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Allela OQB, Ali NAM, Sanghvi G, Roopashree R, Kashyap A, Krithiga T, Panigrahi R, Kubaev A, Kareem RA, Sameer HN, Yaseen A, Athab ZH, Adil M. The Role of Viral Infections in Acute Kidney Injury and Mesenchymal Stem Cell-Based Therapy. Stem Cell Rev Rep 2025:10.1007/s12015-025-10873-0. [PMID: 40198477 DOI: 10.1007/s12015-025-10873-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2025] [Indexed: 04/10/2025]
Abstract
Viruses may cause a wide range of renal problems. Furthermore, many kidney diseases may be brought on by viral infections. Both the primary cause and a contributing factor of acute kidney injury (AKI) may be viral infections. As an example, it is recommended that patients with dengue virus (DENV) infections undergo careful monitoring of their AKI levels. Also, researchers' data so far lend credence to the several hypothesized pathophysiological mechanisms via which AKI can develop in SARS-CoV- 2 infection. Thus, it is critical to comprehend how viral infections cause AKI. Finding an effective method of treating AKI caused by viruses is also vital. Thus, a potential cell-free method for treating AKI that uses regenerative and anti-inflammatory processes is mesenchymal stem cells (MSCs) and their exosomes (MSC-EXOs). MSCs alleviate tissue damage and enhance protective effects on damaged kidneys in AKI. Furthermore, MSC-EXOs have exhibited substantial regulatory impact on a range of immune cells and exhibit robust immune regulation in the therapy of AKI. Thus, in models of AKI caused by ischemia-reperfusion damage, nephrotoxins, or sepsis, MSCs and MSC-EXOs improved renal function, decreased inflammation, and improved healing. Therefore, MSCs and MSC-EXOs may help treat AKI caused by different viruses. Consequently, we have explored several innovative and significant processes in this work that pertain to the role of viruses in AKI and the significance of viral illness in the onset of AKI. After that, we assessed the key aspects of MSCs and MSC-EXOs for AKI therapy. We have concluded by outlining the current state of and plans for future research into MSC- and EXO-based therapeutic approaches for the treatment of AKI brought on by viruses.
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Affiliation(s)
| | | | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Aditya Kashyap
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - T Krithiga
- Department of Chemistry, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Rajashree Panigrahi
- Department of Microbiology, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, 751003, Odisha, India
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, 140100, Uzbekistan
| | | | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Mohaned Adil
- Pharmacy college, Al-Farahidi University, Baghdad, Iraq
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2
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Graciotti M, Kandalaft LE. Vaccines for cancer prevention: exploring opportunities and navigating challenges. Nat Rev Drug Discov 2025; 24:134-150. [PMID: 39622986 DOI: 10.1038/s41573-024-01081-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 02/06/2025]
Abstract
Improved understanding of cancer immunology has gradually brought increasing attention towards cancer-preventive vaccines as an important tool in the fight against cancer. The aim of this approach is to reduce cancer occurrence by inducing a specific immune response targeting tumours at an early stage before they can fully develop. The great advantage of preventive cancer vaccines lies in the potential to harness a less-compromised immune system in vaccine recipients before their immune responses become affected by the advanced status of the disease itself or by aggressive treatments such as chemotherapy. Successful implementation of immunoprevention against oncogenic viruses such as hepatitis B and papillomavirus has led to a dramatic decrease in virally induced cancers. Extending this approach to other cancers holds great promise but remains a major challenge. Here, we provide a comprehensive review of preclinical evidence supporting this approach, encouraging results from pioneering clinical studies as well as a discussion on the key aspects and open questions to address in order to design potent prophylactic cancer vaccines in the near future.
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Affiliation(s)
- Michele Graciotti
- Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Lana E Kandalaft
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
- Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland.
- AGORA Cancer Research Center, Lausanne, Lausanne, Switzerland.
- Swiss Medical Network, Genolier Innovation Network, Genolier Clinic, Genolier, Switzerland.
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3
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Mackesy-Amiti ME, Gutfraind A, Tatara E, Collier NT, Cotler SJ, Page K, Ozik J, Boodram B, Major M, Dahari H. Modeling of randomized hepatitis C vaccine trials: Bridging the gap between controlled human infection models and real-word testing. PNAS NEXUS 2025; 4:pgae564. [PMID: 39777292 PMCID: PMC11704953 DOI: 10.1093/pnasnexus/pgae564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025]
Abstract
Global elimination of chronic hepatitis C (CHC) remains difficult without an effective vaccine. Since injection drug use is the leading cause of hepatitis C virus (HCV) transmission in Western Europe and North America, people who inject drugs (PWID) are an important population for testing HCV vaccine effectiveness in randomized-clinical trials (RCTs). However, RCTs in PWID are inherently challenging. To accelerate vaccine development, controlled human infection (CHI) models have been suggested as a means to identify effective vaccines. To bridge the gap between CHI models and real-world testing, we developed an agent-based model simulating a two-dose vaccine to prevent CHC in PWID, representing 32,000 PWID in metropolitan Chicago and accounting for networks and HCV infections. We ran 500 trial simulations under 50 and 75% assumed vaccine efficacy (aVE) and sampled HCV infection status of recruited in silico PWID. The mean estimated vaccine efficacy (eVE) for 50 and 75% aVE was 48% (SD ± 12) and 72% (SD ± 11), respectively. For both conditions, the majority of trials (∼71%) resulted in eVEs within 1 SD of the mean, demonstrating a robust trial design. Trials that resulted in eVEs >1 SD from the mean (lowest eVEs of 3 and 35% for 50 and 75% aVE, respectively), were more likely to have imbalances in acute infection rates across trial arms. Modeling indicates robust trial design and high success rates of finding vaccines to be effective in real-life trials in PWID. However, with less effective vaccines (aVEs∼50%) there remains a higher risk of concluding poor vaccine efficacy due to post-randomization imbalances.
