|
1
|
Chu YD, Hsu CW, Ho PH, Chiou CY, Lin CL, Liang KH, Lai MW, Yeh CT. Evolution of hepatitis B virus polymerase and surface genes in patients receiving finite antiviral therapy. J Gastroenterol Hepatol 2025; 40:265-273. [PMID: 39500510 DOI: 10.1111/jgh.16791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/15/2024] [Accepted: 10/20/2024] [Indexed: 01/02/2025]
Abstract
BACKGROUND AND AIM Hepatitis B virus (HBV) reactivation could develop after withdrawal following a finite course of nucleoside analog (NA) therapy, leading to virological and clinical relapses. The genetic heterogeneity in the HBV surface and polymerase genes during finite NA therapy has not been carefully studied. METHODS Seven chronic HBV-infected patients experiencing relapses following entecavir (ETV; n = 5; Patients 1 to 5) or tenofovir disoproxil fumarate (TDF; n = 2; Patients 6 and 7) withdrawal were included. Sera obtained before treatment and at relapses were retrieved and submitted for DNA extraction and amplicon-specific deep sequencing. RESULTS ETV-treated patients had a longer time-to-relapse than that of TDF-treated patients (P = 0.0357). No drug-resistance related polymerase mutation was detected during relapses, except for a low percentage (1.4%) of rtM204I mutation in Patient 1. Two surface truncation mutations (sW216*; 40.9% and sW182*; 4.7%) detected before treatment in two TDF-treated patients (Patients 6 and 7, respectively) were overtaken by the wild types during subsequent drug-withdrawal-related relapses. The simultaneous presence of sG44E (T-cell epitope) and sE164G (B-cell epitope) mutations was associated with failure of HBV e antigen (HBeAg) seroclearance in ETV-treated patients. CONCLUSIONS In conclusion, HBV genome continues to evolve during the courses of finite antiviral therapies. Pre-existing surface truncation mutations can be overtaken by the wild types after relapses. The sG44E/sE164G mutations are associated with failure of HBeAg seroclearance.
Collapse
Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Pei-Huan Ho
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chih-Yung Chiou
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chih-Lang Lin
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Liver Research Unit and Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Kung-Hao Liang
- Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Wei Lai
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Pediatrics, Division of Pediatric Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Department of Hepatology and Gastroenterology, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan
- Institute of Stem Cell and Translational Cancer Research, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| |
Collapse
|
|
2
|
Zhong S, Liu Z, Zhou Y, Zhang T, Fu X, Guo L, Gu S, Tang L, Hou J, Li Y. Longitudinal mapping of hepatitis B vaccine-induced B-cell linear epitopes in healthy individuals. J Med Virol 2022; 94:4993-5006. [PMID: 35676468 DOI: 10.1002/jmv.27926] [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: 03/31/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 11/08/2022]
Abstract
The elimination of hepatitis B virus (HBV) infection is partially facilitated by the prophylactic HB vaccine. As the loss of seroprotection over time remains a conundrum for long-lasting protection, a comprehensive dynamic analysis of immunogenic targets of the HB vaccine will provide novel insights into the improvement and design of potential targets. In this study, 36 healthy subjects without prior history of hepatitis B infection and negative for hepatitis B surface antibody (anti-HBs) were enrolled. Participants were given a series of three doses of HB vaccine on a 0-, 1-, and 6-month schedule and longitudinally followed up. We systematically mapped 55 overlapping 15-mer peptides covering the small S protein of hepatitis B virus (SHBs) of vaccinees' serum samples at seven time points by performing an ELISA assay. Additionally, the frequencies and function dynamics of adaptive immune response were assessed by flow cytometry. We found that the SHBs peptide coverage presented an overall upward trend along with the vaccination progress, and the individual subpartition recognition was strongly correlated with the anti-HBs titers. Moreover, we identified one dominant epitope (S29) located on "a determinant region" associated with effective vaccine response. Besides, significant correlations between the proportion of plasmablasts and proliferating B cells and levels of anti-HBs were ascertained. Taken together, our data characterized the dynamics of HB vaccine-induced neutralizing antibodies against B-cell linear epitopes on SHBs and adaptive immune response, which will be constructive to develop the next-generation vaccine.
