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Marjani A, Alavian SM, Nassiri Toosi M, Alavian SH, Abazari MF, Khamseh A, Jazayeri SM. Hepatitis B virus infection after immunization: How serious it is? An updated review. Clin Exp Med 2025; 25:113. [PMID: 40210771 PMCID: PMC11985588 DOI: 10.1007/s10238-025-01645-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/19/2025] [Indexed: 04/12/2025]
Abstract
Infection with hepatitis B virus (HBV) is one of the significant challenges worldwide. Despite the availability of antiviral drugs against this virus, the most critical strategy to prevent HBV infection is HB vaccination. Basically, despite widespread conventional HB vaccination, due to various reasons, including waning of hepatitis B surface antibody (HBsAb) titer after vaccination, the emergence of vaccine-escape mutants, failure to respond to the vaccine due to viral and host factors, levels of response in high-risk individuals and non-responders to conventional HB vaccination remains a major, unsolved and severe concern. This review focuses on the underlying reasons for conventional hepatitis B vaccination failures. It also suggests solutions to overcome these failures by highlighting significant advances in vaccination, including hepatitis B third-generation vaccines and adjuvanted hepatitis B vaccines as efficient alternatives to second-generation vaccines. Potentially, these new strategies will compensate for the shortcomings caused by second-generation vaccines. Adherence to these denouements has a significant role in preventing the circulation of HBV among individuals and reducing the global burden of HBV-related diseases.
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Affiliation(s)
- Arezoo Marjani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohssen Nassiri Toosi
- Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Foad Abazari
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
- Division of Medical Sciences, Island Medical Program, University of British Columbia, Victoria, BC, Canada
| | - Azam Khamseh
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Science, Shiraz, Iran
| | - Seyed Mohammad Jazayeri
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran.
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Boateng WK, Carlin N, Spira E, Szabela ME, Ezeh KJ. Acute Hepatitis B Infection in a Patient With Confirmed Immunity on Long-Acting Cabotegravir/Rilpivirine. ACG Case Rep J 2025; 12:e01575. [PMID: 39734393 PMCID: PMC11671078 DOI: 10.14309/crj.0000000000001575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 11/18/2024] [Indexed: 12/31/2024] Open
Abstract
Long-acting injectable formulation of cabotegravir/rilpivirine (CAB/RPV) is a promising novel maintenance therapy for HIV infection. However, coinfection with active hepatitis B virus (HBV) infection is a contraindication to initiating this therapy. Despite guidelines, patients with HBV immunity can still contract acute HBV infection. We report a case of a 30-year-old man with HIV who transitioned from antiretroviral therapy to CAB/RPV and had confirmed HBV immunity. The patient, though asymptomatic, showed significantly elevated liver function tests (LFTs) before his monthly CAB/RPV injection. He was hospitalized and diagnosed with acute HBV infection. His LFTs improved, and he was taken off CAB/RPV and returned to antiretroviral therapy for the treatment of HIV and HBV. During subsequent follow-ups as an outpatient, the patient's LFTs normalized, and his HBV viral load significantly decreased. This case highlights the potential need for routine HBV testing in patients on CAB/RPV therapy.
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Affiliation(s)
| | - Neil Carlin
- Gastroenterology and Hepatology, Jersey City Medical Center, Jersey City, NJ
| | - Etan Spira
- Gastroenterology and Hepatology, Jersey City Medical Center, Jersey City, NJ
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Pondé RADA, Amorim GDSP. Exchanges in the 'a' determinant of the hepatitis B virus surface antigen revisited. Virology 2024; 599:110184. [PMID: 39127000 DOI: 10.1016/j.virol.2024.110184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/02/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024]
Abstract
The hepatitis B virus surface antigen's (HBsAg) 'a' determinant comprises a sequence of amino acid residues located in the major hydrophilic region of the S protein, whose exchanges are closely associated with compromising the antigenicity and immunogenicity of that antigen. The HBsAg is generally present in the bloodstream of individuals with acute or chronic hepatitis B virus (HBV) infection. It is classically known as the HBV infection marker, and is therefore the first marker to be investigated in the laboratory in the clinical hypothesis of infection by this agent. One of the factors that compromises the HBsAg detection in the bloodstream by the assays adopted in serological screening in both clinical contexts is the loss of S protein antigenicity. This can occur due to mutations that emerge in the HBV genome regions that encode the S protein, especially for its immunodominant region - the 'a' determinant. These mutations can induce exchanges of amino acid residues in the S protein's primary structure, altering its tertiary structure and the antigenic conformation, which may not be recognized by anti-HBs antibodies, compromising the infection diagnosis. In addition, these exchanges can render ineffective the anti-HBs antibodies action acquired by vaccination, compromise the effectiveness of the chronically HBV infected patient's treatment, and also the HBsAg immunogenicity, by promoting its retention within the cell. In this review, the residues exchange that alter the S protein's structure is revisited, as well as the mechanisms that lead to the HBsAg antigenicity loss, and the clinical, laboratory and epidemiological consequences of this phenomenon.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde -SES/Superintendência de Vigilância Em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil; Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil.
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Lazarevic I, Banko A, Miljanovic D, Cupic M. Hepatitis B Surface Antigen Isoforms: Their Clinical Implications, Utilisation in Diagnosis, Prevention and New Antiviral Strategies. Pathogens 2024; 13:46. [PMID: 38251353 PMCID: PMC10818932 DOI: 10.3390/pathogens13010046] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 12/27/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024] Open
Abstract
The hepatitis B surface antigen (HBsAg) is a multifunctional glycoprotein composed of large (LHB), middle (MHB), and small (SHB) subunits. HBsAg isoforms have numerous biological functions during HBV infection-from initial and specific viral attachment to the hepatocytes to initiating chronic infection with their immunomodulatory properties. The genetic variability of HBsAg isoforms may play a role in several HBV-related liver phases and clinical manifestations, from occult hepatitis and viral reactivation upon immunosuppression to fulminant hepatitis and hepatocellular carcinoma (HCC). Their immunogenic properties make them a major target for developing HBV vaccines, and in recent years they have been recognised as valuable targets for new therapeutic approaches. Initial research has already shown promising results in utilising HBsAg isoforms instead of quantitative HBsAg for correctly evaluating chronic infection phases and predicting functional cures. The ratio between surface components was shown to indicate specific outcomes of HBV and HDV infections. Thus, besides traditional HBsAg detection and quantitation, HBsAg isoform quantitation can become a useful non-invasive biomarker for assessing chronically infected patients. This review summarises the current knowledge of HBsAg isoforms, their potential usefulness and aspects deserving further research.
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Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (A.B.); (D.M.); (M.C.)
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Osasona OG, Oguntoye OO, Arowosaye AO, Abdulkareem LO, Adewumi MO, Happi C, Folarin O. Patterns of hepatitis b virus immune escape and pol/rt mutations across clinical cohorts of patients with genotypes a, e and occult hepatitis b infection in Nigeria: A multi-centre study. Virulence 2023; 14:2218076. [PMID: 37262110 DOI: 10.1080/21505594.2023.2218076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/27/2023] [Accepted: 05/20/2023] [Indexed: 06/03/2023] Open
Abstract
Hepatitis B virus (HBV) immune escape and Pol/RT mutations account for HBV immunoprophylactic, therapeutic, and diagnostic failure globally. Little is known about circulating HBV immune escape and Pol/RT mutants in Nigeria. This study focused on narrowing the knowledge gap of the pattern and prevalence of the HBV mutants across clinical cohorts of infected patients in southwestern Nigeria. Ninety-five enrollees were purposively recruited across clinical cohorts of HBV-infected patients with HBsAg or anti-HBc positive serological outcome and occult HBV infection. Total DNA was extracted from patients' sera. HBV S and Pol gene-specific nested PCR amplification was carried out. The amplicons were further sequenced for serotypic, genotypic, phylogenetic, and mutational analysis. HBV S and Pol genes were amplified in 60 (63.2%) and 19 (20%) of HBV isolates, respectively. All the sixty HBV S gene and 14 of 19 Pol gene sequences were exploitable. The ayw4 serotype was predominant (95%) while ayw1 serotype was identified in 5% of isolates. Genotype E predominates in 95% of sequences, while genotype A, sub-genotype A3 was observed in 5%. Prevalence of HBV IEMs in the "a" determinant region was 29%. Commonest HBV IEM was S113T followed by G145A and D144E. The Pol/RT mutations rtV214A and rtI163V among others were identified in this study. This study provided data on the occurrence of existing and new HBV IEMs and Pol gene mutations in Nigeria.
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Affiliation(s)
- Oluwadamilola G Osasona
- African Centre of Excellence for the Genomics of Infectious Diseases, Redeemers University, Ede, Nigeria
| | | | - Abiola O Arowosaye
- Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Lukman O Abdulkareem
- Department of Internal Medicine, University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria
| | - Moses O Adewumi
- Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Christian Happi
- African Centre of Excellence for the Genomics of Infectious Diseases, Redeemers University, Ede, Nigeria
| | - Onikepe Folarin
- African Centre of Excellence for the Genomics of Infectious Diseases, Redeemers University, Ede, Nigeria
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Angelo L, Vaillant A, Blanchet M, Labonté P. Pangenomic antiviral effect of REP 2139 in CRISPR/Cas9 engineered cell lines expressing hepatitis B virus surface antigen. PLoS One 2023; 18:e0293167. [PMID: 37910550 PMCID: PMC10619774 DOI: 10.1371/journal.pone.0293167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/06/2023] [Indexed: 11/03/2023] Open
Abstract
Chronic hepatitis B remains a global health problem with 296 million people living with chronic HBV infection and being at risk of developing cirrhosis and hepatocellular carcinoma. Non-infectious subviral particles (SVP) are produced in large excess over infectious Dane particles in patients and are the major source of Hepatitis B surface antigen (HBsAg). They are thought to exhaust the immune system, and it is generally considered that functional cure requires the clearance of HBsAg from blood of patient. Nucleic acid polymers (NAPs) antiviral activity lead to the inhibition of HBsAg release, resulting in rapid clearance of HBsAg from circulation in vivo. However, their efficacy has only been demonstrated in limited genotypes in small scale clinical trials. HBV exists as nine main genotypes (A to I). In this study, the HBsAg ORFs from the most prevalent genotypes (A, B, C, D, E, G), which account for over 96% of human cases, were inserted into the AAVS1 safe-harbor of HepG2 cells using CRISPR/Cas9 knock-in. A cell line producing the D144A vaccine escape mutant was also engineered. The secretion of HBsAg was confirmed into these new genotype cell lines (GCLs) and the antiviral activity of the NAP REP 2139 was then assessed. The results demonstrate that REP 2139 exerts an antiviral effect in all genotypes and serotypes tested in this study, including the vaccine escape mutant, suggesting a pangenomic effect of the NAPs.