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Affiliation(s)
- Mary-Ellen Mackesy-Amiti
- Division of Community Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Alexander Gutfraind
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Eric Tatara
- Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL 60637, USA
- Decision and Infrastructure Sciences, Argonne National Laboratory, Lemont, IL 60439, USA
| | - Nicholson T Collier
- Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL 60637, USA
- Decision and Infrastructure Sciences, Argonne National Laboratory, Lemont, IL 60439, USA
| | - Scott J Cotler
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Kimberly Page
- Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
| | - Jonathan Ozik
- Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL 60637, USA
- Decision and Infrastructure Sciences, Argonne National Laboratory, Lemont, IL 60439, USA
| | - Basmattee Boodram
- Division of Community Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Marian Major
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
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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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Donnison T, McGregor J, Chinnakannan S, Hutchings C, Center RJ, Poumbourios P, Klenerman P, Drummer HE, Barnes E. A pan-genotype hepatitis C virus viral vector vaccine generates T cells and neutralizing antibodies in mice. Hepatology 2022; 76:1190-1202. [PMID: 35313015 PMCID: PMC9790311 DOI: 10.1002/hep.32470] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS A prophylactic vaccine targeting multiple HCV genotypes (gt) is urgently required to meet World Health Organization elimination targets. Neutralizing antibodies (nAbs) and CD4+ and CD8+ T cells are associated with spontaneous clearance of HCV, and each may contribute to protective immunity. However, current vaccine candidates generate either nAbs or T cells targeting genetically variable epitopes and have failed to show efficacy in human trials. We have previously shown that a simian adenovirus vector (ChAdOx1) encoding conserved sequences across gt1-6 (ChAd-Gt1-6), and separately gt-1a E2 protein with variable regions deleted (E2Δ123HMW ), generates pan-genotypic T cells and nAbs, respectively. We now aim to develop a vaccine to generate both viral-specific B- and T-cell responses concurrently. APPROACH AND RESULTS We show that vaccinating with ChAd-Gt1-6 and E2Δ123HMW sequentially in mice generates T-cell and antibody (Ab) responses comparable to either vaccine given alone. We encoded E2Δ123 in ChAdOx1 (ChAd-E2Δ123) and show that this, given with an E2Δ123HMW protein boost, induces greater CD81-E2 inhibitory and HCV-pseudoparticle nAb titers compared to the E2Δ123HMW prime boost. We developed bivalent viral vector vaccines (ChAdOx1 and modified vaccinia Ankara [MVA]) encoding both Gt1-6 and E2Δ123 immunogens (Gt1-6-E2Δ123) generating polyfunctional CD4+ and CD8+ T cells and nAb titers in prime/boost strategies. This approach generated nAb responses comparable to monovalent E2Δ123 ChAd/MVA vaccines and superior to three doses of recombinant E2Δ123HMW protein, while also generating high-magnitude T-cell responses. CONCLUSIONS These data are an important step forward for the development of a pan-genotype HCV vaccine to elicit T cells and nAbs for future assessment in humans.
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Affiliation(s)
- Timothy Donnison
- Nuffield Department of MedicinePeter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUK
| | - Joey McGregor
- Burnet InstituteMelbourneVictoriaAustralia
- Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and ImmunityUniversity of MelbourneParkvilleVictoriaAustralia
| | - Senthil Chinnakannan
- Nuffield Department of MedicinePeter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUK
| | - Claire Hutchings
- Nuffield Department of MedicinePeter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUK
| | - Rob J. Center
- Burnet InstituteMelbourneVictoriaAustralia
- Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and ImmunityUniversity of MelbourneParkvilleVictoriaAustralia
| | - Pantelis Poumbourios
- Burnet InstituteMelbourneVictoriaAustralia
- Department of MicrobiologyMonash UniversityClaytonVictoriaAustralia
| | - Paul Klenerman
- Nuffield Department of MedicinePeter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUK
| | - Heidi E. Drummer
- Burnet InstituteMelbourneVictoriaAustralia
- Department of Microbiology and Immunology at The Peter Doherty Institute for Infection and ImmunityUniversity of MelbourneParkvilleVictoriaAustralia
- Department of MicrobiologyMonash UniversityClaytonVictoriaAustralia
| | - Eleanor Barnes
- Nuffield Department of MedicinePeter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUK
- Nuffield Department of MedicineJenner InstituteUniversity of OxfordOxfordUK
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6
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Non-Invasive Diagnosis of Liver Fibrosis in Chronic Hepatitis C using Mathematical Modeling and Simulation. ELECTRONICS 2022. [DOI: 10.3390/electronics11081260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hepatitis C is a viral infection (HCV) that causes liver inflammation, and it was found that it affects over 170 million people around the world, with Egypt having the highest rate in the world. Unfortunately, serial liver biopsies, which can be invasive, expensive, risky, and inconvenient to patients, are typically used for the diagnosis of liver fibrosis progression. This study presents the development, validation, and evaluation of a prediction mathematical model for non-invasive diagnosis of liver fibrosis in chronic HCV. The proposed model in this article uses a set of nonlinear ordinary differential equations as its core and divides the population into six groups: Susceptible, Treatment, Responder, Non-Responder, Cured, and Fibrosis. The validation approach involved the implementation of two equivalent simulation models that examine the proposed process from different perspectives. A system dynamics model was developed to understand the nonlinear behavior of the diagnosis process over time. The system dynamics model was then transformed to an equivalent agent-based model to examine the system at the individual level. The numerical analysis and simulation results indicate that the earlier the HCV treatment is implemented, the larger the group of people who will become responders, and less people will develop complications such as fibrosis.
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7
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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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8
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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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9
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Echeverría N, Comas V, Aldunate F, Perbolianachis P, Moreno P, Cristina J. In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet? World J Hepatol 2021; 13:1234-1268. [PMID: 34786164 PMCID: PMC8568586 DOI: 10.4254/wjh.v13.i10.1234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/14/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is responsible for no less than 71 million people chronically infected and is one of the most frequent indications for liver transplantation worldwide. Despite direct-acting antiviral therapies fuel optimism in controlling HCV infections, there are several obstacles regarding treatment accessibility and reinfection continues to remain a possibility. Indeed, the majority of new HCV infections in developed countries occur in people who inject drugs and are more plausible to get reinfected. To achieve global epidemic control of this virus the development of an effective prophylactic or therapeutic vaccine becomes a must. The coronavirus disease 19 (COVID-19) pandemic led to auspicious vaccine development against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which has renewed interest on fighting HCV epidemic with vaccination. The aim of this review is to highlight the current situation of HCV vaccine candidates designed to prevent and/or to reduce HCV infectious cases and their complications. We will emphasize on some of the crossroads encountered during vaccine development against this insidious virus, together with some key aspects of HCV immunology which have, so far, hampered the progress in this area. The main focus will be on nucleic acid-based as well as recombinant viral vector-based vaccine candidates as the most novel vaccine approaches, some of which have been recently and successfully employed for SARS-CoV-2 vaccines. Finally, some ideas will be presented on which methods to explore for the design of live-attenuated vaccines against HCV.
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Affiliation(s)
- Natalia Echeverría
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Victoria Comas
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Fabián Aldunate
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Paula Perbolianachis
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Pilar Moreno
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Juan Cristina
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
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10
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Abstract
The immunoprevention of cancer and cancer recurrence is an important area of concern for the scientific community and society as a whole. Researchers have been working for decades to develop vaccines with the potential to alleviate these health care and economic burdens. So far, vaccines have made more progress in preventing cancer than in eliminating already established cancer. In particular, vaccines targeting oncogenic viruses, such as the human papillomavirus and the hepatitis B virus, are exceptional examples of successful prevention of virus-associated cancers, such as cervical cancer and hepatocellular carcinoma. Cancer-preventive vaccines targeting nonviral antigens, such as tumor-associated antigens and neoantigens, are also being extensively tested. Here, we review the currently approved preventive cancer vaccines; discuss the challenges in this field by covering ongoing preclinical and clinical human trials in various cancers; and address various issues related to maximizing cancer vaccine benefit.