Collapse
Affiliation(s)
- Shihong Zhong
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhipeng Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tianling Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xin Fu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ling Guo
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Peking University Shenzhen Hospital, Shenzhen, China
| | - Shuqin Gu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Libo Tang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yongyin Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
3
|
Olagbenro M, Anderson M, Gaseitsiwe S, Powell EA, Gededzha MP, Selabe SG, Blackard JT. In silico analysis of mutations associated with occult hepatitis B virus (HBV) infection in South Africa. Arch Virol 2021; 166:3075-3084. [PMID: 34468889 PMCID: PMC11930061 DOI: 10.1007/s00705-021-05196-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 06/09/2021] [Indexed: 01/02/2023]
Abstract
Occult hepatitis B virus (OBI) infection is defined by the presence of viral DNA in the liver and/or serum in absence of hepatitis B surface antigen (HBsAg). While multiple studies have identified mutations that are associated with OBI, only a small portion of these mutations have been functionally characterized in vitro. Using complementary in silico approaches, the effects of OBI-associated amino acid mutations on HBV protein function in HBV/HIV-positive ART-naïve South Africans were evaluated. Two OBI-associated mutations in the PreS1 region, one in the PreS2 region, and seven in the surface region of subgenotype A1 sequences were identified as deleterious. In subgenotype A2 sequences, 11 OBI-associated mutations in the PreS1 region, seven in the PreS2 region, and 31 in the surface region were identified as deleterious. In the polymerase region, 14 OBI-associated mutations in subgenotype A1 and 71 OBI-associated mutations in subgenotype A2 were identified as deleterious. This study utilized in silico approaches to characterize the likely impact of OBI-associated mutations on viral function, thereby identifying and prioritizing candidates and reducing the significant cost associated with functional studies that are essential for mechanistic studies of the OBI phenotype.
Collapse
Affiliation(s)
- Matthew Olagbenro
- Division of Digestive Diseases, University of Cincinnati College of Medicine, ML 0595, Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
| | | | | | - Eleanor A Powell
- Division of Digestive Diseases, University of Cincinnati College of Medicine, ML 0595, Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Maemu P Gededzha
- Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Selokela G Selabe
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Jason T Blackard
- Division of Digestive Diseases, University of Cincinnati College of Medicine, ML 0595, Albert Sabin Way, Cincinnati, OH, 45267-0595, USA.
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa.
| |
Collapse
|
|
4
|
Lai MW, Liang KH, Yeh CT. Diverse immune responses to HBV surface epitope variants after vaccine booster in adolescents immunized in infancy. Clin Microbiol Infect 2019; 25:1140-1146. [PMID: 30771531 DOI: 10.1016/j.cmi.2019.02.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 02/01/2019] [Accepted: 02/02/2019] [Indexed: 11/28/2022]
Abstract
OBJECTIVES We aimed to investigate immunity against hepatitis B surface antigen (HBsAg) mutants before and after boosters in adolescents who had lost antibodies against HBsAg (anti-HBs) despite neonatal vaccination. METHODS We recruited 142 participants from 15 to 21 years old who had received complete vaccination in infancy but became anti-HBs-negative. Cellular immunity to HBsAg and T-cell epitope variants was assessed before and after boosters. Antibody affinity to variants was assessed after boosters. RESULTS After one dose of booster, 12 out of 140 (8.6%) participants remained anti-HBs-negative. Anti-HBs titres were higher in those participants <17 (geometric mean, 337.9 ± 10.9 vs. 157.4 ± 16.6 mIU/mL, p = 0.012). Before the booster, HBsAg-specific cell proliferation was present in 58 out of 64 (90.6%) participants. The proliferation response rates to T-cell epitopes were 37.8% and 72.6% (p < 0.001) before and after the booster, respectively. The stimulation index improved from 1.25 ± 1.70 to 2.53 ± 2.32 (p < 0.001) for various T-cell epitopes. HBsAg-specific interleukin (IL)-5- and interferon (IFN)-γ-secreting T-cells were enhanced (45 ± 10 and 50 ± 4 to 420 ± 328 and 355 ± 424 spot-forming cells/106 cells, respectively, p < 0.001). IFN-γ-secreting T cells to epitope 16-33 containing R24K and the antibody affinity to sG145R were still significantly lower than to the wild type. CONCLUSIONS In immunized adolescents who lost anti-HBs, around 10% also lost immune memory. Cellular immunity to some T-cell epitope variants improved after the booster. Antibody affinity to sG145R and the IFN-γ-secreting cell response to some epitope 16-33 variants were still impaired even after booster administration.