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Affiliation(s)
- Léna Angelo
- Institut National de la Recherche Scientifique–Centre Armand-Frappier Santé Biotechnologies, Laval, Canada
| | | | - Matthieu Blanchet
- Institut National de la Recherche Scientifique–Centre Armand-Frappier Santé Biotechnologies, Laval, Canada
- Replicor Inc, Montréal, Canada
| | - Patrick Labonté
- Institut National de la Recherche Scientifique–Centre Armand-Frappier Santé Biotechnologies, Laval, Canada
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Sobajo OA, Oguzie JU, Adegboyega B, Eromon P, Happi C, Komolafe I, Folarin O. Detection of Immune Escape and Basal Core Promoter/Precore Gene Mutations in Hepatitis B Virus Isolated from Asymptomatic Hospital Attendees in Two Southwestern States in Nigeria. Viruses 2023; 15:2188. [PMID: 38005866 PMCID: PMC10674980 DOI: 10.3390/v15112188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/22/2023] [Accepted: 10/29/2023] [Indexed: 11/26/2023] Open
Abstract
Several mutations in the surface (S), basal core promoter (BCP), and precore (PC) genes of the hepatitis B virus have been linked to inaccurate diagnosis and the development of immune escape mutants (IEMs) of the infection, which can lead to chronic infection. Understanding the prevalence and spread of these mutations is critical in the global effort to eliminate HBV. Blood samples were collected from 410 people in Osun and Ekiti states, southwest Nigeria, between 2019 and 2021. Participants were drawn from a group of asymptomatic people who were either blood donors, outpatients, or antenatal patients with no record of HBV infection at the medical outpatients' unit of the hospital. DNA was extracted from plasma using a Qiagen DNEasy kit, followed by nested PCR targeting HBV S and BCP/PC genes. The Sanger sequencing method was used to sequence the positive PCR amplicons, which were further analyzed for IEMs, BCP, and PC mutations. HBV-DNA was detected in 12.4% (51/410) of individuals. After DNA amplification and purification, 47.1% (24) of the S gene and 76.5% (39) of the BCP/PC gene amplicons were successfully sequenced. Phylogenetic analysis showed that all the HBV sequences obtained in this study were classified as HBV genotype E. Mutational analysis of the major hydrophilic region (MHR) and a-determinant domain of S gene sequences revealed the presence of three immune escape mutations: two samples harbored a T116N substitution, six samples had heterogenous D144A/N/S/H substitution, and one sample had a G145E substitution, respectively. The BCP/PC region analysis revealed a preponderance of major BCP mutants, with the prevalence of BCP double substitutions ranging from 38.5% (A1762T) to 43.6% (G1764A). Previously reported classical PC mutant variants were observed in high proportion, including G1896A (33.3%) and G1899A (12.8%) mutations. This study confirms the strong presence of HBV genotype E in Nigeria, the ongoing circulation of HBV IEMs, and a high prevalence of BCP/PC mutants in the cohorts. This has implications for diagnosis and vaccine efficacy for efficient management and control of HBV in the country.
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Affiliation(s)
- Oguntope Adeorike Sobajo
- Department of Biological Sciences, Faculty of Natural Sciences, Redeemer’s University, Ede 232102, Osun State, Nigeria or (O.A.S.); (J.U.O.); (C.H.); (I.K.)
- African Centre of Excellence for Genomics of Infectious Diseases, Redeemer’s University, Ede 232102, Osun State, Nigeria; (B.A.); (P.E.)
- Department of Biological Science, College of Sciences, Afe Babalola University, Ado-Ekiti 360101, Ekiti State, Nigeria
| | - Judith Uche Oguzie
- Department of Biological Sciences, Faculty of Natural Sciences, Redeemer’s University, Ede 232102, Osun State, Nigeria or (O.A.S.); (J.U.O.); (C.H.); (I.K.)
- African Centre of Excellence for Genomics of Infectious Diseases, Redeemer’s University, Ede 232102, Osun State, Nigeria; (B.A.); (P.E.)
| | - Benjamin Adegboyega
- African Centre of Excellence for Genomics of Infectious Diseases, Redeemer’s University, Ede 232102, Osun State, Nigeria; (B.A.); (P.E.)
| | - Philomena Eromon
- African Centre of Excellence for Genomics of Infectious Diseases, Redeemer’s University, Ede 232102, Osun State, Nigeria; (B.A.); (P.E.)
| | - Christian Happi
- Department of Biological Sciences, Faculty of Natural Sciences, Redeemer’s University, Ede 232102, Osun State, Nigeria or (O.A.S.); (J.U.O.); (C.H.); (I.K.)
- African Centre of Excellence for Genomics of Infectious Diseases, Redeemer’s University, Ede 232102, Osun State, Nigeria; (B.A.); (P.E.)
| | - Isaac Komolafe
- Department of Biological Sciences, Faculty of Natural Sciences, Redeemer’s University, Ede 232102, Osun State, Nigeria or (O.A.S.); (J.U.O.); (C.H.); (I.K.)
| | - Onikepe Folarin
- Department of Biological Sciences, Faculty of Natural Sciences, Redeemer’s University, Ede 232102, Osun State, Nigeria or (O.A.S.); (J.U.O.); (C.H.); (I.K.)
- African Centre of Excellence for Genomics of Infectious Diseases, Redeemer’s University, Ede 232102, Osun State, Nigeria; (B.A.); (P.E.)
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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Asai A, Hirai S, Yokohama K, Nishikawa T, Nishikawa H, Higuchi K. Effect of an Electronic Alert System on Hepatitis B Virus Reactivation in Patients Receiving Immunosuppressive Drug Therapy. J Clin Med 2022; 11:jcm11092446. [PMID: 35566572 PMCID: PMC9104084 DOI: 10.3390/jcm11092446] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/19/2022] [Accepted: 04/23/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis B virus (HBV) reactivation (HBVr) can occur in patients receiving immunosuppressive drug therapies, causing significant morbidity and mortality. Although the guidelines for HBVr have been proposed by several academic societies, some providers do not follow them, resulting in HBVr and death. As HBV-DNA levels increase before liver enzyme levels do, we previously constructed an electronic alert system that recommends the measurement of HBV-DNA. Here, we investigated whether this alert system improves the HBV-DNA measurement rate and elicits responses according to guidelines. A total of 5329 patients were divided into two groups, before and after the introduction of the alert system, and the HBV-DNA measurement rates in both groups were compared. Because of the introduction of the alert system, the HBV-DNA measurement rate among HBsAg-negative patients with anti-HBs and/or anti-HBc before immunosuppressive drug therapy improved significantly. The HBV-DNA monitoring rate within 3 months also improved significantly (p = 0.0034) in HBV-remission phase patients. HBVr was detected immediately, and the affected patients were treated with nucleotide analogs before severe hepatitis onset. The introduction of the alert system for HBVr improved the HBV-DNA measurement rates in patients receiving immunosuppressive drug therapy, leading to the rapid treatment of patients with HBVr.
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Affiliation(s)
- Akira Asai
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
- Correspondence: ; Tel.: +81-(726)-83-1221
| | - Saho Hirai
- Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan;
| | - Keisuke Yokohama
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Tomohiro Nishikawa
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Hiroki Nishikawa
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
| | - Kazuhide Higuchi
- The Second Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan; (K.Y.); (T.N.); (H.N.); (K.H.)
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Mokaya J, Vasylyeva TI, Barnes E, Ansari MA, Pybus OG, Matthews PC. Global prevalence and phylogeny of hepatitis B virus (HBV) drug and vaccine resistance mutations. J Viral Hepat 2021; 28:1110-1120. [PMID: 33893696 PMCID: PMC8581767 DOI: 10.1111/jvh.13525] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/08/2021] [Indexed: 12/29/2022]
Abstract
Vaccination and anti-viral therapy with nucleos(t)ide analogues (NAs) are key approaches to reducing the morbidity, mortality and transmission of hepatitis B virus (HBV) infection. However, the efficacy of these interventions may be reduced by the emergence of drug resistance-associated mutations (RAMs) and/or vaccine escape mutations (VEMs). We have assimilated data on the global prevalence and distribution of HBV RAMs/VEMs from publicly available data and explored the evolution of these mutations. We analysed sequences downloaded from the HBV Database and calculated prevalence of 41 RAMs and 38 VEMs catalogued from published studies. We generated maximum likelihood phylogenetic trees and used treeBreaker to investigate the distribution and estimated the age of selected mutations across tree branches. RAM M204I/V had the highest prevalence, occurring in 3.8% (109/2838) of all HBV sequences in our data set, and a significantly higher rate in genotype C at 5.4% (60/1102, p = 0.0007). VEMs had an overall prevalence of 1.3% (37/2837) and had the highest prevalence in genotype C and in Asia at 2.2% (24/1102; p = 0.002) and 1.6% (34/2109; p = 0.009), respectively. Phylogenetic analysis suggested that RAM/VEMs can arise independently of treatment/vaccine exposure. In conclusion, HBV RAMs/VEMs have been found globally and across genotypes, with the highest prevalence observed in genotype C. Screening for genotype and for resistance-associated mutations may help to improve stratified patient treatment. As NAs and HBV vaccines are increasingly being deployed for HBV prevention and treatment, monitoring for resistance and advocating for better treatment regimens for HBV remains essential.
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Affiliation(s)
| | - Tetyana I. Vasylyeva
- Division of Infectious Diseases & Global Public HealthDepartment of MedicineUniversity of CaliforniaSan DiegoCAUSA
| | - Eleanor Barnes
- Nuffield Department of MedicineOxfordUK
- Department of HepatologyOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK
- National Institutes of Health Research Health Informatics CollaborativeNIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
| | - M. Azim Ansari
- Nuffield Department of MedicineOxfordUK
- Wellcome Centre for Human GeneticsOxfordUK
| | | | - Philippa C. Matthews
- Nuffield Department of MedicineOxfordUK
- National Institutes of Health Research Health Informatics CollaborativeNIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
- Department of Infectious Diseases and MicrobiologyOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK
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Adesina OA, Akanbi OA, Opaleye OO, Japhet MO, Wang B, Oluyege AO, Klink P, Bock CT. Detection of Q129H Immune Escape Mutation in Apparently Healthy Hepatitis B Virus Carriers in Southwestern Nigeria. Viruses 2021; 13:1273. [PMID: 34210073 PMCID: PMC8310067 DOI: 10.3390/v13071273] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/27/2021] [Accepted: 06/27/2021] [Indexed: 12/12/2022] Open
Abstract
As the global effort to eradicate hepatitis B continues, immune escape mutations (IEMs) and drug resistance mutations (DRMs) affecting its diagnosis, treatment, and prevention are compromising this goal. However, knowledge about the prevalence and circulation of these mutations in Nigeria is scarce. Serum samples (n = 199) from apparently healthy prospective blood donors, pregnant women, and individuals presenting with fever in southwestern Nigeria were analyzed for the presence of IEMs and DRMs by means of nested PCR in the HBV S (HBs) and HBV polymerase (Pol) genes, followed by phylogenetic and mutational analyses. In total, 25.1% (n = 50/199) of samples were positive for HBV, as measured by PCR. In 41 samples (20.6%), both fragments could be amplified, whereas the HBs gene and the Pol gene fragment alone were detected in 0.5% (n = 1/199) and 4% (n = 8/199) of samples, respectively. Sequences were successfully obtained for all 42 HBs gene fragments but for only 31/49 Pol gene fragments (totaling 73 sequences from 44 individuals). All sequences were identified as HBV genotype E. IEMs were present in 18.2% (n = 8/44) of the sequences of HBV-positive individuals with available sequences. IEM Q129H was detected in eight out of the 44 (18.2%) HBV isolates sequenced in this study; however, no DRMs were observed. This study confirms the circulation of HBV IEMs and reports the presence of Q129H IEM for the first time in Nigeria. Intensified research on the dynamics of IEM is necessary in order to enhance the elimination of HBV.