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Affiliation(s)
- Tomohiro Enokida
- Department of Medicine, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Alvaro Moreira
- Department of Medicine, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Kimberly and Eric J. Waldman Department of Dermatology at Mount Sinai, New York, New York, USA
| | - Nina Bhardwaj
- Department of Medicine, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Kimberly and Eric J. Waldman Department of Dermatology at Mount Sinai, New York, New York, USA
- Extramural member of the Parker Institute for Cancer Immunotherapy, San Francisco, California, USA
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11
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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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12
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Cox A, Sulkowski M, Sugarman J. Ethical and Practical Issues Associated With the Possibility of Using Controlled Human Infection Trials in Developing a Hepatitis C Virus Vaccine. Clin Infect Dis 2020; 71:2986-2990. [PMID: 32442262 PMCID: PMC7778335 DOI: 10.1093/cid/ciaa640] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 05/21/2020] [Indexed: 01/15/2023] Open
Abstract
Despite the existence of established treatments for hepatitis C virus (HCV), more effective means of preventing infection, such as a vaccine, are arguably needed to help reduce substantial global morbidity and mortality. Given the expected challenges of developing such a vaccine among those at heightened risk of infection, controlled human infection studies seem to be a promising potential approach to HCV vaccine development, but they raise substantial ethical and practical concerns. In this article, we describe some of the challenges related to the possibility of using controlled human infection studies to accelerate HCV vaccine development. The related ethical and practical concerns require further deliberation before such studies are planned and implemented.
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Affiliation(s)
- Andrea Cox
- School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Mark Sulkowski
- School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Jeremy Sugarman
- School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland, USA
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13
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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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14
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Esposito I, Cicconi P, D'Alise AM, Brown A, Esposito M, Swadling L, Holst PJ, Bassi MR, Stornaiuolo M, Mori F, Vassilev V, Li W, Donnison T, Gentile C, Turner B, von Delft A, Del Sorbo M, Barra F, Contino AM, Abbate A, Novellino E, Thomsen AR, Christensen JP, Lahm A, Grazioli F, Ammendola V, Siani L, Colloca S, Klenerman P, Nicosia A, Dorrell L, Folgori A, Capone S, Barnes E. MHC class II invariant chain-adjuvanted viral vectored vaccines enhances T cell responses in humans. Sci Transl Med 2020; 12:12/548/eaaz7715. [PMID: 32554708 PMCID: PMC7610808 DOI: 10.1126/scitranslmed.aaz7715] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 05/26/2020] [Indexed: 12/27/2022]
Abstract
Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II-associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.
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Affiliation(s)
- Ilaria Esposito
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Paola Cicconi
- The Jenner Institute Laboratories, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK
| | | | - Anthony Brown
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | | | - Leo Swadling
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Peter Johannes Holst
- Center for Medical Parasitology, University of Copenhagen, DK-2200 Copenhagen, Denmark.,Department of Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark.,InProTher ApS, BioInnovation Institute, 2200 Copenhagen, Denmark
| | - Maria Rosaria Bassi
- Center for Medical Parasitology, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Mariano Stornaiuolo
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | | | | | - Wenqin Li
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Timothy Donnison
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Chiara Gentile
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Bethany Turner
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | - Annette von Delft
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| | | | | | | | | | - Ettore Novellino
- Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy
| | - Allan Randrup Thomsen
- Department of Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | | | | | | | | | | | | | - Paul Klenerman
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.,The Jenner Institute Laboratories, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK
| | - Alfredo Nicosia
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.,CEINGE-Biotecnologie Avanzate, via Gaetano Salvatore 486, 80145 Naples, Italy.,Keires AG, 4051 Basel, Switzerland
| | - Lucy Dorrell
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.,Oxford NIHR Biomedical Research Centre, Headington OX3 9DU, UK
| | | | | | - Eleanor Barnes
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. .,The Jenner Institute Laboratories, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK
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15
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Sepulveda-Crespo D, Resino S, Martinez I. Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants. Vaccines (Basel) 2020; 8:vaccines8020313. [PMID: 32560440 PMCID: PMC7350220 DOI: 10.3390/vaccines8020313] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023] Open
Abstract
Despite successful treatments, hepatitis C virus (HCV) infections continue to be a significant world health problem. High treatment costs, the high number of undiagnosed individuals, and the difficulty to access to treatment, particularly in marginalized susceptible populations, make it improbable to achieve the global control of the virus in the absence of an effective preventive vaccine. Current vaccine development is mostly focused on weakly immunogenic subunits, such as surface glycoproteins or non-structural proteins, in the case of HCV. Adjuvants are critical components of vaccine formulations that increase immunogenic performance. As we learn more information about how adjuvants work, it is becoming clear that proper stimulation of innate immunity is crucial to achieving a successful immunization. Several hepatic cell types participate in the early innate immune response and the subsequent inflammation and activation of the adaptive response, principally hepatocytes, and antigen-presenting cells (Kupffer cells, and dendritic cells). Innate pattern recognition receptors on these cells, mainly toll-like receptors, are targets for new promising adjuvants. Moreover, complex adjuvants that stimulate different components of the innate immunity are showing encouraging results and are being incorporated in current vaccines. Recent studies on HCV-vaccine adjuvants have shown that the induction of a strong T- and B-cell immune response might be enhanced by choosing the right adjuvant.
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Affiliation(s)
| | - Salvador Resino
- Correspondence: (S.R.); (I.M.); Tel.: +34-91-8223266 (S.R.); +34-91-8223272 (I.M.); Fax: +34-91-5097919 (S.R. & I.M.)
| | - Isidoro Martinez
- Correspondence: (S.R.); (I.M.); Tel.: +34-91-8223266 (S.R.); +34-91-8223272 (I.M.); Fax: +34-91-5097919 (S.R. & I.M.)
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16
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Center RJ, Boo I, Phu L, McGregor J, Poumbourios P, Drummer HE. Enhancing the antigenicity and immunogenicity of monomeric forms of hepatitis C virus E2 for use as a preventive vaccine. J Biol Chem 2020; 295:7179-7192. [PMID: 32299914 PMCID: PMC7247312 DOI: 10.1074/jbc.ra120.013015] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/13/2020] [Indexed: 12/13/2022] Open
Abstract
The E2 glycoprotein of hepatitis C virus (HCV) is the major target of broadly neutralizing antibodies (bNAbs) that are critical for the efficacy of a prophylactic HCV vaccine. We previously showed that a cell culture-derived, disulfide-linked high-molecular-weight (HMW) form of the E2 receptor-binding domain lacking three variable regions, Δ123-HMW, elicits broad neutralizing activity against the seven major genotypes of HCV. A limitation to the use of this antigen is that it is produced only at low yields and does not have a homogeneous composition. Here, we employed a sequential reduction and oxidation strategy to efficiently refold two high-yielding monomeric E2 species, D123 and a disulfide-minimized version (D123A7), into disulfide-linked HMW-like species (Δ123r and Δ123A7r). These proteins exhibited normal reactivity to bNAbs with continuous epitopes on the neutralizing face of E2, but reduced reactivity to conformation-dependent bNAbs and nonneutralizing antibodies (non-NAbs) compared with the corresponding monomeric species. Δ123r and Δ123A7r recapitulated the immunogenic properties of cell culture-derived D123-HMW in guinea pigs. The refolded antigens elicited antibodies that neutralized homologous and heterologous HCV genotypes, blocked the interaction between E2 and its cellular receptor CD81, and targeted the AS412, AS434, and AR3 domains. Of note, antibodies directed to epitopes overlapping with those of non-NAbs were absent. The approach to E2 antigen engineering outlined here provides an avenue for the development of preventive HCV vaccine candidates that induce bNAbs at higher yield and lower cost.
