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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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Hammel A, Cucos LM, Caras I, Ionescu I, Tucureanu C, Tofan V, Costache A, Onu A, Hoepfner L, Hippler M, Neupert J, Popescu CI, Stavaru C, Branza-Nichita N, Bock R. The red alga Porphyridium as a host for molecular farming: Efficient production of immunologically active hepatitis C virus glycoprotein. Proc Natl Acad Sci U S A 2024; 121:e2400145121. [PMID: 38833465 PMCID: PMC11181018 DOI: 10.1073/pnas.2400145121] [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: 01/08/2024] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Abstract
Microalgae are promising production platforms for the cost-effective production of recombinant proteins. We have recently established that the red alga Porphyridium purpureum provides superior transgene expression properties, due to the episomal maintenance of transformation vectors as multicopy plasmids in the nucleus. Here, we have explored the potential of Porphyridium to synthesize complex pharmaceutical proteins to high levels. Testing expression constructs for a candidate subunit vaccine against the hepatitis C virus (HCV), we show that the soluble HCV E2 glycoprotein can be produced in transgenic algal cultures to high levels. The antigen undergoes faithful posttranslational modification by N-glycosylation and is recognized by conformationally selective antibodies, suggesting that it adopts a proper antigenic conformation in the endoplasmic reticulum of red algal cells. We also report the experimental determination of the structure of the N-glycan moiety that is attached to glycosylated proteins in Porphyridium. Finally, we demonstrate the immunogenicity of the HCV antigen produced in red algae when administered by injection as pure protein or by feeding of algal biomass.
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Affiliation(s)
- Alexander Hammel
- Max-Planck-Institut für Molekulare Pflanzenphysiologie, Department of Organelle Biology, Biotechnology and Molecular Ecophysiology, D-14476Potsdam-Golm, Germany
| | - Lia-Maria Cucos
- Institute of Biochemistry of the Romanian Academy, Department of Viral Glycoproteins, 060031Bucharest, Romania
| | - Iuliana Caras
- ”Cantacuzino” Medico-Military National Research Institute, 050096Bucharest, Romania
| | - Irina Ionescu
- ”Cantacuzino” Medico-Military National Research Institute, 050096Bucharest, Romania
| | - Catalin Tucureanu
- ”Cantacuzino” Medico-Military National Research Institute, 050096Bucharest, Romania
| | - Vlad Tofan
- ”Cantacuzino” Medico-Military National Research Institute, 050096Bucharest, Romania
| | - Adriana Costache
- ”Cantacuzino” Medico-Military National Research Institute, 050096Bucharest, Romania
| | - Adrian Onu
- ”Cantacuzino” Medico-Military National Research Institute, 050096Bucharest, Romania
| | - Lara Hoepfner
- Institute of Plant Biology and Biotechnology, University of Münster, D-48143Münster, Germany
| | - Michael Hippler
- Institute of Plant Biology and Biotechnology, University of Münster, D-48143Münster, Germany
- Institute of Plant Science and Resources, Okayama University, Kurashiki710-0046, Japan
| | - Juliane Neupert
- Max-Planck-Institut für Molekulare Pflanzenphysiologie, Department of Organelle Biology, Biotechnology and Molecular Ecophysiology, D-14476Potsdam-Golm, Germany
| | - Costin-Ioan Popescu
- Institute of Biochemistry of the Romanian Academy, Department of Viral Glycoproteins, 060031Bucharest, Romania
| | - Crina Stavaru
- ”Cantacuzino” Medico-Military National Research Institute, 050096Bucharest, Romania
| | - Norica Branza-Nichita
- Institute of Biochemistry of the Romanian Academy, Department of Viral Glycoproteins, 060031Bucharest, Romania
| | - Ralph Bock
- Max-Planck-Institut für Molekulare Pflanzenphysiologie, Department of Organelle Biology, Biotechnology and Molecular Ecophysiology, D-14476Potsdam-Golm, Germany
- NIBIO, Norwegian Institute of Bioeconomy Research, NO-1431 Ås, Norway
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Elbahrawy A, Atalla H, Alboraie M, Alwassief A, Madian A, El Fayoumie M, Tabll AA, Aly HH. Recent Advances in Protective Vaccines against Hepatitis Viruses: A Narrative Review. Viruses 2023; 15:214. [PMID: 36680254 PMCID: PMC9862019 DOI: 10.3390/v15010214] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/03/2023] [Accepted: 01/07/2023] [Indexed: 01/15/2023] Open
Abstract