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Affiliation(s)
- Olufisayo Adeyemi Adesina
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife 220282, Nigeria; (O.A.A.); (M.O.J.)
- Department of Microbiology, Ekiti State University, Ado-Ekiti 360213, Nigeria;
| | - Olusola Anuoluwapo Akanbi
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
| | - Oluyinka Oladele Opaleye
- Department of Medical Microbiology and Parasitology, Ladoke Akintola University of Technology, Ogbomoso 230232, Nigeria;
| | | | - Bo Wang
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
| | | | - Patrycja Klink
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
| | - C.-Thomas Bock
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
- Institute of Tropical Medicine, University of Tuebingen, 72076 Tuebingen, Germany
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12
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Zheng Z, Zeng QL, Zhou YH. Reply letter regarding seroconversion of hepatitis B surface antigen in a successful long-term immune cohort. Hum Vaccin Immunother 2021; 17:2775-2776. [PMID: 33849386 DOI: 10.1080/21645515.2021.1897488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Zhigang Zheng
- Department of Epidemiology and Statistic, School of Public Health, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Qing-Lei Zeng
- Department of Epidemiology and Statistic, School of Public Health, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Yi-Hua Zhou
- Department of Epidemiology and Statistic, School of Public Health, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
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13
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Implications of Birth-Dose Vaccination against Hepatitis B Virus in Southeast Asia. Vaccines (Basel) 2021; 9:vaccines9040374. [PMID: 33921259 PMCID: PMC8069988 DOI: 10.3390/vaccines9040374] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/09/2021] [Accepted: 04/10/2021] [Indexed: 02/07/2023] Open
Abstract
The World Health Organization (WHO) South-East Asia Regional Office (SEARO) covers 11 countries with a combined population of about 2 billion people, making it the most populous of the six WHO regions. In 1992, the WHO advocated including the hepatitis B vaccine in the Expanded Program of Immunization (EPI) and vaccinating all infants and children three times within 1 year of birth (HepB3). Recently, the WHO advocate birth-dose hepatitis B vaccination (HepB-BD) as soon as possible after birth, preferably within 24 hours. In 2016, the SEARO endorsed a regional hepatitis B control goal with a target of hepatitis B surface antigen (HBsAg) seroprevalence of ≤1% among children aged ≥5 years by 2020. Of the 11 SEARO countries, four achieved this target on schedule. Out of these four countries, two countries (Bangladesh and Nepal) have not adopted HepB-BD in EPI program. On the other hand, the coverage of HepB3 is not satisfactory in some SEARO countries, including India which adopted HepB-BD but could not achieve the overall target of SEARO. Thus, it is a point of debate whether emphasis should be placed on proper implementation of HepB3 or whether a new agenda of HepB-BD should be incorporated in developing countries of SEARO. The article discusses strengthening and expanding the Hepatitis B vaccination program in SEARO countries with an emphasis on HepB and HepB-BD programs.
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Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.
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Affiliation(s)
- Jiyoung Lee
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA.
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15
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Raheel M, Choga WT, Blackard JT. The distribution of hepatitis B virus surface antigen polymorphisms at positions associated with vaccine escape. J Med Virol 2020; 92:3336-3343. [PMID: 32104912 DOI: 10.1002/jmv.25730] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 02/24/2020] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus (HBV) infects over 250 million people worldwide. Vaccination is effective at preventing infection, although several mutations within the "a" determinant region of the HBV surface antigen (HBsAg) are associated with vaccine escape. We evaluated the frequency, genotype, and global distribution of polymorphisms at sites associated with vaccine escape in 4244 unique full-length HBV genomes. The "a" determinant within the Surface gene was inspected for polymorphisms at sites identified previously associated with vaccine escape. Nearly, 268 (6.3%) sequences from 36 countries contained a polymorphism at a site associated with vaccine escape including 22 genotype A, 99 genotype B, 93 genotype C, 32 genotype D, 14 genotype E, 3 genotype F, 2 genotype G, and 3 genotype I. In genotype A, the most common polymorphism occurred at M133. In genotype B, Q129 and M133 occurred 45 and 51 times, respectively, accounting for 94% of polymorphisms. Polymorphisms at G145 were most frequent in genotype C, while P120 was most common in genotype D. Among all genotypes, polymorphisms at M133 were the most common and accounted for 30.9% of polymorphisms. Polymorphisms at T116, P120, F134, K141, and P142 occurred in geographically diverse locations, whereas polymorphisms at Q129, M133, D144, and G145 were concentrated in East Asia. While the sample size is large, this approach relied on convenience sampling within each country, and many countries have no data available, thereby highlighting the need for additional routine surveillance of surface antigen mutations associated with vaccine escape.
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Affiliation(s)
- Mahad Raheel
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Wonderful T Choga
- Botswana-Harvard AIDS Partnership, Gaborone, Botswana
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Jason T Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio
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16
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Meier-Stephenson V, Deressa T, Genetu M, Damtie D, Braun S, Fonseca K, Swain MG, van Marle G, Coffin CS. Prevalence and molecular characterization of occult hepatitis B virus in pregnant women from Gondar, Ethiopia. CANADIAN LIVER JOURNAL 2020; 3:323-333. [PMID: 35990510 PMCID: PMC9202741 DOI: 10.3138/canlivj-2019-0031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
BACKGROUND: The greatest risk of chronic hepatitis B (CHB) is from mother-to-child transmission. Approximately 20% of individuals in sub-Saharan Africa are hepatitis B virus (HBV) surface antigen–positive (HBsAg+), but the prevalence of occult hepatitis B (OHB) is unknown. Aim: This study investigated CHB and OHB prevalence and viral variants in a cohort of pregnant women in Gondor, Ethiopia. METHODS: Patients were prospectively recruited from the University of Gondar Hospital ( N = 200; median age 27 [inter-quartile range] 8.3y) from March through June 2016. Data were collected using an investigator-administered questionnaire. Plasma was tested for HBsAg and HBV core antibody (anti-HBc), and HBV genotype and presence of HBV variants (ie, vaccine escape mutants [VEMs]) were determined by polymerase chain reaction, Sanger sequencing, and phylogenetic analysis. RESULTS: Of women tested, 1% (2/200) were HBsAg+; 26.8% (47/182) of HBsAg-negative patients were anti-HBc+, of whom 37/47 (78.7%) had detectable HBV DNA. The overall rate of OHB was 20.3%. Both HBsAg+ cases were HBV genotype D, and 36/37 (97.3%) of OHB individuals were genotype D. None carried VEM, but both HBsAg+ cases and 32/37 (86.5%) of the OHB cases showed lamivudine-resistant mutations. CONCLUSIONS: Twenty-seven percent of pregnant women in this cohort showed evidence of CHB or prior HBV exposure (ie, HBsAg+ or anti-HBc+) and clinically relevant HBV variants. Data from this single-centre study suggests high HBV prevalence, reinforcing the World Health Organization’s recommendation for universal prenatal HBV screening and infant vaccination.
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Affiliation(s)
- Vanessa Meier-Stephenson
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- co-first authors
| | - Tekalign Deressa
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
- Ethiopian Public Health Institute, Addis Ababa, Ethiopia
- co-first authors
| | - Meaza Genetu
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Debasu Damtie
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Sheila Braun
- Provincial Laboratory for Public Health, Alberta Health Services, Calgary, Alberta, Canada
| | - Kevin Fonseca
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Provincial Laboratory for Public Health, Alberta Health Services, Calgary, Alberta, Canada
| | - Mark G Swain
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Guido van Marle
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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17
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Zheng Z, Li G, Liao F, Zhang L, Wang X, Fang Z, Chen Q, Liu H, Hu L. Seroconversion of hepatitis B surface antigen among those with previously successful immune response in Southern China. Hum Vaccin Immunother 2020; 17:845-851. [PMID: 32961084 PMCID: PMC7996079 DOI: 10.1080/21645515.2020.1801076] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Recommendations promoted worldwide have suggested a period of protection lasting more than 20 years against hepatitis B (HB) following primary immunization. Starting in 1987, universal HB vaccinations were carried out in Long An County, Guangxi Province, one of the earliest counties in which plasma-derived HB vaccine was delivered to newborns across China. Data collection targeted toward understanding the long term (26–33 years since primary immunization) immune effects of the plasma-derived HB vaccine was conducted in 2015; a second data collection was carried out in 2019 to assess seroconversion in the same cohort. This study qualitatively compared positive vs negative results and quantitatively assessed HB biomarkers – HB surface antigen (HBsAg), antibody to HBsAg (anti-HBs), HB e-antigen (HBeAg), antibody to HBeAg (anti-HBe), and antibody to HB core antigen (anti-HBc) – in serum 26–33 years after the full initial course of HB vaccination, then analyzed anti-HBs seroconversion using the two-phase sampling method in the same cohort and calculated the anti-HBs seroconversion rate from 2015 to 2019. The protective sero-conversion rate (anti-HBs ≥10mIU/mL) was 37.6% (192/511); the HBsAg-positive rate was 5.3% (27/511); the anti-HBs mean geometric titer (GMT) was 11.1 mIU/mL. Among the 143 participants involved in both 2015 and 2019 data collections, the seroconversion rate was 3.5% (5/143); two individuals had protective anti-HBs levels in 2015. These findings indicate that anti-HBs status can be seroconverted to a protective concentration level 4 years earlier in a high HBV epidemic region. The role of genomic mutations and the disappearance of immune memory and seroconversion should be investigated.