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Affiliation(s)
- Rob J Center
- Burnet Institute, 85 Commercial Road, Melbourne 3004, Australia; Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne 3000, Australia
| | - Irene Boo
- Burnet Institute, 85 Commercial Road, Melbourne 3004, Australia
| | - Lilian Phu
- Burnet Institute, 85 Commercial Road, Melbourne 3004, Australia; Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne 3000, Australia
| | - Joey McGregor
- Burnet Institute, 85 Commercial Road, Melbourne 3004, Australia; Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne 3000, Australia
| | - Pantelis Poumbourios
- Burnet Institute, 85 Commercial Road, Melbourne 3004, Australia; Department of Microbiology, Monash University, Clayton 3056, Australia
| | - Heidi E Drummer
- Burnet Institute, 85 Commercial Road, Melbourne 3004, Australia; Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne 3000, Australia; Department of Microbiology, Monash University, Clayton 3056, Australia.
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17
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Roingeard P, Beaumont E. Hepatitis C Vaccine: 10 Good Reasons for Continuing. Hepatology 2020; 71:1845-1850. [PMID: 32060946 DOI: 10.1002/hep.31182] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/11/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Philippe Roingeard
- Faculté de Médecine, INSERM U1259, Université de Tours and CHRU de Tours, Tours, France
| | - Elodie Beaumont
- Faculté de Médecine, INSERM U1259, Université de Tours and CHRU de Tours, Tours, France
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18
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Abstract
INTRODUCTION The recent availability of highly effective hepatitis C medications, with a cure rate approaching 100%, has created a wide range of questions and uncertainties. AREAS COVERED The most recent data around hepatitis C virus (HCV) elimination will be reviewed. In addition, the impact of HCV cure or sustained virologic response (SVR) on the risk for hepatocellular carcinoma (HCC) development will be discussed. Although the terms 'SVR' and 'cure' are used interchangeably, there are little data to support that they are actually the same. In this review, we will shed some light on the status of HCV vaccine development, obstacles, and published experience. Finally, in the face of decreasing HCV patients needing transplantation, and increasing available organs from donors infected with HCV, the question is that, is it possible to transplant an organ infected with HCV to a patient who is not infected? The pros and cons of transplanting HCV-positive organs to HCV-negative recipients will be discussed. EXPERT OPINION Although the new advances in HCV treatment have solved many problems, it created several new issues which the medical community has to deal with and which will likely remain in the near future.
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Affiliation(s)
- Omar Massoud
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham , Birmingham, AL, USA
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19
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Cosset FL, Mialon C, Boson B, Granier C, Denolly S. HCV Interplay with Lipoproteins: Inside or Outside the Cells? Viruses 2020; 12:v12040434. [PMID: 32290553 PMCID: PMC7232430 DOI: 10.3390/v12040434] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/05/2020] [Accepted: 04/10/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major public health issue leading to chronic liver diseases. HCV particles are unique owing to their particular lipid composition, namely the incorporation of neutral lipids and apolipoproteins. The mechanism of association between HCV virion components and these lipoproteins factors remains poorly understood as well as its impact in subsequent steps of the viral life cycle, such as entry into cells. It was proposed that the lipoprotein biogenesis pathway is involved in HCV morphogenesis; yet, recent evidence indicated that HCV particles can mature and evolve biochemically in the extracellular medium after egress. In addition, several viral, cellular and blood components have been shown to influence and regulate this specific association. Finally, this specific structure and composition of HCV particles was found to influence entry into cells as well as their stability and sensitivity to neutralizing antibodies. Due to its specific particle composition, studying the association of HCV particles with lipoproteins remains an important goal towards the rational design of a protective vaccine.
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20
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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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21
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Pitcher AB, Borquez A, Skaathun B, Martin NK. Mathematical modeling of hepatitis c virus (HCV) prevention among people who inject drugs: A review of the literature and insights for elimination strategies. J Theor Biol 2019; 481:194-201. [PMID: 30452959 PMCID: PMC6522340 DOI: 10.1016/j.jtbi.2018.11.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 11/13/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023]
Abstract
In 2016, the World Health Organization issued global elimination targets for hepatitis C virus (HCV), including an 80% reduction in HCV incidence by 2030. The vast majority of new HCV infections occur among people who inject drugs (PWID), and as such elimination strategies require particular focus on this population. As governments urgently require guidance on how to achieve elimination among PWID, mathematical modeling can provide critical information on the level and targeting of intervention are required. In this paper we review the epidemic modeling literature on HCV transmission and prevention among PWID, highlight main differences in mathematical formulation, and discuss key insights provided by these models in terms of achieving WHO elimination targets among PWID. Overall, the vast majority of modeling studies utilized a deterministic compartmental susceptible-infected-susceptible structure, with select studies utilizing individual-based network transmission models. In general, these studies found that harm reduction alone is unlikely to achieve elimination targets among PWID. However, modeling indicates elimination is achievable in a wide variety of epidemic settings with harm reduction scale-up combined with modest levels of HCV treatment for PWID. Unfortunately, current levels of testing and treatment are generally insufficient to achieve elimination in most settings, and require further scale-up. Additionally, network-based treatment strategies as well as prison-based treatment and harm reduction provision could provide important additional population benefits. Overall, epidemic modeling has and continues to play a critical role in informing HCV elimination strategies worldwide.
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Affiliation(s)
| | - Annick Borquez
- Division of Infectious Diseases and Global Public Health, University of California San Diego, CA, USA
| | - Britt Skaathun
- Division of Infectious Diseases and Global Public Health, University of California San Diego, CA, USA
| | - Natasha K Martin
- Division of Infectious Diseases and Global Public Health, University of California San Diego, CA, USA.