Collapse
Affiliation(s)
- M-W Lai
- Division of Paediatric Gastroenterology, Department of Paediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taiwan; Liver Research Centre, Chang Gung Memorial Hospital, Linkou Branch, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - K-H Liang
- Liver Research Centre, Chang Gung Memorial Hospital, Linkou Branch, Taiwan; Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - C-T Yeh
- Department of Hepato-gastroenterology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan; Liver Research Centre, Chang Gung Memorial Hospital, Linkou Branch, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
| |
Collapse
|
|
5
|
Inuzuka T, Ueda Y, Arasawa S, Takeda H, Matsumoto T, Osaki Y, Uemoto S, Seno H, Marusawa H. Expansion of viral variants associated with immune escape and impaired virion secretion in patients with HBV reactivation after resolved infection. Sci Rep 2018; 8:18070. [PMID: 30584239 PMCID: PMC6305382 DOI: 10.1038/s41598-018-36093-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 11/05/2018] [Indexed: 02/07/2023] Open
Abstract
HBV reactivation could be induced under immunosuppressive conditions in patients with resolved infection. This study aimed to clarify the viral factors associated with the pathogenesis of HBV reactivation in association with the immunosuppressive status. Whole HBV genome sequences were determined from the sera of 24 patients with HBV reactivation, including 8 cases under strong immunosuppression mediated by hematopoietic stem cell transplantation (HSCT) and 16 cases without HSCT. Ultra-deep sequencing revealed that the prevalence of genotype B and the ratio of non-synonymous to synonymous evolutionary changes in the surface (S) gene were significantly higher in non-HSCT cases than in patients with HSCT. Those non-synonymous variants included immune escape (6/16 cases) and MHC class II-restricted T-cell epitope variants (6/16 cases). Furthermore, reactivated HBV in 11 of 16 (69%) non-HSCT cases possessed substitutions associated with impaired virion secretion, including E2G, L77R, L98V, T118K, and Q129H in the S region, and M1I/V in the PreS2 region. In conclusion, virologic features of reactivated HBV clones differed depending on the intensity of the immunosuppressive condition. HBV reactivation triggered by immunosuppressive conditions, especially those without HSCT, was characterized by the expansion of variants associated with immune escape, MHC class II-restricted T-cell epitope alterations, and/or impaired virion secretion.
Collapse
Affiliation(s)
- Tadashi Inuzuka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Research Center for Hepatitis and Immunology National Center for Global Health and Medicine, Chiba, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Soichi Arasawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Tomonori Matsumoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. .,Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.
| |
Collapse
|
|
6
|
Pu Z, Li D, Wang A, Su H, Shao Z, Zhang J, Ji Z, Gao J, Choi BCK, Yan Y. Epidemiological characteristics of the carriers with coexistence of HBsAg and anti-HBs based on a community cohort study. J Viral Hepat 2016; 23:286-93. [PMID: 26663578 DOI: 10.1111/jvh.12492] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 10/07/2015] [Indexed: 02/05/2023]
Abstract
The coexistence of HBsAg and anti-HBs is an atypical serological pattern in HBV infection. There is no epidemiological characteristics of this serological pattern in the community and there is controversy over the molecular mechanisms underlying this pattern. We investigated the epidemiological characteristics of the carriers with HBsAg and anti-HBs in a longitudinal community cohort study. The prevalence of this atypical serological pattern was 2.93% (122/4169) in HBsAg-positive populations. The prevalence progressively increased with age from 40 to 70 years old. The rate of HBeAg positive and detectable HBV DNA were both significantly higher in carriers with this pattern than in carriers who were HBsAg positive but anti-HBs negative (26/122 verse 598/4047, P = 0.046; 86/122 verse 275/529,P < 0.001). After 1 year of follow-up, 85.19% of the carriers still had coexistence HBsAg and anti-HBs, 14.81% of the carriers lost their anti-HBs. Viral sequencing showed that carriers with coexistence of HBsAg and anti-HBs had higher numbers of residue changes within the S gene than carriers who were HBsAg positive but anti-HBs negative (2.42 verse 1.33 changes per 100 residues, P < 0.05). Hence, the coexistence of HBsAg and anti-HBs is a unique serological pattern which may be associated with an increased risk of adverse clinical outcome and may be related to HBsAg immune variants which have genotypic heterogeneity.