Vaccination has been confirmed to be the safest and, sometimes, the only tool of defense against threats from infectious diseases. The successful history of vaccination is evident in the control of serious viral infections, such as smallpox and polio. Viruses that infect human livers are known as hepatitis viruses and are classified into five major types from A to E, alphabetically. Although infection with hepatitis A virus (HAV) is known to be self-resolving after rest and symptomatic treatment, there were 7134 deaths from HAV worldwide in 2016. In 2019, hepatitis B virus (HBV) and hepatitis C virus (HCV) resulted in an estimated 820,000 and 290,000 deaths, respectively. Hepatitis delta virus (HDV) is a satellite virus that depends on HBV for producing its infectious particles in order to spread. The combination of HDV and HBV infection is considered the most severe form of chronic viral hepatitis. Hepatitis E virus (HEV) is another orally transmitted virus, common in low- and middle-income countries. In 2015, it caused 44,000 deaths worldwide. Safe and effective vaccines are already available to prevent hepatitis A and B. Here, we review the recent advances in protective vaccines against the five major hepatitis viruses.
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Affiliation(s)
- Ashraf Elbahrawy
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Hassan Atalla
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed Alboraie
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Ahmed Alwassief
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Al-Azhar University, Cairo 11884, Egypt
- Gastroenterology Unit, Department of Internal Medicine, Sultan Qaboos University Hospital, P.O. Box 50, Muscat 123, Oman
| | - Ali Madian
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Assiut 71524, Egypt
| | - Mohammed El Fayoumie
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Al-Azhar University, Cairo 11884, Egypt
| | - Ashraf A. Tabll
- Microbial Biotechnology Department, Biotechnology Research Institute, National Research Center, Giza 12622, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Hussein H. Aly
- Department of Virology II, National Institute of Infectious Diseases, Toyama1-23-1, Shinjuku-ku, Tokyo 162-8640, Japan
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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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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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Guest JD, Pierce BG. Computational Modeling of Hepatitis C Virus Envelope Glycoprotein Structure and Recognition. Front Immunol 2018; 9:1117. [PMID: 29892287 PMCID: PMC5985375 DOI: 10.3389/fimmu.2018.01117] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 05/03/2018] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is a major global health concern, and though therapeutic options have improved, no vaccine is available despite decades of research. As HCV can rapidly mutate to evade the immune response, an effective HCV vaccine must rely on identification and characterization of sites critical for broad immune protection and viral neutralization. This knowledge depends on structural and mechanistic insights of the E1 and E2 envelope glycoproteins, which assemble as a heterodimer on the surface of the virion, engage coreceptors during host cell entry, and are the primary targets of antibodies. Due to the challenges in determining experimental structures, structural information on E1 and E2 and their interaction is relatively limited, providing opportunities to model the structures, interactions, and dynamics of these proteins. This review highlights efforts to model the E2 glycoprotein structure, the assembly of the functional E1E2 heterodimer, the structure and binding of human coreceptors, and recognition by key neutralizing antibodies. We also discuss a comparison of recently described models of full E1E2 heterodimer structures, a simulation of the dynamics of key epitope sites, and modeling glycosylation. These modeling efforts provide useful mechanistic hypotheses for further experimental studies of HCV envelope assembly, recognition, and viral fitness, and underscore the benefit of combining experimental and computational modeling approaches to reveal new insights. Additionally, computational design approaches have produced promising candidates for epitope-based vaccine immunogens that specifically target key epitopes, providing a possible avenue to optimize HCV vaccines versus using native glycoproteins. Advancing knowledge of HCV envelope structure and immune recognition is highly applicable toward the development of an effective vaccine for HCV and can provide lessons and insights relevant to modeling and characterizing other viruses.