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22
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Boyd A, Duchesne L, Lacombe K. Research gaps in viral hepatitis. J Int AIDS Soc 2019; 21 Suppl 2:e25054. [PMID: 29633564 PMCID: PMC5978714 DOI: 10.1002/jia2.25054] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 12/20/2017] [Indexed: 12/21/2022] Open
Abstract
Introduction The World Health Organization has aimed for global elimination of both hepatitis B virus (HBV) and hepatitis C virus (HCV) by 2030. Treatments available to cure HCV and control HBV, as well as vaccination to prevent HBV infection, have certainly allowed for such bold goals, yet the final steps to usher in elimination require further evidence. Discussion We broadly discuss the needs for three major public health approaches. First, an effective vaccine exists for HBV and mass‐vaccination campaigns have resulted in decreases in hepatitis B surface antigen seroprevalence and overall rates of liver‐related morality. Still, HBV vaccination coverage is poor in certain regions of the world, while the reasons for such low coverage require further study. A prophylactic vaccine is probably needed to eliminate HCV, but is not being readily developed. Second, identifying HBV/HCV infected individuals remains a priority to increase awareness of disease status, particularly for key populations. Research evaluating large‐scale implementation of novel, rapid and mobile point‐of‐care tests would be helpful to determine whether increased awareness is achievable in these settings. Third, antiviral therapy allows for strong HBV suppression and HCV cure, while its access depends on financial factors among many others. Although there is strong evidence to treat key populations and specific groups with progressed disease, as stated in current guidelines, the advantages of extending treatment eligibility to decrease onward spread of HBV/HCV infection and prevent further burden of disease are lacking “real world” evidence. Novel anti‐HBV treatments are being developed to target intrahepatocellular HBV replication, but are still in the early phases of clinical development. Each of the strategies mentioned above has specific implications for HIV infection. Conclusions There are certainly effective tools to combat the spread of viral hepatitis and treat infected individuals – yet how they are able to reach key populations, and the infrastructure required to do so, continue to represent the largest research gap when evaluating the progress towards elimination. Continuously adapted and informed research is required to establish the priorities in achieving elimination goals.
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Affiliation(s)
- Anders Boyd
- INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.,Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, Netherlands
| | - Léa Duchesne
- INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France
| | - Karine Lacombe
- Department of Infectious and Tropical Diseases, Saint-Antoine Hospital, AP-HP, Paris, France.,Sorbonne Universités, INSERM, UPMC Univ Paris 06, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
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23
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Page K, Cox A, Lum PJ. Opioids, Hepatitis C Virus Infection, and the Missing Vaccine. Am J Public Health 2019; 108:156-157. [PMID: 29320280 DOI: 10.2105/ajph.2017.304201] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Kimberly Page
- Kimberly Page is a professor in the Department of Internal Medicine and chief of the Division of Epidemiology, Biostatistics and Preventive Medicine, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque. Andrea Cox is a professor of medicine at the Johns Hopkins University School of Medicine, Baltimore, MD, and holds joint appointments in molecular microbiology and immunology. Paula J. Lum is professor of medicine and program director of the Primary Care Addiction Medicine Fellowship, University of California, San Francisco
| | - Andrea Cox
- Kimberly Page is a professor in the Department of Internal Medicine and chief of the Division of Epidemiology, Biostatistics and Preventive Medicine, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque. Andrea Cox is a professor of medicine at the Johns Hopkins University School of Medicine, Baltimore, MD, and holds joint appointments in molecular microbiology and immunology. Paula J. Lum is professor of medicine and program director of the Primary Care Addiction Medicine Fellowship, University of California, San Francisco
| | - Paula J Lum
- Kimberly Page is a professor in the Department of Internal Medicine and chief of the Division of Epidemiology, Biostatistics and Preventive Medicine, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque. Andrea Cox is a professor of medicine at the Johns Hopkins University School of Medicine, Baltimore, MD, and holds joint appointments in molecular microbiology and immunology. Paula J. Lum is professor of medicine and program director of the Primary Care Addiction Medicine Fellowship, University of California, San Francisco
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24
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Echevarria D, Gutfraind A, Boodram B, Layden J, Ozik J, Page K, Cotler SJ, Major M, Dahari H. Modeling indicates efficient vaccine-based interventions for the elimination of hepatitis C virus among persons who inject drugs in metropolitan Chicago. Vaccine 2019; 37:2608-2616. [PMID: 30962092 DOI: 10.1016/j.vaccine.2019.02.081] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/07/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Persons who inject drugs (PWID) are at highest risk for acquiring and transmitting hepatitis C (HCV) infection. The recent availability of oral direct-acting antiviral (DAA) therapy with reported cure rates >90% can prevent HCV transmission, making HCV elimination an attainable goal among PWID. The World Health Organization (WHO) recently proposed a 90% reduction in HCV incidence as a key objective. However, given barriers to the use of DAAs in PWID, including cost, restricted access to DAAs, and risk of reinfection, combination strategies including the availability of effective vaccines are needed to eradicate HCV as a public health threat. This study aims to model the cost and efficacy of a dual modality approach using HCV vaccines combined with DAAs to reduce HCV incidence by 90% and prevalence by 50% in PWID populations. METHODS We developed a mathematical model that represents the HCV epidemic among PWID and calibrated it to empirical data from metropolitan Chicago, Illinois. Four medical interventions were considered: vaccination of HCV naive PWID, DAA treatment, DAA treatment followed by vaccination, and, a combination of vaccination and DAA treatment. RESULTS The combination of vaccination and DAAs is the lowest cost-expensive intervention for achieving the WHO target of 90% incidence reduction. The use of DAAs without a vaccine is much less cost-effective with the additional risk of reinfection after treatment. Vaccination of naïve PWID alone, even when scaled-up to all reachable PWID, cannot achieve 90% reduction of incidence in high-prevalence populations due to infections occurring before vaccination. Similarly, the lowest cost-expensive way to halve prevalence in 15 years is through the combination of vaccination and DAAs. CONCLUSIONS The modeling results underscore the importance of developing an effective HCV vaccine and augmenting DAAs with vaccines in HCV intervention strategies in order to achieve efficient reductions in incidence and prevalence.
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Affiliation(s)
- Desarae Echevarria
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA
| | - Alexander Gutfraind
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA; Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Basmattee Boodram
- Community Health Sciences, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Jennifer Layden
- Health Protection Office, Illinois Department of Public Health, Chicago, IL, USA
| | - Jonathan Ozik
- Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA; Decision and Infrastructure Sciences, Argonne National Laboratory, Argonne, IL, USA
| | - Kimberly Page
- Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
| | - Scott J Cotler
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA
| | - Marian Major
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University, Medical Center, Maywood, IL, USA.
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25
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Mekonnen ZA, Grubor-Bauk B, Masavuli MG, Shrestha AC, Ranasinghe C, Bull RA, Lloyd AR, Gowans EJ, Wijesundara DK. Toward DNA-Based T-Cell Mediated Vaccines to Target HIV-1 and Hepatitis C Virus: Approaches to Elicit Localized Immunity for Protection. Front Cell Infect Microbiol 2019; 9:91. [PMID: 31001491 PMCID: PMC6456646 DOI: 10.3389/fcimb.2019.00091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 03/14/2019] [Indexed: 01/07/2023] Open
Abstract
Human immunodeficiency virus (HIV)-1 and hepatitis C virus (HCV) are major contributors to the global disease burden with many experts recognizing the requirement of an effective vaccine to bring a durable end to these viral epidemics. The most promising vaccine candidates that have advanced into pre-clinical models and the clinic to eliminate or provide protection against these chronic viruses are viral vectors [e.g., recombinant cytomegalovirus, Adenovirus, and modified vaccinia Ankara (MVA)]. This raises the question, is there a need to develop DNA vaccines against HIV-1 and HCV? Since the initial study from Wolff and colleagues which showed that DNA represents a vector that can be used to express transgenes durably in vivo, DNA has been regularly evaluated as a vaccine vector albeit with limited success in large animal models and humans. However, several recent studies in Phase I-IIb trials showed that vaccination of patients with recombinant DNA represents a feasible therapeutic intervention to even cure cervical cancer, highlighting the potential of using DNA for human vaccinations. In this review, we will discuss the limitations and the strategies of using DNA as a vector to develop prophylactic T cell-mediated vaccines against HIV-1 and HCV. In particular, we focus on potential strategies exploiting DNA vectors to elicit protective localized CD8+ T cell immunity in the liver for HCV and in the cervicovaginal mucosa for HIV-1 as localized immunity will be an important, if not critical component, of an efficacious vaccine against these viral infections.