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Affiliation(s)
- Zhigang Zheng
- Department of Epidemiology and Statistic, School of Public Health, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Guojian Li
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Fuhui Liao
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Lujuan Zhang
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Xueyan Wang
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Zhongliao Fang
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Qinyan Chen
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Huabin Liu
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
| | - Liping Hu
- Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, China
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18
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Inoue T, Tanaka Y. Cross-Protection of Hepatitis B Vaccination among Different Genotypes. Vaccines (Basel) 2020; 8:456. [PMID: 32824318 PMCID: PMC7563454 DOI: 10.3390/vaccines8030456] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 08/09/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B (HB) vaccination is the most effective method for preventing HB virus (HBV) infection. Universal HB vaccination containing recombinant HB surface antigens (HBsAg) is recommended. Our data revealed that human monoclonal HB surface antibody (anti-HBs) from individuals inoculated with genotype C-based HB vaccine induced cross-protection against HBV genotype A infection. An in vitro infection model demonstrated anti-HBs-positive sera from individuals inoculated with genotype A- or C-based HB vaccine harbored polyclonal anti-HBs that could bind to non-vaccinated genotype HBV. However, because there were low titers of anti-HBs specific for HBsAg of non-vaccinated genotype, high anti-HBs titers would be required to prevent non-vaccinated genotype HBV infection. Clinically, the 2015 Centers for Disease Control and Prevention guidelines state that periodic monitoring of anti-HBs levels after routine HB vaccination is not needed and that booster doses of HB vaccine are not recommended. However, the American Red Cross suggests that HB-vaccine-induced immune memory might be limited; although HB vaccination can prevent clinical liver injury (hepatitis), subclinical HBV infections of non-vaccinated genotypes resulting in detectable HB core antibody could not be completely prevented. Therefore, monitoring anti-HBs levels after routine vaccination might be necessary for certain subjects in high-risk groups.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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19
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Wang Q, Michailidis E, Yu Y, Wang Z, Hurley AM, Oren DA, Mayer CT, Gazumyan A, Liu Z, Zhou Y, Schoofs T, Yao KH, Nieke JP, Wu J, Jiang Q, Zou C, Kabbani M, Quirk C, Oliveira T, Chhosphel K, Zhang Q, Schneider WM, Jahan C, Ying T, Horowitz J, Caskey M, Jankovic M, Robbiani DF, Wen Y, de Jong YP, Rice CM, Nussenzweig MC. A Combination of Human Broadly Neutralizing Antibodies against Hepatitis B Virus HBsAg with Distinct Epitopes Suppresses Escape Mutations. Cell Host Microbe 2020; 28:335-349.e6. [PMID: 32504577 DOI: 10.1016/j.chom.2020.05.010] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 03/09/2020] [Accepted: 05/08/2020] [Indexed: 02/08/2023]
Abstract
Although there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and correlate with recovery from infection. To examine the human antibody response to HBV, we screened 124 vaccinated and 20 infected, spontaneously recovered individuals. The selected individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection but selected for resistance mutations in mice with prior established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. The co-crystal structure of one of the bNAbs with an HBsAg peptide epitope revealed a stabilized hairpin loop. This structure, which contains residues frequently mutated in clinical immune escape variants, provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.
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Affiliation(s)
- Qiao Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Eleftherios Michailidis
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Yingpu Yu
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Zijun Wang
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Arlene M Hurley
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Deena A Oren
- Structural Biology Resource Center, The Rockefeller University, New York, NY 10065, USA
| | - Christian T Mayer
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Anna Gazumyan
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Zhenmi Liu
- West China School of Public Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yunjiao Zhou
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Till Schoofs
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Kai-Hui Yao
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Jan P Nieke
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Jianbo Wu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Qingling Jiang
- West China School of Public Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chenhui Zou
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Mohanmmad Kabbani
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Corrine Quirk
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Thiago Oliveira
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Kalsang Chhosphel
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Qianqian Zhang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - William M Schneider
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Cyprien Jahan
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Tianlei Ying
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jill Horowitz
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Marina Caskey
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Mila Jankovic
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Davide F Robbiani
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Yumei Wen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ype P de Jong
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA.
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Michel C Nussenzweig
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA
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20
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Immunopathogenesis of HBV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:71-107. [DOI: 10.1007/978-981-13-9151-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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21
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A Global View to HBV Chronic Infection: Evolving Strategies for Diagnosis, Treatment and Prevention in Immunocompetent Individuals. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16183307. [PMID: 31505743 PMCID: PMC6766235 DOI: 10.3390/ijerph16183307] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/22/2019] [Accepted: 08/23/2019] [Indexed: 02/07/2023]
Abstract
Hepatitis B Virus (HBV) is a significant public health challenge. Around 250 million people live with chronic HBV infection. With a global approach to this issue, we focus on new perspective in diagnosis, management and prevention of HBV chronic infection. Precise diagnosis of HBV status is crucial to guide patient management. Although available drugs reduce the risk of liver disease progression, they are not able to definitely eradicate HBV, and new therapeutic options are urgently needed. Thus, prevention of HBV infection is still the most effective strategy to achieve the control of the disease. Key aspects of prevention programs include surveillance of viral hepatitis, screening programs and immunization strategies. In spite of the high success rate of licensed HBV vaccines, a need for improved vaccine persists, especially in order to provide coverage of current non-responders.
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22
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Lazarevic I, Banko A, Miljanovic D, Cupic M. Immune-Escape Hepatitis B Virus Mutations Associated with Viral Reactivation upon Immunosuppression. Viruses 2019; 11:v11090778. [PMID: 31450544 PMCID: PMC6784188 DOI: 10.3390/v11090778] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) reactivation occurs as a major complication of immunosuppressive therapy among persons who have recovered from acute hepatitis and those who have controlled chronic infection. Recent literature data emphasize the presence of a high degree of S gene variability in HBV isolates from patients who developed reactivation. In reactivated HBV, the most frequently detected mutations belong to the second loop of “a” determinant in HBsAg. These mutations were identified to be immune escape and responsible for vaccine- and diagnostic-escape phenomena. Their emergence clearly provides survival in the presence of a developed humoral immune response and is often associated with impaired serological diagnosis of HBV reactivation. The knowledge of their existence and roles can elucidate the process of reactivation and strongly highlights the importance of HBV DNA detection in monitoring all patients with a history of HBV infection who are undergoing immunosuppression. This review discusses the possible influence of the most frequently found immune-escape mutations on HBV reactivation.
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Affiliation(s)
- Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia.
| | - Ana Banko
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Danijela Miljanovic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
| | - Maja Cupic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia
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23
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Schlabe S, Bremen KV, Aldabbagh S, Glebe D, Bremer CM, Marsen T, Mellin W, Cristanziano VD, Eis-Hübinger AM, Spengler U. Hepatitis B virus subgenotype F3 reactivation with vaccine escape mutations: A case report and review of the literature. World J Hepatol 2018; 10:509-516. [PMID: 30079137 PMCID: PMC6068847 DOI: 10.4254/wjh.v10.i7.509] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/08/2018] [Accepted: 06/08/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B represents a global health threat because its chronic course and sequelae contribute to a high morbidity and mortality. Hepatitis B virus (HBV) infection can be controlled by vaccines, antiviral treatment, and by interrupting transmission. Rare vaccine escape mutants are serious because they eliminate vaccine protection. Here, we present a 74-year-old vaccinated patient with HBV reactivation 11 years after kidney transplantation. The patient was HBV-positive but HBsAg-negative prior to vaccination 6 years before transplantation. The reactivated virus was HBV genotype F3 with vaccine escape mutations G145R, P120Q, and Q129P. The patient was successfully treated with entecavir. The epidemiological reasons for this subgenotype, which is extremely rare in Western Europe, were unclear. This case illustrates that second-generation vaccines are not always effective in a specific group of patients.
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Affiliation(s)
- Stefan Schlabe
- German Center of Infectious Diseases Research (DZIF), Partner-Site Cologne-Bonn, Bonn-Cologne35392, Germany
- Department of Internal Medicine I, University Hospital of Bonn, Bonn 53127, Germany
| | - Kathrin van Bremen
- German Center of Infectious Diseases Research (DZIF), Partner-Site Cologne-Bonn, Bonn-Cologne35392, Germany
- Department of Internal Medicine I, University Hospital of Bonn, Bonn 53127, Germany
| | - Souhaib Aldabbagh
- German Center of Infectious Diseases Research (DZIF), Partner-Site Cologne-Bonn, Bonn-Cologne35392, Germany
- Institute of Virology, University Hospital of Bonn, Bonn 53127, Germany
| | - Dieter Glebe
- Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg, Giessen 35392, Germany
- German Center of Infectious Diseases Research (DZIF), Partner-Site Giessen, Giessen 35392, Germany
| | - Corinna M Bremer
- Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B and D Viruses, Biomedical Research Center Seltersberg, Giessen 35392, Germany
- German Center of Infectious Diseases Research (DZIF), Partner-Site Giessen, Giessen 35392, Germany
| | - Tobias Marsen
- Practice of Nephrology and Dialysis, Nephrological Center Cologne-Lindenthal, Cologne 50937, Germany
| | - Walter Mellin
- Practice of Pathology and Cytology, Cologne 50931, Germany
| | | | - Anna M Eis-Hübinger
- German Center of Infectious Diseases Research (DZIF), Partner-Site Cologne-Bonn, Bonn-Cologne35392, Germany
- Institute of Virology, University Hospital of Bonn, Bonn 53127, Germany
| | - Ulrich Spengler
- German Center of Infectious Diseases Research (DZIF), Partner-Site Cologne-Bonn, Bonn-Cologne35392, Germany
- Department of Internal Medicine I, University Hospital of Bonn, Bonn 53127, Germany
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24
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Corti D, Benigni F, Shouval D. Viral envelope-specific antibodies in chronic hepatitis B virus infection. Curr Opin Virol 2018; 30:48-57. [PMID: 29738926 DOI: 10.1016/j.coviro.2018.04.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/26/2018] [Accepted: 04/02/2018] [Indexed: 12/20/2022]
Abstract
While the cellular immune response associated with acute and chronic HBV infection has been thoroughly studied, the B cell response in chronic hepatitis B and the role of antibodies raised against the HBV envelope antigens in controlling and prevention of infection requires further investigation. The detection of anti-HBs antibodies is considered as one of the biomarkers for functional cure of chronic hepatitis B virus infection, as well as for protective immunity. Indeed, vaccine-induced neutralizing anti-HBs antibodies have been shown to protect against HBV challenge. Yet, the therapeutic potential of viral envelope-specific antibodies and the mechanism involved in protection and prevention of cell-to-cell transmission warrants additional investigative efforts. In this review, we will provide a critical overview of the available preclinical and clinical literature supporting the putative role of active and passive vaccination and neutralizing envelope-specific antibodies for therapeutic intervention in combination regimens intended to cure persistent HBV infection.