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Affiliation(s)
- Johnathan D Guest
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, United States.,Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, United States
| | - Brian G Pierce
- Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, United States.,Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, United States
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Tabll A, El-Shenawy R, Abd YE. Progress in Vaccine Development for HCV Infection. UPDATE ON HEPATITIS C 2017. [DOI: 10.5772/intechopen.70649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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Hepatitis C: Review of the Epidemiology, Clinical Care, and Continued Challenges in the Direct Acting Antiviral Era. CURR EPIDEMIOL REP 2017; 4:174-185. [PMID: 28785531 DOI: 10.1007/s40471-017-0108-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This review highlights key studies and recently published data, policies, and recommendations related to hepatitis C virus (HCV) epidemiology, transmission, and treatment. RECENT FINDINGS HCV is a leading cause of liver-related deaths, cirrhosis, and hepatocellular carcinoma. Since 2011 and accelerating since 2013, new, safe, tolerable, and curative therapies have considerably altered clinical and public health frameworks related to the prevention, control and clinical management of HCV. Nevertheless, there are several populations in the United States that are important to consider because of disparities in HCV prevalence and transmission risk. Adults born during 1945-1965 have an estimated anti-HCV antibody prevalence of ~3%, which is six times higher than among other adults, are often unaware of their infections, and are at increased risk of having HCV-associated morbidity and mortality from decades of chronic infection. Since the early 2000s, increasing incidence of acute HCV infections among young, white, non-urban people who inject drugs have been reported. Despite promising therapeutic advances, significant challenges remain for reducing HCV-associated morbidity and mortality. SUMMARY The high burden of HCV and significant health consequences associated with chronic infection make HCV a critical public health priority. Advances in HCV treatment have created new opportunities for reducing HCV-associated morbidity and mortality. These treatments are safe, well-tolerated, and highly effective; however, benefits cannot be realized without a significant increase in the number of persons tested for HCV so that all chronically infected individuals can be aware of their diagnosis and linked to appropriate clinical care.
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Abad S, Vega A, Rincón D, Hernández E, Mérida E, Macías N, Muñoz R, Milla M, Luño J, López-Gómez JM. Effectiveness of direct-acting antivirals in Hepatitis C virus infection in haemodialysis patients. Nefrologia 2017; 37:158-163. [PMID: 27914803 DOI: 10.1016/j.nefroe.2017.04.010] [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: 05/19/2016] [Revised: 09/29/2016] [Accepted: 10/02/2016] [Indexed: 01/03/2025] Open
Abstract
Hepatitis C virus (HCV) infection is highly prevalent among patients on haemodialysis and leads to a poorer prognosis compared to patients who do not have said infection. Treatment with interferon and ribavirin is poorly tolerated and there are limited data on the experience with new direct-acting antivirals (DAAs). The aim of this study is to retrospectively analyse the current prevalence of HCV infection and efficacy and safety results with different DAA regimens in the haemodialysis population of 2hospital areas. This is a multicentre, retrospective and observational study in which HCV antibodies were analysed in 465 patients, with positive antibody findings in 54 of them (11.6%). Among these, 29 cases (53.7%) with genotypes 1 and 4 were treated with different DAA regimens, including combinations of paritaprevir/ritonavir, ombitasvir, dasabuvir, sofosbuvir, simeprevir, daclatasvir and ledipasvir, with/without ribavirin. Mean age was 53.3±7.9 years, 72.4% of patients were male and the most important aetiology of chronic kidney disease involved glomerular abnormalities. In 100% of cases, a sustained viral response was achieved after 24 weeks, regardless of DAA regimen received. Adverse effects were not relevant and no case required stopping treatment. In 15 cases, ribavirin was combined with the DAA. In these cases, the most significant adverse effect was anaemic tendency, which was reflected in the increase of the dose of erythropoietin stimulating agents, although none required transfusions. In summary, we conclude that new DAAs for the treatment of HCV in haemodialysis patients are highly effective with minimal adverse effects; it is a very important advance in HCV management. These patients are therefore expected to have a much better prognosis than they have had until very recently.
