPULATIONS 2020. [PMCID: PMC7153035 DOI: 10.1016/b978-0-12-816331-3.00008-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Medical interventions to prevent and treat viral disease constitute evolutionary forces that may modify the genetic composition of viral populations that replicate in an infected host and influence the genomic composition of those viruses that are transmitted and progress at the epidemiological level. Given the adaptive potential of viruses in general and the RNA viruses in particular, the selection of viral mutants that display some degree of resistance to inhibitors or vaccines is a tangible challenge. Mutant selection may jeopardize control of the viral disease. Strategies intended to minimize vaccination and treatment failures are proposed and justified based on fundamental features of viral dynamics explained in the preceding chapters. The recommended use of complex, multiepitopic vaccines, and combination therapies as early as possible after initiation of infection falls under the general concept that complexity cannot be combated with simplicity. It also follows that sociopolitical action to interrupt virus replication and spread as soon as possible is as important as scientifically sound treatment designs to control viral disease on a global scale.
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29
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Abstract
Evidence for the existence of another hepatitis-causing pathogen, other than the known hepatitis A and B viruses, emerged in the mid-1970s. A frustrating search of 15 years was ended by the identification of the hepatitis C virus in 1989 using a recombinant DNA immunoscreening method. This discovery quickly led to blood tests that eliminated posttransfusion hepatitis C and could show the partial efficacy of type 1 interferon-based therapies. Subsequent knowledge of the viral replication cycle then led to the development of effective direct-acting antivirals targeting its serine protease, polymerase, and nonstructural protein 5A that resulted in the approval of orally available drug combinations that can cure patients within a few months with few side effects. Meanwhile, vaccine strategies have been shown to be feasible, and they are still required to effectively control this global epidemic.
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Affiliation(s)
- Michael Houghton
- Li Ka Shing Applied Virology Institute, Department of Medical Microbiology & Immunology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
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HCV p7 as a novel vaccine-target inducing multifunctional CD4 + and CD8 + T-cells targeting liver cells expressing the viral antigen. Sci Rep 2019; 9:14085. [PMID: 31575882 PMCID: PMC6773770 DOI: 10.1038/s41598-019-50365-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 09/11/2019] [Indexed: 02/07/2023] Open
Abstract
Despite recent treatment advances for chronic hepatitis C virus (HCV) infection, a vaccine is urgently needed for global control of this important liver pathogen. The lack of robust immunocompetent HCV infection models makes it challenging to identify correlates of protection and test vaccine efficacy. However, vigorous CD4+ and CD8+ T-cell responses are detected in patients that spontaneously resolve acute infection, whereas dysfunctional T-cell responses are a hallmark of chronic infection. The HCV p7 protein, forming ion-channels essential for viral assembly and release, has not previously been pursued as a vaccine antigen. Herein, we demonstrated that HCV p7 derived from genotype 1a and 1b sequences are highly immunogenic in mice when employed as overlapping peptides formulated as nanoparticles with the cross-priming adjuvant, CAF09. This approach induced multifunctional cytokine producing CD4+ and CD8+ T-cells targeting regions of p7 that are subject to immune pressure during HCV infection in chimpanzees and humans. Employing a surrogate in vivo challenge model of liver cells co-expressing HCV-p7 and GFP, we found that vaccinated mice cleared transgene expressing cells. This study affirms the potential of a T-cell inducing nanoparticle vaccine platform to target the liver and introduces HCV p7 as a potential target for HCV vaccine explorations.
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31
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Virus-Like Particle Systems for Vaccine Development against Viruses in the Flaviviridae Family. Vaccines (Basel) 2019; 7:vaccines7040123. [PMID: 31547131 PMCID: PMC6963367 DOI: 10.3390/vaccines7040123] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/07/2019] [Accepted: 09/13/2019] [Indexed: 01/07/2023] Open
Abstract
Viruses in the Flaviviridae family are important human and animal pathogens that impose serious threats to global public health. This family of viruses includes emerging and re-emerging viruses, most of which are transmitted by infected mosquito or tick bites. Currently, there is no protective vaccine or effective antiviral treatment against the majority of these viruses, and due to their growing spread, several strategies have been employed to manufacture prophylactic vaccines against these infectious agents including virus-like particle (VLP) subunit vaccines. VLPs are genomeless viral particles that resemble authentic viruses and contain critical repetitive conformational structures on their surface that can trigger the induction of both humoral and cellular responses, making them safe and ideal vaccine candidates against these viruses. In this review, we focus on the potential of the VLP platform in the current vaccine development against the medically important viruses in the Flaviviridae family.