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Affiliation(s)
- Davide Corti
- Humabs BioMed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
| | - Fabio Benigni
- Humabs BioMed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
| | - Daniel Shouval
- Liver Unit, Institute for Gastroenterology and Hepatology, Hadassah-Hebrew University Hospital, P.O. Box 12000, 91120 Jerusalem, Israel.
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25
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Fusco DN, Ganova-Raeva L, Khudyakov Y, Punkova L, Mohamed A, Cheon SSY, Koirala P, Andersson KL, Jourdain G, Sureau C, Chung RT, Lauer G. Reactivation of a Vaccine Escape Hepatitis B Virus Mutant in a Cambodian Patient During Anti-Hepatitis C Virus Therapy. Front Med (Lausanne) 2018; 5:97. [PMID: 29761102 PMCID: PMC5936758 DOI: 10.3389/fmed.2018.00097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 03/26/2018] [Indexed: 12/17/2022] Open
Abstract
A 76-year-old Cambodian man co-infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) 6c-1 presented for care. HBV DNA was intermittently detectable despite anti-HBs levels being above the protective threshold. During treatment for HCV, HBV DNA levels increased. Sequencing revealed multiple mutations including vaccine escape mutation and mutations predicted to enhance fitness. This case represents exacerbation of an HBV vaccine escape mutant during a direct-acting antiviral therapy.
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Affiliation(s)
- Dahlene N. Fusco
- Medicine/General Internal Medicine and Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, United States
| | - Lilia Ganova-Raeva
- Molecular Epidemiology and Bioinformatics Team, DVH/NCHHSTP/CDC, Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States
| | - Yury Khudyakov
- Molecular Epidemiology and Bioinformatics Team, DVH/NCHHSTP/CDC, Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States
| | - Lili Punkova
- Molecular Epidemiology and Bioinformatics Team, DVH/NCHHSTP/CDC, Centers for Disease Control and Prevention (CDC), Atlanta, GA, United States
| | - Aisha Mohamed
- Cooper Medical School of Rowan University, Camden, NJ, United States
| | | | | | - Karin L. Andersson
- Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Gonzague Jourdain
- Institut de recherche pour le développement(IRD), Marseille, France
- Chiang Mai University, Chiang Mai, Thailand
- Harvard School of Public Health, Boston, MA, United States
| | - Camille Sureau
- Institut National de la Tranfusion Sanguine INSER U1134, Paris, France
| | - Raymond T. Chung
- Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Georg Lauer
- Gastrointestinal Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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26
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Gencay M, Vermeulen M, Neofytos D, Westergaard G, Pabinger S, Kriegner A, Seffner A, Gohl P, Huebner K, Nauck M, Kaminski WE. Substantial variation in the hepatitis B surface antigen (HBsAg) in hepatitis B virus (HBV)-positive patients from South Africa: Reliable detection of HBV by the Elecsys HBsAg II assay. J Clin Virol 2018; 101:38-43. [DOI: 10.1016/j.jcv.2018.01.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/12/2018] [Accepted: 01/21/2018] [Indexed: 02/07/2023]
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27
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Kennedy DA, Read AF. Why does drug resistance readily evolve but vaccine resistance does not? Proc Biol Sci 2018; 284:rspb.2016.2562. [PMID: 28356449 PMCID: PMC5378080 DOI: 10.1098/rspb.2016.2562] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 02/28/2017] [Indexed: 01/12/2023] Open
Abstract
Why is drug resistance common and vaccine resistance rare? Drugs and vaccines both impose substantial pressure on pathogen populations to evolve resistance and indeed, drug resistance typically emerges soon after the introduction of a drug. But vaccine resistance has only rarely emerged. Using well-established principles of population genetics and evolutionary ecology, we argue that two key differences between vaccines and drugs explain why vaccines have so far proved more robust against evolution than drugs. First, vaccines tend to work prophylactically while drugs tend to work therapeutically. Second, vaccines tend to induce immune responses against multiple targets on a pathogen while drugs tend to target very few. Consequently, pathogen populations generate less variation for vaccine resistance than they do for drug resistance, and selection has fewer opportunities to act on that variation. When vaccine resistance has evolved, these generalities have been violated. With careful forethought, it may be possible to identify vaccines at risk of failure even before they are introduced.
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Affiliation(s)
- David A Kennedy
- Center for Infectious Disease Dynamics, Departments of Biology and Entomology, The Pennsylvania State University, University Park, PA, USA
| | - Andrew F Read
- Center for Infectious Disease Dynamics, Departments of Biology and Entomology, The Pennsylvania State University, University Park, PA, USA
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28
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29
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Farooq A, Waheed U, Zaheer HA, Aldakheel F, Alduraywish S, Arshad M. Detection of HBsAg mutants in the blood donor population of Pakistan. PLoS One 2017; 12:e0188066. [PMID: 29166662 PMCID: PMC5699832 DOI: 10.1371/journal.pone.0188066] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 10/31/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Infection with the Hepatitis B virus (HBV) continues to be one of the leading healthcare issues in Pakistan, affecting over 6 million people. The existence of HBsAg mutants is well documented in many countries. In Pakistan, HBV screening in the majority of the blood banks is performed by Rapid Detection Devices or ELISA tests. These tests are designed to detect HBsAg, but may not detect the mutant HBsAg. Failure to detect the HBsAg mutant may result in the transmission of HBV infection from donor to recipient. Hence, there is a need to identify a HBsAg assay which can detect mutants in a country where simple and conventional HBsAg assays with varying sensitivity and specificity are used to detect HBV infections. MATERIAL AND METHODS Three routinely used diagnostic tests (Rapid Detection Devices, ELISA and CLIA) for HBsAg were compared with the LIAISON® XL Murex HBsAg Quant Assay to determine the prevalence of HBV mutants in the Pakistani blood donor population. The samples of blood donors from different cities of Pakistan were collected. The testing was performed using SD Bioline rapid assay (n = 1500), ELISA (n = 1500), and Abbott ARCHITECT®CLIA system (n = 1500) at the centers where the donations were collected. All samples (n = 4500) were re-tested for comparative analysis on the LIAISON® XL Murex HBsAg Quant assay (DiaSorin S.p.A.). PCR testing was performed as a gold standard on all discordant samples. RESULTS 119/4500 (2.64%) of the samples were positive for antibodies against HBsAg. The sensitivity of SD Bioline Rapid, GB HBsAg ELISA, Abbott ARCHITECT® and LIAISON® XL Murex HBsAg Quant assay was 17.24%, 43.75%, 90.91%and 100% respectively. The specificity of SD Bioline Rapid, GB HBsAg ELISA, Abbott ARCHITECT® and LIAISON® XL Murex HBsAg Quant Assay was 98.82%, 99.59%, 100% and 100%, respectively. CONCLUSION LIAISON® XL Murex HBsAg Quant assay is a highly sensitive, specific and accurate screening assay for detecting wild type as well as mutant HBsAg.
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Affiliation(s)
- Ahmad Farooq
- Department of Bioinformatics & Biotechnology, International Islamic University, Islamabad, Pakistan
| | - Usman Waheed
- Departments of Pathology and Blood Bank, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
| | - Hasan Abbas Zaheer
- Departments of Pathology and Blood Bank, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
- Safe Blood Transfusion Programme, Ministry of National Health Services, Government of Pakistan, Islamabad, Pakistan
| | - Fahad Aldakheel
- Department of Clinical Laboratory Medicine, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Shatha Alduraywish
- Department of Family & Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Muhammad Arshad
- Department of Bioinformatics & Biotechnology, International Islamic University, Islamabad, Pakistan
- * E-mail:
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30
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Wang J, Qiu J, Zhu Y, Zhou H, Yu L, Ding Y, Zhang L, Guo Z, Dong C. Molecular evolution of hepatitis B vaccine escape variants in China, during 2000-2016. Vaccine 2017; 35:5808-5813. [PMID: 28939157 DOI: 10.1016/j.vaccine.2017.09.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 09/02/2017] [Accepted: 09/08/2017] [Indexed: 02/07/2023]
Abstract
Hepatitis B vaccine escape variants are the main threat to hepatitis B virus (HBV) infection in vaccination era worldwide. With 215 genotype B HBV and 313 genotype C HBV vaccine escape variants isolated from China during 2000-2016, we reported that genotype B HBV vaccine escape strains diverged in ∼1997 (95% HPD; 1987-2005), while genotype C HBV vaccine escape strains diverged in ∼1976 (95% HPD; 1955-2003). Additionally, the p-distance of genotype C HBV vaccine escape strains was 0.0291±0.0169, which was significantly higher than that in the genotype B HBV (t=131.02, p<0.05). However, genotype B HBV vaccine escape strains evolved more rapidly than genotype C HBV (2.103×10-3 vs 1.083×10-3 substitutions/site/year). Bayesian skyline plot analysis showed that the populations of genotype C HBV vaccine escape strains fluctuated more than those in genotype B HBV. Four sites (A5T/S, L21S, T/A126S and T/N131I/A) and 13 sites (N3S, T5A, G10Q/R/E, L21S, T47K/A/V, L98V/P, I/S126N/V/T, Q129H/R/L, T131P/I/N/A, G145A/R, L175S/F, L213I/S, V224A/G) were found to be under positive selection in genotype B and C HBV vaccine escape strains, respectively. More importantly, N3S, L21S, T47K, L98V, I/S126T and L213I mutations were detected in 1 (2.5%), 1 (2.5%), 1 (2.5%), 3 (7.5%), 1 (2.5%), 1 (2.5%) genotype C HBV infected Chinese younger with neonatal HBV vaccination, respectively. Therefore, our results should be valuable in further understanding the molecular evolution of HBV and providing new ideas for the elimination of HBV infection.
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Affiliation(s)
- Jie Wang
- Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Jing Qiu
- Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Yinwei Zhu
- Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Hui Zhou
- Suzhou Industrial Park Centers for Disease Control and Prevention, Suzhou 215123, China
| | - Lugang Yu
- Suzhou Industrial Park Centers for Disease Control and Prevention, Suzhou 215123, China
| | - Yi Ding
- Suzhou Industrial Park Centers for Disease Control and Prevention, Suzhou 215123, China
| | - Lige Zhang
- Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Zhirong Guo
- Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Chen Dong
- Department of Epidemiology and Statistics, School of Public Health, Jiangsu Key Laboratory and Translational Medicine for Geriatric Disease, Medical College of Soochow University, Suzhou, Jiangsu, China.