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Affiliation(s)
- Soraya Abad
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - Almudena Vega
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - Diego Rincón
- Servicio de Aparato Digestivo, Hospital Universitario Gregorio Marañón, Madrid, España
| | | | | | - Nicolás Macías
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - Raquel Muñoz
- Servicio de Medicina del Aparato Digestivo, Hospital 12 de Octubre, Madrid, España
| | - Mónica Milla
- Servicio de Nefrología. Hospital 12 de Octubre, Madrid, España
| | - Jose Luño
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
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Abad S, Vega A, Hernández E, Mérida E, de Sequera P, Albalate M, Macías N, Milla M, López-Gómez JM. Universal Sustained Viral Response to the Combination of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with/without Ribavirin in Patients on Hemodialysis Infected with Hepatitis C Virus Genotypes 1 and 4. Am J Nephrol 2017; 45:267-272. [PMID: 28166520 DOI: 10.1159/000454819] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 11/12/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is highly prevalent among patients on hemodialysis (HD) and is associated with poor prognosis. Treatment with interferon and ribavirin is poorly tolerated, and few data are available on the impact of new direct-acting antivirals (DAAs). This study was intended to analyze the efficacy and safety of treatment with a combination of ombitasvir/paritaprevir/ritonavir and dasabuvir with/without ribavirin in HCV-infected patients on HD from 3 hospitals. METHODS This is a multicentric study. We analyze the clinical course of all patients on HD with HCV infection who had been treated with the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir in 3 hospitals in Madrid, Spain. All patients under treatment had undergone Transient elastography (FibroScan®) and HCV RNA (PCR) and HCV genotype were determined simultaneously. RESULTS Thirty-five patients aged 53.3 ± 8.9 years (68.6% males) and with genotypes 1 and 4 were treated with the DAA regimen, and 17 were also given ribavirin. The most common etiology was glomerular disease. Sustained viral response was achieved in 100% of patients. Adverse effects were negligible, and no patient had to discontinue treatment. The most significant side effect was anemia, which led to a significant increase in the dose of erythropoiesis-stimulating agents. Anemia was more marked in patients receiving ribavirin. No patients required transfusions. CONCLUSION A combination of ombitasvir/paritaprevir/ritonavir and dasabuvir with/without ribavirin for the treatment of HCV in patients on HD is highly effective and causes minimal side effects. This regimen represents a major advance in disease management. A considerable improvement in prognosis seems likely.
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Affiliation(s)
- Soraya Abad
- Service of Nephrology, Hospital Universitario Gregorio Marañón, Madrid, Spain
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Abad S, Vega A, Rincón D, Hernández E, Mérida E, Macías N, Muñoz R, Milla M, Luño J, López-Gómez JM. Effectiveness of direct-acting antivirals in Hepatitis C virus infection in haemodialysis patients. Nefrologia 2016; 37:158-163. [PMID: 27914803 DOI: 10.1016/j.nefro.2016.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 09/29/2016] [Accepted: 10/02/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection is highly prevalent among patients on haemodialysis and leads to a poorer prognosis compared to patients who do not have said infection. Treatment with interferon and ribavirin is poorly tolerated and there are limited data on the experience with new direct-acting antivirals (DAAs). The aim of this study is to retrospectively analyse the current prevalence of HCV infection and efficacy and safety results with different DAA regimens in the haemodialysis population of 2hospital areas. This is a multicentre, retrospective and observational study in which HCV antibodies were analysed in 465 patients, with positive antibody findings in 54 of them (11.6%). Among these, 29 cases (53.7%) with genotypes 1 and 4 were treated with different DAA regimens, including combinations of paritaprevir/ritonavir, ombitasvir, dasabuvir, sofosbuvir, simeprevir, daclatasvir and ledipasvir, with/without ribavirin. Mean age was 53.3±7.9 years, 72.4% of patients were male and the most important aetiology of chronic kidney disease involved glomerular abnormalities. In 100% of cases, a sustained viral response was achieved after 24 weeks, regardless of DAA regimen received. Adverse effects were not relevant and no case required stopping treatment. In 15 cases, ribavirin was combined with the DAA. In these cases, the most significant adverse effect was anaemic tendency, which was reflected in the increase of the dose of erythropoietin stimulating agents, although none required transfusions. In summary, we conclude that new DAAs for the treatment of HCV in haemodialysis patients are highly effective with minimal adverse effects; it is a very important advance in HCV management. These patients are therefore expected to have a much better prognosis than they have had until very recently.