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32
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Pre-clinical evaluation of a quadrivalent HCV VLP vaccine in pigs following microneedle delivery. Sci Rep 2019; 9:9251. [PMID: 31239471 PMCID: PMC6592879 DOI: 10.1038/s41598-019-45461-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 05/29/2019] [Indexed: 02/07/2023] Open
Abstract
The introduction of directly acting antiviral agents (DAAs) has produced significant improvements in the ability to cure chronic hepatitis C infection. However, with over 2% of the world’s population infected with HCV, complications arising from the development of cirrhosis of the liver, chronic hepatitis C infection remains the leading indication for liver transplantation. Several modelling studies have indicated that DAAs alone will not be sufficient to eliminate HCV, but if combined with an effective vaccine this regimen would provide a significant advance towards achieving this critical World Health Organisation goal. We have previously generated a genotype 1a, 1b, 2a, 3a HCV virus like particle (VLP) quadrivalent vaccine. The HCV VLPs contain the core and envelope proteins (E1 and E2) of HCV and the vaccine has been shown to produce broad humoral and T cell immune responses following vaccination of mice. In this report we further advanced this work by investigating vaccine responses in a large animal model. We demonstrate that intradermal microneedle vaccination of pigs with our quadrivalent HCV VLP based vaccine produces long-lived multi-genotype specific and neutralizing antibody (NAb) responses together with strong T cell and granzyme B responses and normal Th1 and Th2 cytokine responses. These responses were achieved without the addition of adjuvant. Our study demonstrates that our vaccine is able to produce broad immune responses in a large animal that, next to primates, is the closest animal model to humans. Our results are important as they show that the vaccine can produce robust immune responses in a large animal model before progressing the vaccine to human trials.
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33
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Collett S, Torresi J, Earnest-Silveira L, Christiansen D, Elbourne A, Ramsland PA. Probing and pressing surfaces of hepatitis C virus-like particles. J Colloid Interface Sci 2019; 545:259-268. [DOI: 10.1016/j.jcis.2019.03.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 03/07/2019] [Accepted: 03/09/2019] [Indexed: 02/09/2023]
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Bailey JR, Barnes E, Cox AL. Approaches, Progress, and Challenges to Hepatitis C Vaccine Development. Gastroenterology 2019; 156:418-430. [PMID: 30268785 PMCID: PMC6340767 DOI: 10.1053/j.gastro.2018.08.060] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 08/12/2018] [Accepted: 08/14/2018] [Indexed: 12/16/2022]
Abstract
Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV.
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Affiliation(s)
- Justin R. Bailey
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, Oxford University, UK
| | - Andrea L. Cox
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland,Reprint requests Address requests for reprints to: Andrea L. Cox, MD, PhD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 551 Rangos Building, 855 N Wolfe Street, Baltimore, Maryland 21205. fax: (443)769-1221.
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35
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Dominguez-Molina B, Machmach K, Perales C, Tarancon-Diez L, Gallego I, Sheldon JL, Leal M, Domingo E, Ruiz-Mateos E. Toll-Like Receptor 7 (TLR-7) and TLR-9 Agonists Improve Hepatitis C Virus Replication and Infectivity Inhibition by Plasmacytoid Dendritic Cells. J Virol 2018; 92:e01219-18. [PMID: 30232187 PMCID: PMC6232477 DOI: 10.1128/jvi.01219-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 08/27/2018] [Indexed: 12/20/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are innate immune cells with high antiviral activity triggered by Toll-like receptor 7 (TLR-7) and TLR-9 stimulation. Moreover, they are important mediators between innate and adaptive immunity. Although nowadays there is available an effective therapeutic arsenal against hepatitis C virus (HCV), a protective vaccine is not available. We have analyzed the pDCs' response to HCV infection in a hepatitis C virus (HCV)-Huh7.5 virus-cell system, which allows completion of the virus infectious cycle. pDCs were cocultured following human immunodeficiency virus (HIV) aldrithiol-2 (AT-2 [TLR-7 agonist]) inactivation and CpG (TLR-9 agonist) stimulation. We employed three virus derivatives-wild-type Jc1, interferon (IFN)-resistant virus IR, and high-replicative-fitness virus P100-in order to explore additional IFN-α-related virus inhibition mechanisms. pDCs inhibited HCV infectivity and replication and produced IFN-α. After TLR-7 and TLR-9 stimulation, inhibition of infectivity and IFN-α production by pDCs were enhanced. TLR-7 stimulation drove higher TNF-related apoptosis-inducing ligand (TRAIL) expression in pDCs. Additionally, TLR-7- and TLR-9-stimulated pDCs exhibited a mature phenotype, improving the antigen presentation and lymph node homing-related markers. In conclusion, pDCs could serve as a drug target against HCV in order to improve antiviral activity and as an enhancer of viral immunization.IMPORTANCE We implemented a coculture system of pDCs with HCV-infected hepatoma cell line, Huh7.5. We used three HCV derivatives in order to gain insight into pDCs' behavior against HCV and associated antiviral mechanisms. The results with this cell coculture system support the capacity of pDCs to inhibit HCV replication and infectivity mainly via IFN-α, but also through additional mechanisms associated with pDC maturation. We provided evidence that TLR agonists can enhance antiviral pDCs' function and can induce phenotypic changes that may facilitate the interplay with other immune cells. These findings suggest the possibility of including TLR agonists in the strategies of HCV vaccine development.
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Affiliation(s)
- B Dominguez-Molina
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain
| | - K Machmach
- Department of Medical Microbiology and Immunology, University of California, Davis, California, USA
- California National Primate Research Center, Davis, California, USA
| | - C Perales
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Liver Unit, Internal Medicine Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - L Tarancon-Diez
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain
| | - I Gallego
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - J L Sheldon
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - M Leal
- Servicio de Medicina Interna, Hospital Viamed, Santa Ángela de la Cruz, Seville, Spain
- Laboratory of Immunovirology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - E Domingo
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - E Ruiz-Mateos
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain
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