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Affiliation(s)
- Zelalem A. Mekonnen
- Virology Laboratory, Basil Hetzel Institute for Translational Health Research, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Branka Grubor-Bauk
- Virology Laboratory, Basil Hetzel Institute for Translational Health Research, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Makutiro G. Masavuli
- Virology Laboratory, Basil Hetzel Institute for Translational Health Research, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Ashish C. Shrestha
- Virology Laboratory, Basil Hetzel Institute for Translational Health Research, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Charani Ranasinghe
- Molecular Mucosal Vaccine Immunology Group, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Rowena A. Bull
- Viral Immunology Systems Program, The Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
| | - Andrew R. Lloyd
- Viral Immunology Systems Program, The Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
| | - Eric J. Gowans
- Virology Laboratory, Basil Hetzel Institute for Translational Health Research, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Danushka K. Wijesundara
- Virology Laboratory, Basil Hetzel Institute for Translational Health Research, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia,*Correspondence: Danushka K. Wijesundara
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26
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Lombardi A, Mondelli MU. Hepatitis C: Is eradication possible? Liver Int 2019; 39:416-426. [PMID: 30472772 DOI: 10.1111/liv.14011] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 11/06/2018] [Accepted: 11/19/2018] [Indexed: 02/13/2023]
Abstract
Hepatitis C has a relevant global impact in terms of morbidity, mortality and economic costs, with more than 70 million people infected worldwide. In the resolution, "Transforming our world: the 2030 Agenda for Sustainable Development" was included as a focus area in the health-related goal with world leaders pledging to "combat" it by 2030. In response, WHO drafted the Global Viral Hepatitis Strategy carrying the ambitious targets to reduce the number of deaths by two-thirds and to increase treatment rates up to 80%. Despite the availability of highly effective therapeutic regimens based on direct-acting antivirals many barriers to HCV eradication still remain. They are related to awareness of the infection, linkage to care, availability of the therapeutic drug regimens and reinfection. Overall, if an effective prophylactic vaccine will not be available, HCV eradication appears difficult to achieve in the future.
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Affiliation(s)
- Andrea Lombardi
- Division of Infectious Diseases II and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Mario U Mondelli
- Division of Infectious Diseases II and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
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27
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Cooke GS, Andrieux-Meyer I, Applegate TL, Atun R, Burry JR, Cheinquer H, Dusheiko G, Feld JJ, Gore C, Griswold MG, Hamid S, Hellard ME, Hou J, Howell J, Jia J, Kravchenko N, Lazarus JV, Lemoine M, Lesi OA, Maistat L, McMahon BJ, Razavi H, Roberts T, Simmons B, Sonderup MW, Spearman CW, Taylor BE, Thomas DL, Waked I, Ward JW, Wiktor SZ. Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol Hepatol 2019; 4:135-184. [PMID: 30647010 DOI: 10.1016/s2468-1253(18)30270-x] [Citation(s) in RCA: 383] [Impact Index Per Article: 63.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 08/10/2018] [Accepted: 08/13/2018] [Indexed: 01/26/2023]
Abstract
Viral hepatitis is a major public health threat and a leading cause of death worldwide. Annual mortality from viral hepatitis is similar to that of other major infectious diseases such as HIV and tuberculosis. Highly effective prevention measures and treatments have made the global elimination of viral hepatitis a realistic goal, endorsed by all WHO member states. Ambitious targets call for a global reduction in hepatitis-related mortality of 65% and a 90% reduction in new infections by 2030. This Commission draws together a wide range of expertise to appraise the current global situation and to identify priorities globally, regionally, and nationally needed to accelerate progress. We identify 20 heavily burdened countries that account for over 75% of the global burden of viral hepatitis. Key recommendations include a greater focus on national progress towards elimination with support given, if necessary, through innovative financing measures to ensure elimination programmes are fully funded by 2020. In addition to further measures to improve access to vaccination and treatment, greater attention needs to be paid to access to affordable, high-quality diagnostics if testing is to reach the levels needed to achieve elimination goals. Simplified, decentralised models of care removing requirements for specialised prescribing will be required to reach those in need, together with sustained efforts to tackle stigma and discrimination. We identify key examples of the progress that has already been made in many countries throughout the world, demonstrating that sustained and coordinated efforts can be successful in achieving the WHO elimination goals.
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Affiliation(s)
- Graham S Cooke
- Division of Infectious Diseases, Imperial College London, London, UK.
| | | | | | - Rifat Atun
- Harvard T H Chan School of Public Health, Harvard University, Boston, MA, USA; Harvard Medical School, Harvard University, Boston, MA, USA
| | | | - Hugo Cheinquer
- Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | | | - Jordan J Feld
- Toronto Center for Liver Disease, Toronto General Hospital, Toronto, Canada
| | | | - Max G Griswold
- Institute of Health Metrics and Evaluation, University of Washington, Seattle, WA, USA
| | | | | | - JinLin Hou
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Guangzhou, China
| | - Jess Howell
- Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, VIC, Australia
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Beijing, China
| | | | - Jeffrey V Lazarus
- Health Systems Research Group, Barcelona Institute for Global Health (ISGlobal), Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Maud Lemoine
- Division of Surgery and Cancer, Imperial College London, London, UK
| | | | | | - Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AL, USA
| | - Homie Razavi
- Center for Disease Analysis Foundation, Lafayette, CO, USA
| | | | - Bryony Simmons
- Division of Infectious Diseases, Imperial College London, London, UK
| | - Mark W Sonderup
- Division of Hepatology, Department of Medicine, University of Cape Town, South Africa
| | - C Wendy Spearman
- Division of Hepatology, Department of Medicine, University of Cape Town, South Africa
| | | | - David L Thomas
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Imam Waked
- National Liver Institute, Menoufiya University, Egypt
| | - John W Ward
- Program for Viral Hepatitis Elimination, Task Force for Global Health, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Stefan Z Wiktor
- Department of Global Health, University of Washington, Seattle, WA, USA
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28
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Hartnell F, Brown A, Capone S, Kopycinski J, Bliss C, Makvandi-Nejad S, Swadling L, Ghaffari E, Cicconi P, Del Sorbo M, Sbrocchi R, Esposito I, Vassilev V, Marriott P, Gardiner CM, Bannan C, Bergin C, Hoffmann M, Turner B, Nicosia A, Folgori A, Hanke T, Barnes E, Dorrell L. A Novel Vaccine Strategy Employing Serologically Different Chimpanzee Adenoviral Vectors for the Prevention of HIV-1 and HCV Coinfection. Front Immunol 2019; 9:3175. [PMID: 30713538 PMCID: PMC6346592 DOI: 10.3389/fimmu.2018.03175] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 12/24/2018] [Indexed: 12/21/2022] Open
Abstract