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Affiliation(s)
- Soraya Abad
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - Almudena Vega
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - Diego Rincón
- Servicio de Aparato Digestivo, Hospital Universitario Gregorio Marañón, Madrid, España
| | | | | | - Nicolás Macías
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
| | - Raquel Muñoz
- Servicio de Medicina del Aparato Digestivo, Hospital 12 de Octubre, Madrid, España
| | - Mónica Milla
- Servicio de Nefrología. Hospital 12 de Octubre, Madrid, España
| | - Jose Luño
- Servicio de Nefrología, Hospital Universitario Gregorio Marañón, Madrid, España
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Viral evasion and challenges of hepatitis C virus vaccine development. Curr Opin Virol 2016; 20:55-63. [PMID: 27657659 DOI: 10.1016/j.coviro.2016.09.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 08/24/2016] [Accepted: 09/06/2016] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) is a major global disease burden, often leading to chronic liver diseases, cirrhosis, cancer, and death in those infected. Despite the recent approval of antiviral therapeutics, a preventative vaccine is recognized as the most effective means to control HCV globally, particularly in at-risk and developing country populations. Here we describe the efforts and challenges related to the development of an HCV vaccine, which after decades of research have not been successful. Viral sequence variability poses a major challenge, yet recent research has provided unprecedented views of the atomic structure of HCV epitopes and immune recognition by antibodies and T cell receptors. This, coupled with insights from deep sequencing, robust neutralization assays, and other technological advances, is spurring research toward rationally HCV designed vaccines that preferentially elicit responses toward conserved epitopes of interest that are associated with viral neutralization and clearance.
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Large scale production of a mammalian cell derived quadrivalent hepatitis C virus like particle vaccine. J Virol Methods 2016; 236:87-92. [PMID: 27373602 DOI: 10.1016/j.jviromet.2016.06.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 12/14/2022]
Abstract
A method for the large-scale production of a quadrivalent mammalian cell derived hepatitis C virus-like particles (HCV VLPs) is described. The HCV core E1 and E2 coding sequences of genotype 1a, 1b, 2a or 3a were co-expressed in Huh7 cell factories using a recombinant adenoviral expression system. The structural proteins self-assembled into VLPs that were purified from Huh7 cell lysates by iodixanol ultracentrifugation and Stirred cell ultrafiltration. Electron microscopy, revealed VLPs of the different genotypes that are morphologically similar. Our results show that it is possible to produce large quantities of individual HCV genotype VLPs with relative ease thus making this approach an alternative for the manufacture of a quadrivalent mammalian cell derived HCV VLP vaccine.
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Fauvelle C, Colpitts CC, Keck ZY, Pierce BG, Foung SKH, Baumert TF. Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies. Expert Rev Vaccines 2016; 15:1535-1544. [PMID: 27267297 DOI: 10.1080/14760584.2016.1194759] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION With more than 150 million chronically infected people, hepatitis C virus (HCV) remains a substantial global health burden. Direct-acting antivirals have dramatically improved viral cure. However, limited access to therapy, late stage detection of infection and re-infection following cure illustrate the need for a vaccine for global control of infection. Vaccines with induction of neutralizing antibodies (nAbs) have been shown to protect successfully against infections by multiple viruses and are currently developed for HCV. Areas covered: Here we review the progress towards the development of vaccines aiming to confer protection against chronic HCV infection by inducing broadly nAbs. The understanding or viral immune evasion in infected patients, the development of novel model systems and the recent structural characterization of viral envelope glycoprotein E2 has markedly advanced our understanding of the molecular mechanisms of virus neutralization with the concomitant development of several vaccine candidates. Expert commentary: While HCV vaccine development remains challenged by the high viral diversity and immune evasion, marked progress in HCV research has advanced vaccine design. Several vaccine candidates have shown robust induction of nAbs in animal models and humans. Randomized clinical trials are the next step to assess their clinical efficacy for protection against chronic infection.