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Aghasadeghi MR, Velayati AA, Mamishi S, Nabavi M, Aghakhani A, Bidari-Zerehpoosh F, Haghi Ashtiani MT, Sabeti S, Banifazl M, Azimian-Zavareh F, Motevalli F, Soleymani S, Ramezani A. Low prevalence of hepatitis B vaccine escape mutants among individuals born after the initiation of a nationwide vaccination program in Iran. Arch Virol 2016; 161:3405-3411. [PMID: 27613286 DOI: 10.1007/s00705-016-3050-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 09/03/2016] [Indexed: 01/04/2023]
Abstract
A nationwide hepatitis B virus (HBV) vaccination program for neonates was launched in Iran in 1993. Despite the success of this program, concern about its long-term success still remains, because breakthrough infections due to emergence of surface mutants have been reported in immunized children. We aimed to evaluate the seroprevalence of HBV and vaccine escape mutants among individuals born after the initiation of the nationwide vaccination program in Iran. This study included 1115 participants younger than 23 years old, with 223 in each age cohort. The presence of HBsAg, anti-HBs and anti-HBc was evaluated using an ELISA kit. HBV-DNA levels were measured in anti-HBc and/or HBsAg-positive subjects. PCR products were sequenced and mutations were identified. The overall HBsAg prevalence was 0.27 %. Anti-HBs and anti-HBc positive rates were 48 % and 0.18 %, respectively. Two individuals were positive for anti-HBc, one of whom was also positive for HBsAg, and the other was positive for anti-HBc only. HBV DNA was detected in three out of four anti-HBc-and /or HBsAg-positive subjects. An I195M mutation within the S gene was detected in two of the three HBV-DNA-positive cases. A very low prevalence of HBsAg and isolated anti-HBc were found in this study. The I195M mutation found in the surface gene could have been induced by immune pressure. Although the number of ''vaccine escape'' mutants found in this cohort was low, ongoing surveillance of breakthrough infections and escape mutants is still needed.
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Affiliation(s)
| | - Ali Akbar Velayati
- Pediatric Respiratory Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Setareh Mamishi
- Pediatric Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmood Nabavi
- Center for Communicable Disease Control, Ministry of Health and Medical Education, Tehran, Iran
| | - Arezoo Aghakhani
- Clinical Research Deptartment, Pasteur Institute of Iran, 13164, Pasteur Ave., Tehran, Iran
| | | | | | - Shahram Sabeti
- Pathology Ward, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Banifazl
- Iranian Society for Support of Patients with Infectious Disease, Tehran, Iran
| | - Fatemeh Azimian-Zavareh
- Hepatitis Deptartment, Center for Communicable Disease Control, Ministry of Health and Medical Education, Tehran, Iran
| | - Fatemeh Motevalli
- Hepatitis and AIDS Deptartment, Pasteur Institute of Iran, Tehran, Iran
| | - Sepehr Soleymani
- Hepatitis and AIDS Deptartment, Pasteur Institute of Iran, Tehran, Iran
| | - Amitis Ramezani
- Clinical Research Deptartment, Pasteur Institute of Iran, 13164, Pasteur Ave., Tehran, Iran.
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32
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Leong J, Lin D, Nguyen MH. Hepatitis B surface antigen escape mutations: Indications for initiation of antiviral therapy revisited. World J Clin Cases 2016; 4:71-75. [PMID: 26989671 PMCID: PMC4792167 DOI: 10.12998/wjcc.v4.i3.71] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 11/16/2015] [Accepted: 12/14/2015] [Indexed: 02/05/2023] Open
Abstract
Approximately 240 million people are chronically infected with hepatitis B. The implementation of rigorous vaccination programs has led to an overall decrease in the prevalence of this disease worldwide but this may also have led to emergence of viral mutations that can escape the protection of hepatitis B surface antibody. As this phenomenon is increasingly recognized, concern for transmission to vaccinated individuals has also been raised. Herein, we describe two cases where the suspected presence of a hepatitis B surface antigen escape mutation impacted the decision to initiate early antiviral therapy, as well as provide a brief review of these mutations. Our findings described here suggest that a lower threshold for initiating therapy in these individuals should be considered in order to reduce the risk of transmission, as vaccination does not provide protection.
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33
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Coppola N, Onorato L, Minichini C, Di Caprio G, Starace M, Sagnelli C, Sagnelli E. Clinical significance of hepatitis B surface antigen mutants. World J Hepatol 2015; 7:2729-2739. [PMID: 26644816 PMCID: PMC4663392 DOI: 10.4254/wjh.v7.i27.2729] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/27/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major public health problem in many countries, with nearly 300 million people worldwide carrying HBV chronic infection and over 1 million deaths per year due to cirrhosis and liver cancer. Several hepatitis B surface antigen (HBsAg) mutations have been described, most frequently due to a single amino acid substitution and seldom to a nucleotide deletion. The majority of mutations are located in the S region, but they have also been found in the pre-S1 and pre-S2 regions. Single amino acid substitutions in the major hydrophilic region of HBsAg, called the "a" determinant, have been associated with immune escape and the consequent failure of HBV vaccination and HBsAg detection, whereas deletions in the pre-S1 or pre-S2 regions have been associated with the development of hepatocellular carcinoma. This review article will focus on the HBsAg mutants and their biological and clinical implications.
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Affiliation(s)
- Nicola Coppola
- Nicola Coppola, Lorenzo Onorato, Carmine Minichini, Giovanni Di Caprio, Mario Starace, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
| | - Lorenzo Onorato
- Nicola Coppola, Lorenzo Onorato, Carmine Minichini, Giovanni Di Caprio, Mario Starace, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
| | - Carmine Minichini
- Nicola Coppola, Lorenzo Onorato, Carmine Minichini, Giovanni Di Caprio, Mario Starace, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
| | - Giovanni Di Caprio
- Nicola Coppola, Lorenzo Onorato, Carmine Minichini, Giovanni Di Caprio, Mario Starace, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
| | - Mario Starace
- Nicola Coppola, Lorenzo Onorato, Carmine Minichini, Giovanni Di Caprio, Mario Starace, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
| | - Caterina Sagnelli
- Nicola Coppola, Lorenzo Onorato, Carmine Minichini, Giovanni Di Caprio, Mario Starace, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
| | - Evangelista Sagnelli
- Nicola Coppola, Lorenzo Onorato, Carmine Minichini, Giovanni Di Caprio, Mario Starace, Evangelista Sagnelli, Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, 80131 Naples, Italy
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Ultradeep Sequencing for Detection of Quasispecies Variants in the Major Hydrophilic Region of Hepatitis B Virus in Indonesian Patients. J Clin Microbiol 2015. [PMID: 26202119 DOI: 10.1128/jcm.00602-15] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Quasispecies of hepatitis B virus (HBV) with variations in the major hydrophilic region (MHR) of the HBV surface antigen (HBsAg) can evolve during infection, allowing HBV to evade neutralizing antibodies. These escape variants may contribute to chronic infections. In this study, we looked for MHR variants in HBV quasispecies using ultradeep sequencing and evaluated the relationship between these variants and clinical manifestations in infected patients. We enrolled 30 Indonesian patients with hepatitis B infection (11 with chronic hepatitis and 19 with advanced liver disease). The most common subgenotype/subtype of HBV was B3/adw (97%). The HBsAg titer was lower in patients with advanced liver disease than that in patients with chronic hepatitis. The MHR variants were grouped based on the percentage of the viral population affected: major, ≥20% of the total population; intermediate, 5% to <20%; and minor, 1% to <5%. The rates of MHR variation that were present in the major and intermediate viral population were significantly greater in patients with advanced liver disease than those in chronic patients. The most frequent MHR variants related to immune evasion in the major and intermediate populations were P120Q/T, T123A, P127T, Q129H/R, M133L/T, and G145R. The major population of MHR variants causing impaired of HBsAg secretion (e.g., G119R, Q129R, T140I, and G145R) was detected only in advanced liver disease patients. This is the first study to use ultradeep sequencing for the detection of MHR variants of HBV quasispecies in Indonesian patients. We found that a greater number of MHR variations was related to disease severity and reduced likelihood of HBsAg titer.
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35
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Tajiri K, Shimizu Y. Unsolved problems and future perspectives of hepatitis B virus vaccination. World J Gastroenterol 2015; 21:7074-7083. [PMID: 26109794 PMCID: PMC4476869 DOI: 10.3748/wjg.v21.i23.7074] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 03/23/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is still a serious worldwide problem, and vaccination is the most effective strategy for primary prevention of the infection. Although universal vaccination may be required for total eradication, several countries, including Japan, have not yet adopted universal vaccination programs. Some individuals are non-responders to HBV vaccine and several mechanisms responsible for their poor response have been proposed. To overcome non-response, third generation vaccines with pre-S proteins have been developed. These vaccines have shown better anti-HBs responses and may also be effective in preventing infection by HBV with S mutant. Improvement of vaccine efficacy by intradermal administration, or co-administration with cytokines or adjuvants, may also be effective in non-responders. The necessity, timing and method of booster vaccination in responders with decreased anti-HBs responses, and effective vaccination against S-mutant HBV, are issues requiring resolution in the global prevention of HBV infection.
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36
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Induction of humoral and cell-mediated immune responses by hepatitis B virus epitope displayed on the virus-like particles of prawn nodavirus. Appl Environ Microbiol 2014; 81:882-9. [PMID: 25416760 DOI: 10.1128/aem.03695-14] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) is a deadly pathogen that has killed countless people worldwide. Saccharomyces cerevisiae-derived HBV vaccines based upon hepatitis B surface antigen (HBsAg) is highly effective. However, the emergence of vaccine escape mutants due to mutations on the HBsAg and polymerase genes has produced a continuous need for the development of new HBV vaccines. In this study, the "a" determinant within HBsAg was displayed on the recombinant capsid protein of Macrobrachium rosenbergii nodavirus (MrNV), which can be purified easily in a single step through immobilized metal affinity chromatography (IMAC). The purified protein self-assembled into virus-like particles (VLPs) when observed under a transmission electron microscope (TEM). Immunization of BALB/c mice with this chimeric protein induced specific antibodies against the "a" determinant. In addition, it induced significantly more natural killer and cytotoxic T cells, as well as an increase in interferon gamma (IFN-γ) secretion, which are vital for virus clearance. Collectively, these findings demonstrated that the MrNV capsid protein is a potential carrier for the HBV "a" determinant, which can be further extended to display other foreign epitopes. This paper is the first to report the application of MrNV VLPs as a novel platform to display foreign epitopes.