Background: Nearly 3 million people worldwide are coinfected with HIV and HCV. Affordable strategies for prevention are needed. We developed a novel vaccination regimen involving replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by modified vaccinia Ankara (MVA) boosts, for simultaneous delivery of HCV non-structural (NSmut) and HIV-1 conserved (HIVconsv) region immunogens. Methods: We conducted a phase I trial in which 33 healthy volunteers were sequentially enrolled and vaccinated via the intramuscular route as follows: 9 received ChAd3-NSmut [2.5 × 1010 vp] and MVA-NSmut [2 × 108 pfu] at weeks 0 and 8, respectively; 8 received ChAdV63.HIVconsv [5 × 1010 vp] and MVA.HIVconsv [2 × 108 pfu] at the same interval; 16 were co-primed with ChAd3-NSmut [2.5 × 1010 vp] and ChAdV63.HIVconsv [5 × 1010 vp] followed at week 8 by MVA-NSmut and MVA.HIVconsv [both 1 × 108 pfu]. Immunogenicity was assessed using peptide pools in ex vivo ELISpot and intracellular cytokine assays. Vaccine-induced whole blood transcriptome changes were assessed by microarray analysis. Results: All vaccines were well tolerated and no vaccine-related serious adverse events occurred. Co-administration of the prime-boost vaccine regimens induced high magnitude and broad T cell responses that were similar to those observed following immunization with either regimen alone. Median (interquartile range, IQR) peak responses to NSmut were 3,480 (2,728–4,464) and 3,405 (2,307–7,804) spot-forming cells (SFC)/106 PBMC for single and combined HCV vaccinations, respectively (p = 0.8). Median (IQR) peak responses to HIVconsv were 1,305 (1,095–4,967) and 1,005 (169–2,482) SFC/106 PBMC for single and combined HIV-1 vaccinations, respectively (p = 0.5). Responses were maintained above baseline to 34 weeks post-vaccination. Intracellular cytokine analysis indicated that the responding populations comprised polyfunctional CD4+ and CD8+ T cells. Canonical pathway analysis showed that in the single and combined vaccination groups, pathways associated with antiviral and innate immune responses were enriched for upregulated interferon-stimulated genes 24 h after priming and boosting vaccinations. Conclusions: Serologically distinct adenoviral vectors encoding HCV and HIV-1 immunogens can be safely co-administered without reducing the immunogenicity of either vaccine. This provides a novel strategy for targeting these viruses simultaneously and for other pathogens that affect the same populations. Clinical trial registration:https://clinicaltrials.gov, identifier: NCT02362217
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Affiliation(s)
- Felicity Hartnell
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Anthony Brown
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | | - Jakub Kopycinski
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Carly Bliss
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | | - Leo Swadling
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Emma Ghaffari
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Paola Cicconi
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | | | | - Ilaria Esposito
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | | - Paula Marriott
- Centre for Clinical Vaccinology and Tropical Medicine, Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Clair M Gardiner
- School of Biochemistry and Immunology, Trinity College, Dublin, Ireland
| | | | | | - Matthias Hoffmann
- Division of Infectious Diseases and Hospital Epidemiology, Kantonsspital St Gallen, St Gallen, Switzerland
| | - Bethany Turner
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Alfredo Nicosia
- Keires AG, Basel, Switzerland.,Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.,CEINGE-Biotecnologie Avanzate, Naples, Italy
| | | | - Tomáš Hanke
- Jenner Institute Laboratories, University of Oxford, Oxford, United Kingdom.,International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Eleanor Barnes
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.,Oxford NIHR Biomedical Research Centre, Headington, United Kingdom
| | - Lucy Dorrell
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.,Oxford NIHR Biomedical Research Centre, Headington, United Kingdom
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29
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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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30
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Ward JW, Hinman AR. What Is Needed to Eliminate Hepatitis B Virus and Hepatitis C Virus as Global Health Threats. Gastroenterology 2019; 156:297-310. [PMID: 30391470 DOI: 10.1053/j.gastro.2018.10.048] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 10/23/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) cause 1.3 million deaths annually. To prevent more than 7 million deaths by 2030, the World Health Organization set goals to eliminate HBV and HCV, defined as a 90% reduction in new infections and a 65% reduction in deaths, and prevent more than 7 million related deaths by 2030. Elimination of HBV and HCV is feasible because of characteristics of the viruses, reliable diagnostic tools, and available cost-effective or cost-saving interventions. Broad implementation of infant immunization against HBV, blood safety, and infection-control programs have greatly reduced the burden of HBV and HCV infections. To achieve elimination, priorities include implementation of HBV vaccine-based strategies to prevent perinatal transmission, safe injection practices and HCV treatment for persons who inject drugs, and testing and treatment for HBV- and HCV-infected persons. With sufficient capacity, HBV and HCV elimination programs can meet their goals.
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Affiliation(s)
- John W Ward
- The Task Force for Global Health, Decatur, Georgia; Centers for Disease Control and Prevention, Atlanta, Georgia.
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31
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Leoni MC, Ustianowski A, Farooq H, Arends JE. HIV, HCV and HBV: A Review of Parallels and Differences. Infect Dis Ther 2018; 7:407-419. [PMID: 30182282 PMCID: PMC6249183 DOI: 10.1007/s40121-018-0210-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Indexed: 02/06/2023] Open
Abstract
Elimination of the three blood-borne viruses-human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV)-as public health issues may be plausible in the near future. Spectacular advances have been made with the introduction of highly effective antiviral agents into clinical practice, and prevention strategies are available for all three infections. Effective disease control, laid out by WHO global strategies, is currently feasible for all three viruses. However, for worldwide elimination of these viruses, effective vaccines are required that are currently only available for HBV. In this review differences and parallels among HIV, HCV and HBV will be discussed with a focus on virologic and therapeutic issues, and prospects for the future of HBV will be presented.
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Affiliation(s)
- Maria C Leoni
- Department of Internal Medicine, Section Infectious Diseases, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
- Infectious Diseases Department, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Andrew Ustianowski
- Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK
- School of Medical Sciences, University of Manchester, Manchester, UK
| | - Hamzah Farooq
- Regional Infectious Diseases Unit, North Manchester General Hospital, Manchester, UK
| | - Joop E Arends
- Department of Internal Medicine, Section Infectious Diseases, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.
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32
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Shahnazarian V, Ramai D, Reddy M, Mohanty S. Hepatitis C virus genotype 3: clinical features, current and emerging viral inhibitors, future challenges. Ann Gastroenterol 2018; 31:541-551. [PMID: 30174390 PMCID: PMC6102453 DOI: 10.20524/aog.2018.0281] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/18/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) represents a global burden on healthcare that affects over 150 million people worldwide. In the past, HCV genotype 3 was considered difficult to treat relative to other genotypes. Genotype 3 has been associated with a higher rate of complications, including fatty liver disease, fibrosis, hepatocellular carcinoma and mortality. However, with the advent of first- and second-generation direct-acting antivirals, genotype 3 can be treated effectively. Additionally, these new drugs are well tolerated by patients and have significantly fewer side effects compared to ribavirin and interferon-based regimens. However, while great strides have been made in overcoming biological barriers, our next challenge lies in overcoming economic and financial obstacles if we are to eradicate HCV genotype 3. Herein, we review the clinical features associated with HCV genotype 3, current and emerging treatment regimens, and challenges associated with treatment.