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Affiliation(s)
- Catherine Fauvelle
- a Inserm, U1110 , Institut de Recherche sur les Maladies Virales et Hépatiques , Strasbourg , France.,b Université de Strasbourg , Strasbourg , France
| | - Che C Colpitts
- a Inserm, U1110 , Institut de Recherche sur les Maladies Virales et Hépatiques , Strasbourg , France.,b Université de Strasbourg , Strasbourg , France
| | - Zhen-Yong Keck
- c Department of Pathology , Stanford University School of Medicine , Stanford , CA , USA
| | - Brian G Pierce
- d Institute for Bioscience and Biotechnology Research , University of Maryland , Rockville , MD , USA
| | - Steven K H Foung
- c Department of Pathology , Stanford University School of Medicine , Stanford , CA , USA
| | - Thomas F Baumert
- a Inserm, U1110 , Institut de Recherche sur les Maladies Virales et Hépatiques , Strasbourg , France.,b Université de Strasbourg , Strasbourg , France.,e Institut Hospitalo-Universitaire, Pôle Hépato-digestif , Hôpitaux Universitaires de Strasbourg , Strasbourg , France
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Callendret B, Eccleston HB, Satterfield W, Capone S, Folgori A, Cortese R, Nicosia A, Walker CM. Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a direct-acting antiviral. Hepatology 2016; 63:1442-54. [PMID: 26513111 PMCID: PMC4840073 DOI: 10.1002/hep.28309] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/22/2015] [Accepted: 10/25/2015] [Indexed: 02/06/2023]
Abstract
UNLABELLED Exhaustion of antiviral CD8(+) T cells contributes to persistence of hepatitis C viral (HCV) infection. This immune response has proved difficult to restore by therapeutic vaccination, even when HCV replication is suppressed using antiviral regimens containing type I interferon. Because immunomodulatory effects of type I interferon may be a factor in poor T-cell priming, we undertook therapeutic vaccination in two chronically infected chimpanzees during treatment with a direct-acting antiviral (DAA) targeting the HCV NS5b polymerase protein. Immunization with genetic vaccines encoding the HCV NS3-NS5b nonstructural proteins during DAA treatment resulted in a multifunctional CD8(+) T-cell response. However, these antiviral CD8(+) T cells did not prevent persistent replication of DAA-resistant HCV variants that emerged during treatment. Most vaccine-induced CD8(+) T cells targeted class I epitopes that were not conserved in the circulating virus. Exhausted intrahepatic CD8(+) T-cell targeting-conserved epitopes did not expand after vaccination, with a notable exception. A sustained, multifunctional CD8(+) T-cell response against at least one intact class I epitope was detected in blood after vaccination. Persistence of HCV was not due to mutational escape of this epitope. Instead, failure to control HCV replication was likely caused by localized exhaustion in the liver, where CD8(+) T-cell expression of the inhibitory receptor programmed cell death 1 increased 25-fold compared with those in circulation. CONCLUSION Treatment with a DAA during therapeutic vaccination provided transient control of HCV replication and a multifunctional T-cell response, primarily against nonconserved class I epitopes; exhaustion of liver-infiltrating CD8(+) T cells that target conserved epitopes may not be averted when DAA therapy fails prematurely due to emergence of resistant HCV variants.