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37
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Romanò L, Paladini S, Galli C, Raimondo G, Pollicino T, Zanetti AR. Hepatitis B vaccination. Hum Vaccin Immunother 2014; 11:53-7. [PMID: 25483515 DOI: 10.4161/hv.34306] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus is a worldwide leading cause of acute and chronic liver disease including cirrhosis and hepatocellular carcinoma. Effective vaccines have been available since the early '80s and vaccination has proved highly successful in reducing the disease burden, the development of the carrier state and the HB-related morbidity and mortality in the countries where vaccination has been implemented. Neutralizing (protective) antibodies (anti-HBs) induced by vaccination are targeted largely towards the amino acid hydrophilic region, referred to as the common a determinant which is present on the outer protein coat or surface antigen (HBsAg), spanning amino acids 124-149. This provides protection against all HBV genotypes (from A to H) and is responsible for the broad immunity afforded by hepatitis B vaccination. Thus, alterations of residues within this region of the surface antigen may determine conformational changes that can allow replication of the mutated HBV in vaccinated people. An important mutation in the surface antigen region was identified in Italy some 25 years ago in infants born to HBsAg carrier mothers who developed breakthrough infections despite having received HBIG and vaccine at birth. This virus had a point mutation from guanosine to adenosine at nucleotide position 587, resulting in aa substitution from glycine (G) to arginine (R) at position 145 in the a determinant. Since the G145R substitution alters the projecting loop (aa 139-147) of the a determinant, the neutralizing antibodies induced by vaccination are no longer able to recognize the mutated epitope. Beside G145R, other S-gene mutations potentially able to evade neutralizing anti-HBs and infect vaccinated people have been described worldwide. In addition, the emergence of Pol mutants associated with resistance to treatment with nucleos(t)ide analogues can select viruses with crucial changes in the overlapping S-gene, potentially able to alter the S protein immunoreactivity. Thus such mutants have the potential to infect both naïve and immunized people, negatively affecting the efficacy of both the antiviral treatment and the vaccination programs. Despite concern, at present the overall impact of vaccine escapes mutants seems to be low and they do not pose a public health threat or a need to modify the established hepatitis B vaccination programs. The development of novel NAs with a high barrier to resistance is warranted.
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Affiliation(s)
- Luisa Romanò
- a Dipartimento di Scienze Biomediche per la Salute; Università degli Studi di Milano; Milano, Italy
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Lazarevic I. Clinical implications of hepatitis B virus mutations: Recent advances. World J Gastroenterol 2014; 20:7653-7664. [PMID: 24976703 PMCID: PMC4069294 DOI: 10.3748/wjg.v20.i24.7653] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/05/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, and of its long-term complications. It is the most variable among DNA viruses, mostly because of its unique life cycle which includes the activity of error-prone enzyme, reverse transcriptase, and the very high virion production per day. In last two decades, numerous research studies have shown that the speed of disease progression, reliability of diagnostic methods and the success of antiviral therapy and immunization are all influenced by genetic variability of this virus. It was shown that mutations in specific regions of HBV genome could be responsible for unwanted clinical outcomes or evasion of detection by diagnostic tools, thus making the monitoring for these mutations a necessity in proper evaluation of patients. The success of the vaccination programs has now been challenged by the discovery of mutant viruses showing amino acid substitutions in hepatitis B surface antigen (HBsAg), which may lead to evasion of vaccine-induced immunity. However, the emergence of these mutations has not yet raised concern since it was shown that they develop slowly. Investigations of HBV genetic variability and clinical implications of specific mutations have resulted in significant advances over the past decade, particularly in regard to management of resistance to antiviral drugs. In the era of drugs with high genetic barrier for resistance, on-going monitoring for possible resistance is still essential since prolonged therapy is often necessary. Understanding the frequencies and clinical implications of viral mutations may contribute to improvement of diagnostic procedures, more proper planning of immunization programs and creating the most efficient therapeutic protocols.
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Park GC, Hwang S, Ahn CS, Kim KH, Moon DB, Ha TY, Song GW, Jung DH, Shin YW, Kim SH, Chang KH, Namgoong JM, Park CS, Park HW, Park YH, Kang SH, Jung BH, Lee SG. Analysis of S gene mutation of the hepatitis B virus in adult liver transplant recipients showing resistance to hepatitis B immunoglobulin therapy. Transplant Proc 2014; 45:3047-51. [PMID: 24157033 DOI: 10.1016/j.transproceed.2013.08.055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND A considerable proportion of recipients of liver transplantations who are presented hepatitis B immunoglobulin (HBIG) monotherapy for hepatitis B virus (HBV) prophylaxis develop HBIG resistance. In this study, we investigated the mutation patterns in the major hydrophilic region (MHR) of amino acid sequences 100 to 160. METHODS Using the gene sequence analyzer for amino acid sequences 0 to 226 in the S/pre-S region we analyzed blood samples of 15 patients showing HBIG resistance after high-dose HBIG prophylaxis. RESULTS Various mutations in the MHR were observed in 14/15 samples: Gly145Arg mutation in 8/13 Adr subtype and 1/2 Ayw subtype samples (60%). The next most common mutation was Gly165Trp in 8/13 Adr subtype but neither of 2 Ayw subtype samples (53.3%). Concurrent antiviral resistance was noted in 5 patients: lamivudine (n = 5), or entecavir (n = 3), but not adefovir, suggesting the occurrence of simultaneous, antiviral cross-resistances. Two patients underwent retransplantation due to the progression of HBV infection despite vigorous antiviral therapy. At diagnosis of HBV recurrence, the mean HBV DNA load was 6.5 × 10(6) copies/mL; 4 patients showed paradoxical coexistence of anti-HBs and HBsAg. Currently, 2 subjects show low-level HBV DNA replication in peripheral blood, although the other 12 had no DNA replication after prolonged antiviral therapy. CONCLUSIONS This study suggested that various mutations in the "a" determinant were associated with HBIG resistance. Since treatment failure to rescue antiviral therapy was often associated with delayed detection of HBV recurrence rather than concurrent antiviral resistance, frequent HBV surveillance using more sensitive screening tests, such as HBeAg and HBV DNA polymerase chain reaction assay, seems to be mandatory.
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Affiliation(s)
- G-C Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Sticchi L, Caligiuri P, Cacciani R, Alicino C, Bruzzone B. Epidemiology of HBV S-gene mutants in the Liguria Region, Italy: Implications for surveillance and detection of new escape variants. Hum Vaccin Immunother 2013; 9:568-71. [PMID: 23296324 PMCID: PMC3891713 DOI: 10.4161/hv.23236] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 11/05/2012] [Indexed: 12/27/2022] Open
Abstract
HBV surface antigen (HBsAg) variants may impair diagnosis or allow the virus to escape vaccine-induced immunity and their circulation in the population can represent a Public Health threat. Their prevalence, however, is not yet completely established. Evidence indicates that amino acid substitutions within HBsAg can lead to conformational changes which allow mutated HBV to escape the vaccine-induced antibodies used in the screening tests. In such scenario, the aim of this study was to investigate the prevalence of HBV S-Gene escape mutants by sequencing the gene in a cohort of Ligurian patients monitored for viral load, genotype and drug resistance and to evaluate the risk of false negative HBsAg detection by routine screening tests. From 2007 to 2011, in 256 consecutive samples from Ligurian HBV positive patients sequencing assay for detection of RT/S-Gene mutations using Trugene HBV Genotyping kit (Siemens Healthcare Diagnostics Inc., Tarrytown, NY) was performed. Serological HBV tests and viral load were also performed. Analyzed sequences revealed G145R mutation in 8/256 (3.1%) examined sequences, it was alone in 5 patients and accompanied by other HBsAg mutations in 3 samples. HBsAg resulted undetectable by 3 of the 8 samples, derived from patients with multiple mutations: T126I-T131A-C139Y-E/D144G, T126I-M133L, and P120Q-T126I. The emergence of these mutants, at least the G145R, has already been addressed as a public health concern because of its capability of escaping the immune system. In the present study we point out a second aspect connected with their existence and with similar potential negative impact on public health, that is their capability of escape punctual detection.
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Affiliation(s)
- Laura Sticchi
- Department of Health Sciences; University of Genoa; Genoa, Italy
- I.R.C.C.S. “A.O.U. San Martino-IST”; Genoa, Italy
| | | | - Roberto Cacciani
- Department of Health Sciences; University of Genoa; Genoa, Italy
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41
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Hepatitis B vaccines. Vaccines (Basel) 2013. [DOI: 10.1016/b978-1-4557-0090-5.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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Romanò L, Paladini S, Zanetti AR. Twenty years of universal vaccination against hepatitis B in Italy: achievements and challenges. J Public Health Res 2012; 1:126-9. [PMID: 25170454 PMCID: PMC4140357 DOI: 10.4081/jphr.2012.e18] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Accepted: 02/20/2012] [Indexed: 02/07/2023] Open
Abstract
Viral hepatitis B is a vaccine-preventable disease. Vaccination has proved to be safe and highly effective in reducing the incidence, the carrier rate and HBV-related mortality on a global scale. In Italy, universal vaccination against hepatitis B started in 1991 in infants as well as in adolescents, providing an outstanding record of safety and effectiveness. Within a few years, over 95% coverage was consistently reported. Today, some 17 million people are immune against hepatitis B and their immunity has been shown to be long-lasting. At present, no booster is required in healthy vaccinated people to sustain protection. Surveillance data from Italy have shown a clear overall decline in hepatitis B among successfully vaccinated individuals. Furthermore, a generation of children and young people (at present cohorts ranging from 0 to 32 years) is emerging with practically no markers of HBV infection. Italy’s vaccination programme has resulted in substantial progress towards the prevention and control of hepatitis B. The vaccination programme must continue. Maintaining mandatory vaccination of infants and increasing HBV vaccination coverage in high-risk groups, including households of HBsAg carriers as well as immigrants, remain a priority for the future.
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Affiliation(s)
- Luisa Romanò
- Dipartimento di Sanità Pubblica - Microbiologia - Virologia, Università di Milano , Italy
| | - Sara Paladini
- Dipartimento di Sanità Pubblica - Microbiologia - Virologia, Università di Milano , Italy
| | - Alessandro R Zanetti
- Dipartimento di Sanità Pubblica - Microbiologia - Virologia, Università di Milano , Italy
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Taramasso L, Caligiuri P, Di Biagio A, Bruzzone B, Rosso R, Icardi G, Viscoli C. Lamivudine resistance mutations in European patients with hepatitis B and patients co-infected with HIV and hepatitis B. J Med Virol 2012; 83:1905-8. [PMID: 21915864 DOI: 10.1002/jmv.22192] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Evaluation of resistance pattern in patients with chronic hepatitis B. Retrospective study of hepatitis B virus (HBV) resistance mutations in patients found viraemic after first-line treatment. HBV viral load was determined by a real-time polymerase chain reaction and the substitutions in HBV-DNA were studied by polymerase sequencing test. First line treatment had failed in 12 out of 33 patients (36%) receiving anti-HBV drugs. The 12 patients with persistent viraemia were all lamivudine (LAM) experienced and 7 had a polymerase sequencing test available. LAM substitution mutations L180M + M204V/I were found in six out of seven cases, with an accompanying V173L mutation in three cases. These mutations were also related with changes in HBsAg. The use of potent drugs in the first line anti-HBV therapy may reduce the resistance mutations in the future.