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Affiliation(s)
- Vahe Shahnazarian
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
| | - Daryl Ramai
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
- School of Medicine, St George’s University, True Blue, Grenada, WI (Daryl Ramai), USA
| | - Madhavi Reddy
- Division of Gastroenterology, Hepatology, and Advanced Endoscopy, The Brooklyn Hospital Center, Academic Affiliate of The Icahn School of Medicine at Mount Sinai, Clinical Affiliate of The Mount Sinai Hospital, Brooklyn, NY (Vahe Shahnazarian, Daryl Ramai, Madhavi Reddy), USA
| | - Smruti Mohanty
- Division of Gastroenterology and Hepatology, New York Presbyterian Brooklyn Methodist Hospital, Clinical Affiliate of Weill Cornell Medicine, Brooklyn, NY (Smruti Mohanty), USA
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Pimpin L, Cortez-Pinto H, Negro F, Corbould E, Lazarus JV, Webber L, Sheron N. Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies. J Hepatol 2018; 69:718-735. [PMID: 29777749 DOI: 10.1016/j.jhep.2018.05.011] [Citation(s) in RCA: 467] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 05/04/2018] [Accepted: 05/05/2018] [Indexed: 02/06/2023]
Abstract
The burden of liver disease in Europe continues to grow. We aimed to describe the epidemiology of liver diseases and their risk factors in European countries, identifying public health interventions that could impact on these risk factors to reduce the burden of liver disease. As part of the HEPAHEALTH project we extracted information on historical and current prevalence and mortality from national and international literature and databases on liver disease in 35 countries in the World Health Organization European region, as well as historical and recent prevalence data on their main determinants; alcohol consumption, obesity and hepatitis B and C virus infections. We extracted information from peer-reviewed and grey literature to identify public health interventions targeting these risk factors. The epidemiology of liver disease is diverse, with variations in the exact composition of diseases and the trends in risk factors which drive them. Prevalence and mortality data indicate that increasing cirrhosis and liver cancer may be linked to dramatic increases in harmful alcohol consumption in Northern European countries, and viral hepatitis epidemics in Eastern and Southern European countries. Countries with historically low levels of liver disease may experience an increase in non-alcoholic fatty liver disease in the future, given the rise of obesity across most European countries. Liver disease in Europe is a serious issue, with increasing cirrhosis and liver cancer. The public health and hepatology communities are uniquely placed to implement measures aimed at reducing their causes: harmful alcohol consumption, child and adult obesity, and chronic infection with hepatitis viruses, which will in turn reduce the burden of liver disease.
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Affiliation(s)
| | - Helena Cortez-Pinto
- Departamento de Gastrenterologia, CHLN, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - Francesco Negro
- Divisions of Gastroenterology and Hepatology and Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland
| | | | - Jeffrey V Lazarus
- Barcelona Institute for Global Health (ISGlobal), Hospital Clinic, University of Barcelona, Barcelona, Spain; CHIP, Rigshospitalet, University of Copenhagen, Øster Alle 56, 5. sal, DK-2100 Copenhagen, Denmark
| | | | - Nick Sheron
- University of Southampton, Southampton SO17 1BJ, United Kingdom.
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34
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Schleiss MR, Marsh KJ. Viral Infections of the Fetus and Newborn. AVERY'S DISEASES OF THE NEWBORN 2018:482-526.e19. [DOI: 10.1016/b978-0-323-40139-5.00037-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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35
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Torresi J. The Rationale for a Preventative HCV Virus-Like Particle (VLP) Vaccine. Front Microbiol 2017; 8:2163. [PMID: 29163442 PMCID: PMC5674006 DOI: 10.3389/fmicb.2017.02163] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 10/20/2017] [Indexed: 12/16/2022] Open
Abstract
HCV represents a global health problem with ~200 million individuals currently infected, worldwide. With the high cost of antiviral therapies, the global burden of chronic hepatitis C infection (CHCV) infection will be substantially reduced by the development of an effective vaccine for HCV. The field of HCV vaccines is generally divided into proponents of strategies to induce neutralizing antibodies (NAb) and those who propose to elicit cell mediated immunity (CMI). However, for a hepatitis C virus (HCV) vaccine to be effective in preventing infection, it must be capable of generating cross-reactive CD4+, CD8+ T cell, and NAb responses that will cover the major viral genotypes. Simulation models of hepatitis C have predicted that a vaccine of even modest efficacy and coverage will significantly reduce the incidence of hepatitis C. A HCV virus like particle (VLP) based vaccine would fulfill the requirement of delivering critical conformational neutralizing epitopes in addition to providing HCV specific CD4+ and CD8+ epitopes. Several approaches have been reported including insect cell-derived genotype 1b HCV VLPs; a human liver-derived quadrivalent genotype 1a, 1b, 2, and 3a vaccine; a genotype 1a HCV E1 and E2 glycoprotein/MLV Gag pseudotype VLP vaccine; and chimeric HBs-HCV VLP vaccines. All to result in the production of cross-NAb and/or T cell responses against HCV. This paper summarizes the evidence supporting the development of a HCV VLP based vaccine.
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Affiliation(s)
- 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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36
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Designing an HCV vaccine: a unique convergence of prevention and therapy? Curr Opin Virol 2017; 23:113-119. [PMID: 28550816 DOI: 10.1016/j.coviro.2017.03.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 03/27/2017] [Indexed: 12/23/2022]
Abstract
Direct acting antivirals can cure chronic hepatitis C virus (HCV) infection but whether they will reduce global liver disease burden is uncertain. Most chronic infections are undiagnosed and transmission has increased in recent years. The first trial of a preventive vaccine is now underway in humans at risk for HCV infection. It will test the novel hypothesis that T cell-mediated immunity alone can prevent persistent HCV infection. Another vaccine that elicits neutralizing antibodies is at an advanced stage of development. Attention is turning to the understudied question of whether direct acting antiviral (DAA) cure of chronic infection restores HCV immunity. If not, it will be important to determine if preventive vaccines can also act therapeutically to reverse immune dysfunction and protect from re-infection.
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37
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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: 42] [Impact Index Per Article: 5.3] [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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Hepatitis B, C, and Delta—Updates in Screening and Infection Prevention Opportunities for Eradication. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2017. [DOI: 10.1007/s40506-017-0105-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Hajarizadeh B, Grebely J, Martinello M, Matthews GV, Lloyd AR, Dore GJ. Hepatitis C treatment as prevention: evidence, feasibility, and challenges. Lancet Gastroenterol Hepatol 2016; 1:317-327. [DOI: 10.1016/s2468-1253(16)30075-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 07/28/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023]
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