Collapse
Affiliation(s)
- Z Pu
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - D Li
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - A Wang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - H Su
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Z Shao
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - J Zhang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Z Ji
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - J Gao
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - B C K Choi
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Shantou University Medical College, Shantou, China
| | - Y Yan
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, China
| |
Collapse
|
|
7
|
Rybczynska J, Campbell K, Kamili S, Locarnini S, Krawczynski K, Walker CM. CD4+ T Cells Are Not Required for Suppression of Hepatitis B Virus Replication in the Liver of Vaccinated Chimpanzees. J Infect Dis 2015; 213:49-56. [PMID: 26324781 DOI: 10.1093/infdis/jiv348] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 06/12/2015] [Indexed: 01/12/2023] Open
Abstract
Humans vaccinated with hepatitis B virus (HBV) surface antigen (HBsAg) sometimes develop humoral and cellular immunity to HBV proteins such as core and polymerase that are not vaccine components, providing indirect evidence that vaccine-induced immunity is not sterilizing. We previously described CD4(+) T-cell immunity against HBsAg and polymerase in chimpanzees after vaccination and HBV challenge. Here, vaccinated chimpanzees with protective levels of anti-HBsAg antibodies were rechallenged with HBV after antibody-mediated CD4(+) T-cell depletion. HBV DNA was detected in liver for at least 3 months after rechallenge, but virus replication was suppressed, as revealed by the absence of HBV DNA and HBsAg in serum. These observations provide direct virological evidence for nonsterilizing immunity in individuals with anti-HBsAg antibodies and are consistent with translation of HBV proteins to prime immune responses. They also indicate that CD4(+) T cells were not required for suppression of HBV replication in previously vaccinated individuals.
Collapse
Affiliation(s)
- Jolanta Rybczynska
- Department of Pathology, Medical University of Warsaw, Poland Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | | | - Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Stephen Locarnini
- Victorian Infectious Disease Reference Laboratory, North Melbourne, Australia
| | - Krzysztof Krawczynski
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Christopher M Walker
- Center for Vaccines and Immunity, Nationwide Children's Hospital Department of Pediatrics, College of Medicine, The Ohio State University, Columbus
| |
Collapse
|
|
8
|
Fernández-Galindo DA, Sánchez-Ávila F, Bobadilla-Morales L, Gómez-Quiróz P, Bueno-Topete M, Armendáriz-Borunda J, Sánchez-Orozco LV. New amino acid changes in drug resistance sites and HBsAg in hepatitis B virus genotype H. J Med Virol 2015; 87:985-92. [PMID: 25732900 DOI: 10.1002/jmv.24098] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2014] [Indexed: 12/16/2022]
Abstract
Long-term treatment with retrotranscriptase (RT) inhibitors eventually leads to the development of drug resistance. Drug-related mutations occur naturally and these can be found in hepatitis B virus (HBV) carriers who have never received antiviral therapy. HBsAg are overlapped with RT domain, thus nucleot(s)ide analogues (NAs) resistance mutations and naturally-occurring mutations can cause amino acid changes in the HBsAg. Twenty-two patients with chronic hepatitis B were enrolled; three of them were previously treated with NAs and 19 were NAs-naïve treated. HBV reverse transcriptase region was sequenced; genotyping and analysis of missense mutations were performed in both RT domain and HBsAg. There was predominance of genotype H. Drug mutations were present in 18.2% of patients. Classical lamivudine resistance mutations (rtM204V/rtL180M) were present in one naïve-treatment patient infected with genotype G. New amino acid changes were identified in drug resistance sites in HBV strains from patients infected with genotype H; rtQ215E was present in two naïve-NAs treatment patients and rtI169M was identified in a patient previously treated with lamivudine. Mutations at sites rt169, rt204, and rt215 resulted in the Y161C, I195M, and C206W mutations at HBsAg. Also, new amino acid changes were identified in B-cell and T-cell epitopes and were more frequent in HBsAg compared to RT domain. In conclusion, new amino acid changes at antiviral resistance sites, B-cell and T-cell epitopes in HBV genotype H were identified in Mexican patients.