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Affiliation(s)
- Lucia Taramasso
- Infectious Diseases Department, San Martino Hospital and University of Genoa, Genoa, Italy
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44
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Chen SM, Kung CM, Yang WJ, Wang HL. Efficacy of the nationwide hepatitis B infant vaccination program in Taiwan. J Clin Virol 2011; 52:11-6. [PMID: 21767983 DOI: 10.1016/j.jcv.2011.06.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 06/20/2011] [Accepted: 06/24/2011] [Indexed: 12/17/2022]
Abstract
BACKGROUND Taiwan launched a nationwide infant vaccination program for hepatitis B (HB) in 1984. OBJECTIVES This study evaluated the seroprevalence of hepatitis B virus (HBV) and the incidence of high alanine aminotransferase (ALT) level among young adults prior to, during, and since the introduction of the nationwide HBV vaccination program. STUDY DESIGN Researchers recruited 101,584 freshmen (male:female=1.114:1; mean age, 18.5±0.5 years) from 21 universities between 1995 and 2009 (birth cohorts 1977-1991) in Taiwan, testing for serum hepatitis B surface antigens (HBsAg), hepatitis e antigens (HBeAg), antibodies against HBsAg (anti-HBs), and liver function tests, including ALT and aspartate aminotransferase (AST). RESULTS The results showed that the prevalence of HBsAg decreased significantly from 14.3% in 1995 to 1.1% in 2009 and the seroprevalence of HBeAg decreased significantly from 5.9% in 1995 to 0.3% in 2009. Seroconversion to anti-HBs maintained a steady rate above 50% between 1995 and 2007, but declined considerably to 36.6% and 36.4% in 2008 and 2009, respectively. Subject with HBeAg seropositivity was in 43.94% of HBV carriers. Double seronegativity for HBsAg and anti-HBs was observed in 2007 (47.8%), 2008 (62.3%), and 2009 (62.5%). High ALT level was observed in 5.74% of the subjects, particular among HBV-carriers (16.5% of HBV carrier vs. 5.0% of non-HBV carrier; ORs, 3.733; 95% CIs, 3.463-4.023, p<0.0001). Subjects with high ALT level were significantly positively associated with HBeAg (10.5% of HBeAg seropositive vs. 1.9% of HBeAg seronegative; ORs, 6.195; 95%CI, 5.629-6.818; p<0.0001). Male subjects were more easily infected by HBV than female subjects were (HBsAg, ORs, 1.355, 95% CI, 1.283-1.431; HBeAg, ORs, 1.324, 95% CI, 1.218-1.439, p<0.0001), and significantly more male subjects had high ALT levels than female subjects did (ORs, 4.087; 95% CI, 3.819-4.375, p<0.0001). CONCLUSIONS The mass vaccination program successfully reduced the HBV carrier rate and prevalence of chronic hepatitis B in Taiwan. However, the low percentage of anti-HBV in 2008 and 2009 remains unresolved.
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Affiliation(s)
- Szu-Ming Chen
- Department of Medical Laboratory Science and Biotechnology, College of Biomedical Science and Technology, Yuanpei University, No. 306, Rd. Yuanpei, Hsinchu (300), Taiwan
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45
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Hwang S, Ahn CS, Song GW, Kim KH, Moon DB, Oh HB, Lim YS, Lee HC, Ha TY, Jung DH, Chung YH, Lee SG. Posttransplantation prophylaxis with primary high-dose hepatitis B immunoglobulin monotherapy and complementary preemptive antiviral add-on. Liver Transpl 2011; 17:456-65. [PMID: 21445929 DOI: 10.1002/lt.22226] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A considerable proportion of liver transplantation recipients who receive hepatitis B immunoglobulin (HBIG) monotherapy for hepatitis B virus (HBV) prophylaxis develop resistance to HBIG. We retrospectively assessed the efficacy of HBV prophylaxis in 1524 patients who received primary high-dose HBIG monotherapy (n = 1463) or with a preemptive antiviral add-on as secondary combination therapy (n = 61). At a median follow-up time of 57 months, 106 (7.3%) patients receiving HBIG monotherapy experienced HBV recurrence, with a 10-year HBV recurrence rate of 9.8%, compared to none of the patients receiving preemptive combination therapy (P = 0.047). Thirteen patients (12.3%) with HBV recurrence failed antiviral therapy, leading to death or retransplantation. Response rates to rescue therapy before and after use of adefovir/entecavir were 44.4% and 91.8%, respectively. Acute exacerbation was not associated with treatment failure, but required prolonged treatment. Of 84 surviving patients with HBV recurrence, 44 (52.4%) showed no evidence of blood HBV DNA. The Gly145Arg mutation was found in 11 of 15 (73.3%) patients, whereas 25 of 71 (35.2%), 2 of 29 (6.9%), and 4 of 8 (50%) patients were resistant to lamivudine, adefovir, and entecavir, respectively. In conclusion, our finding of a 10-year HBV recurrence rate of 9.8% in patients receiving high-dose HBIG monotherapy indicates that this treatment is effective but requires complementary measures. Strict surveillance following HBIG monotherapy is necessary to enhance responses to rescue antiviral therapy. Preemptive conversion to combination therapy has a complementary role in prophylaxis with primary high-dose HBIG monotherapy, especially for patients at high risk of HBV recurrence.
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Affiliation(s)
- Shin Hwang
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Yokosuka O, Kurosaki M, Imazeki F, Arase Y, Tanaka Y, Chayama K, Tanaka E, Kumada H, Izumi N, Mizokami M, Kudo M. Management of hepatitis B: Consensus of the Japan Society of Hepatology 2009. Hepatol Res 2011; 41:1-21. [PMID: 21070536 DOI: 10.1111/j.1872-034x.2010.00739.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Recently, much progress has been made in the field of hepatitis B, such as natural history of the disease in relation to the amount of hepatitis B virus (HBV) DNA, genotypes of HBV influencing the natural course and treatment effects, mutations of HBV influencing the severity of the disease and development of hepatocellular carcinoma, and antiviral treatment such as nucleos(t)ide analogues and pegylated interferon. To make the consensus for the diagnosis, management and treatment of hepatitis B, a meeting was held during 45th annual meeting of Japan Society of Hepatology (JSH) in June 2009. In the meeting, recommendations and informative statements were discussed on the following subjects: (i) natural history of HBV infection; (ii) clinical implication of HBV genotypes; (iii) HBV mutations and their potential impact on pathogenesis of HBV infection; (iv) indications for antiviral treatment of chronic hepatitis B; (v) nucleos(t)ide analogues for chronic hepatitis B; and (vi) interferon therapy for chronic hepatitis B. The presenters reviewed the data on these subjects and proposed the consensus statements and recommendations. These statements were discussed among the organizers and presenters, and were approved by the participants of the meeting. In the current report, the relevant data were reviewed and the 12 consensus statements and nine recommendations on chronic hepatitis B were described.
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Affiliation(s)
- Osamu Yokosuka
- Department of Medicine and Clinical Oncology, Postgraduate School of Medicine, Chiba University, Japan
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47
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Romano' L, Paladini S, Van Damme P, Zanetti AR. The worldwide impact of vaccination on the control and protection of viral hepatitis B. Dig Liver Dis 2011; 43 Suppl 1:S2-7. [PMID: 21195368 DOI: 10.1016/s1590-8658(10)60685-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Viral hepatitis B is a leading cause of acute and chronic liver disease worldwide, including cirrhosis and hepatocellular carcinoma. Vaccination is the most effective measure for controlling and preventing hepatitis B and its severe long-term sequelae. According to the World Health Organization (WHO), by the end of 2008 177 countries had introduced hepatitis B vaccination into their national routine neonatal, infant and/or adolescent immunisation programmes, and Italy was one of the first countries to implement a universal strategy of hepatitis B vaccination. The implementation of such vaccination programmes has globally resulted in a marked decrease in disease burden, in the carrier rate and in hepatitis B-related morbidity and mortality. Despite this success, work remains to be done to fully achieve the WHO goal of control of hepatitis B and HBV-related diseases on a global scale.
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Affiliation(s)
- Luisa Romano'
- Dipartimento di Sanità Pubblica - Microbiologia - Virologia, Università degli Studi di Milano, Milano, Italy
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48
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Hepatitis B vaccines: Protective efficacy and therapeutic potential. ACTA ACUST UNITED AC 2010; 58:288-95. [DOI: 10.1016/j.patbio.2010.01.006] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Accepted: 01/26/2010] [Indexed: 12/14/2022]
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49
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Sohn YH, Oh HB, Ko SY, Lim YS, Kwon OJ. Analysis of Clinical Characteristics and S Gene Mutation of Hepatitis B Virus (HBV) in Patients with Hepatitis B Surface Antigen RIA Negative and HBV DNA Positive. Ann Lab Med 2009; 29:224-30. [DOI: 10.3343/kjlm.2009.29.3.224] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Yong-Hak Sohn
- Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | - Heung-Bum Oh
- Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | - Sun-Young Ko
- Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
| | - Young-Suk Lim
- Department of Internal Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
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50
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Kamili S, Sozzi V, Thompson G, Campbell K, Walker CM, Locarnini S, Krawczynski K. Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model. Hepatology 2009; 49:1483-91. [PMID: 19274751 DOI: 10.1002/hep.22796] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
UNLABELLED Hepatitis B virus (HBV) mutants resistant to treatment with nucleoside or nucleotide analogs and those with the ability to escape from HBV-neutralizing antibody have the potential to infect HBV-vaccinated individuals. To address this potential serious public health challenge, we tested the efficacy of immunity induced by a commercial hepatitis B vaccine against a tissue culture-derived, clonal HBV polymerase mutant in HBV seronegative chimpanzees. The polymerase gene mutant contained a combination of three mutations (rtV173L, rtL180M, rtM204V), two of which resulted in changes to the overlapping viral envelope of the hepatitis B surface antigen (sE164D, sI195M). Prior to the HBV mutant challenge of vaccinated chimpanzees, we established virologic, serologic, and pathologic characteristics of infections resulting from intravenous inoculation of the HBV polymerase gene mutant and the sG145R vaccine-escape surface gene mutant. Cloning and sequencing experiments determined that the three mutations in the polymerase gene mutant remained stable and that the single mutation in the surface gene mutant reverted to the wild-type sequence. Immunological evidence of HBV replication was observed in the vaccinated chimpanzees after challenge with the polymerase gene mutant as well as after rechallenge with serum-derived wild-type HBV (5,000 chimpanzee infectious doses administered intravenously), despite robust humoral and cellular anti-HBV immune responses after hepatitis B vaccination. CONCLUSION Our data showing successful experimental infection by HBV mutants despite the presence of high anti-HBs levels considered protective in the vaccinated host are consistent with clinical reports on breakthrough infection in anti-HBs-positive patients infected with HBV mutants. In the absence of a protective humoral immunity, adaptive cellular immune responses elicited by infection may limit HBV replication and persistence.
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Affiliation(s)
- Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA
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