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Affiliation(s)
- Benoit Callendret
- Center for Vaccines and Immunity, Nationwide Children’s Hospital, Columbus, OH 43205
| | - Heather B. Eccleston
- Center for Vaccines and Immunity, Nationwide Children’s Hospital, Columbus, OH 43205
| | - William Satterfield
- Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, M. D. Anderson Cancer Center, Bastrop, TX 78602
| | | | | | | | - Alfredo Nicosia
- ReiThera, viale Citta’ d’Europa 679, 00144, Rome, Italy,KEIRES, Bäumleingasse 18, CH 4051, Basel, Switzerland,CEINGE, via Gaetano Salvatore 486, 80145, Naples, Italy
| | - Christopher M. Walker
- Center for Vaccines and Immunity, Nationwide Children’s Hospital, Columbus, OH 43205,Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, via S. Pansini 5, 80131, Naples, Italy
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16
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Adsorption and separation of HCV particles by novel affinity aptamer-functionalized adsorbents. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1017-1018:174-181. [DOI: 10.1016/j.jchromb.2016.03.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/16/2016] [Accepted: 03/03/2016] [Indexed: 01/11/2023]
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17
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Abdelwahab KS, Ahmed Said ZN. Status of hepatitis C virus vaccination: Recent update. World J Gastroenterol 2016; 22:862-873. [PMID: 26811632 PMCID: PMC4716084 DOI: 10.3748/wjg.v22.i2.862] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Revised: 05/16/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is still a major public health problem worldwide since its first identification in 1989. At the start, HCV infection was post-transfusion viral infection, particularly in developing countries. Recently, due to iv drug abuse, HCV infection became number one health problem in well-developed countries as well. Following acute HCV infection, the innate immune response is triggered in the form of activated coordinated interaction of NK cells, dendritic cells and interferon α. The acquired immune response is then developed in the form of the antibody-mediated immune response (ABIR) and the cell-mediated immune response (CMIR). Both are responsible for clearance of HCV infection in about 15% of infected patients. However, HCV has several mechanisms to evade these antivirus immune reactions. The current review gives an overview of HCV structure, immune response and viral evasion mechanisms. It also evaluates the available preventive and therapeutic vaccines that induce innate, ABIR, CMIR. Moreover, this review highlights the progress in recent HCV vaccination studies either in preclinical or clinical phases. The unsatisfactory identification of HCV infection by the current screening system and the limitations of currently available treatments, including the ineligibility of some chronic HCV patients to such antiviral agents, mandate the development of an effective HCV vaccine.
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King B, Temperton NJ, Grehan K, Scott SD, Wright E, Tarr AW, Daly JM. Technical considerations for the generation of novel pseudotyped viruses. Future Virol 2016. [DOI: 10.2217/fvl.15.106] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A pseudotyped virus (PV) is a virus particle with an envelope protein originating from a different virus. The ability to dictate which envelope proteins are expressed on the surface has made pseudotyping an important tool for basic virological studies such as determining the cellular targets of the envelope protein of the virus as well as identification of potential antiviral compounds and measuring specific antibody responses. In this review, we describe the common methodologies employed to generate PVs, with a focus on approaches to improve the efficacy of PV generation.
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Affiliation(s)
- Barnabas King
- School of Life Sciences & NIHR Biomedical Research Unit in Gastrointestinal & Liver Diseases, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
- NIHR Biomedical Research Unit in Gastrointestinal & Liver Diseases, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Nigel J Temperton
- Viral Pseudotype Unit (Medway), School of Pharmacy, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK
| | - Keith Grehan
- Viral Pseudotype Unit (Medway), School of Pharmacy, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK
| | - Simon D Scott
- Viral Pseudotype Unit (Medway), School of Pharmacy, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK
| | - Edward Wright
- Viral Pseudotype Unit (Fitzrovia), Faculty of Science & Technology, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK
| | - Alexander W Tarr
- School of Life Sciences & NIHR Biomedical Research Unit in Gastrointestinal & Liver Diseases, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
- NIHR Biomedical Research Unit in Gastrointestinal & Liver Diseases, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Janet M Daly
- School of Veterinary Medicine & Science, University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD, UK
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Li HC, Lo SY. Hepatitis C virus: Virology, diagnosis and treatment. World J Hepatol 2015; 7:1377-1389. [PMID: 26052383 PMCID: PMC4450201 DOI: 10.4254/wjh.v7.i10.1377] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/22/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti-viral therapy and predict the likelihood of response. In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. However, this therapy is not ideal. To 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral, interferon-free, pan-genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these anti-viral treatments. However, not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus, an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection.
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