Collapse
Affiliation(s)
- D A Fernández-Galindo
- Institute of Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | | | | | | | | | | | | |
Collapse
|
|
9
|
Mirabelli C, Surdo M, Van Hemert F, Lian Z, Salpini R, Cento V, Cortese MF, Aragri M, Pollicita M, Alteri C, Bertoli A, Berkhout B, Micheli V, Gubertini G, Santoro MM, Romano S, Visca M, Bernassola M, Longo R, De Sanctis GM, Trimoulet P, Fleury H, Marino N, Mazzotta F, Cappiello G, Spanò A, Sarrecchia C, Zhang JM, Andreoni M, Angelico M, Verheyen J, Perno CF, Svicher V. Specific mutations in the C-terminus domain of HBV surface antigen significantly correlate with low level of serum HBV-DNA in patients with chronic HBV infection. J Infect 2014; 70:288-98. [PMID: 25452041 DOI: 10.1016/j.jinf.2014.10.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 09/05/2014] [Accepted: 10/17/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND To define HBsAg-mutations correlated with different serum HBV-DNA levels in HBV chronically-infected drug-naive patients. METHODS This study included 187 patients stratified into the following ranges of serum HBV-DNA:12-2000 IU/ml, 2000-100,000 IU/ml, and >100,000 IU/ml. HBsAg-mutations were associated with HBV-DNA levels by applying a Bayesian-Partitional-Model and Fisher-exact test. Mutant and wild-type HBV genotype-D genomes were expressed in Huh7 cells and HBsAg-production was determined in cell-supernatants at 3 days-post-transfection. RESULTS Specific HBsAg-mutations (M197T,-S204N-Y206C/H-F220L) were significantly correlated with serum HBV-DNA <2000 IU/ml (posterior-probability>90%, P < 0.05). The presence of Y206C/H and/or F220L was also associated with lower median (IQR) HBsAg-levels and lower median (IQR) transaminases (for HBsAg:250[115-840] IU/ml for Y206C/H and/or F220L versus 4300[640-11,838] IU/ml for wild-type, P = 0.023; for ALT:28[21-40] IU/ml versus 53[34-90] IU/ml, P < 0.001). These mutations were localized in the HBsAg C-terminus, known to be involved in virion and/or HBsAg secretion. The co-occurrence of Y206C + F220L was found significant by cluster-analysis, (P = 0.02). In addition, in an in-vitro model Y206C + F220L determined a 2.8-3.3 fold-reduction of HBsAg-amount released in supernatants compared to single mutants and wt (Y206C + F220L = 5,679 IU/ml; Y206H = 16,305 IU/ml; F220L = 18,368 IU/ml; Y206C = 18,680 IU/ml; wt = 14,280 IU/ml, P < 0.05). CONCLUSIONS Specific HBsAg-mutations (compartmentalized in the HBsAg C-terminus) correlated with low-serum HBV-DNA and HBsAg-levels. These findings can be important to understand mechanisms underlying low HBV replicative potential including the inactive-carrier state.
Collapse
Affiliation(s)
- Carmen Mirabelli
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Matteo Surdo
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Formijn Van Hemert
- Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, 1000 Amsterdam, The Netherlands
| | - Zhichao Lian
- Yale University, New Haven, CT 06520 United States
| | - Romina Salpini
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Valeria Cento
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Maria Francesca Cortese
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Marianna Aragri
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Michela Pollicita
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Claudia Alteri
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Ada Bertoli
- University Hospital of Rome "Tor Vergata", 00100 Rome, Italy
| | - Ben Berkhout
- Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, 1000 Amsterdam, The Netherlands
| | | | | | - Maria Mercedes Santoro
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy
| | - Sara Romano
- Microbiology and Virology Unit, "S. Pertini" Hospital, 00100 Rome, Italy
| | - Michela Visca
- Microbiology and Virology Unit, "S. Pertini" Hospital, 00100 Rome, Italy
| | - Martina Bernassola
- Microbiology and Virology Unit, "S. Pertini" Hospital, 00100 Rome, Italy
| | - Roberta Longo
- Microbiology and Virology Unit, "S. Pertini" Hospital, 00100 Rome, Italy
| | | | - Pascal Trimoulet
- Virology Laboratory, Centre Hospitalier Régional et Université "Victor Segalen", CHU de Bordeaux, 33300 Bordeaux, France
| | - Hervè Fleury
- Virology Laboratory, Centre Hospitalier Régional et Université "Victor Segalen", CHU de Bordeaux, 33300 Bordeaux, France
| | | | | | | | - Alberto Spanò
- Microbiology and Virology Unit, "S. Pertini" Hospital, 00100 Rome, Italy
| | | | | | | | - Mario Angelico
- University Hospital of Rome "Tor Vergata", 00100 Rome, Italy
| | - Jens Verheyen
- Institute of Virology, University Hospital, 45147 Duisburg-Essen, Germany
| | - Carlo Federico Perno
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy; University Hospital of Rome "Tor Vergata", 00100 Rome, Italy
| | - Valentina Svicher
- Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00100 Rome, Italy.
| |
Collapse
|
|
10
|
Yu DM, Li XH, Mom V, Lu ZH, Liao XW, Han Y, Pichoud C, Gong QM, Zhang DH, Zhang Y, Deny P, Zoulim F, Zhang XX. N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape. J Hepatol 2014; 60:515-522. [PMID: 24239777 DOI: 10.1016/j.jhep.2013.11.004] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 10/08/2013] [Accepted: 11/05/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS HBV immune escape represents a challenge to prevention, diagnosis, and treatment of hepatitis B. Here, we analyzed the molecular and clinical characteristics of HBV immune escape mutants in a Chinese cohort of chronically infected patients. METHODS Two hundred sixteen patients with HBsAg and anti-HBs were studied, with one hundred eighty-two HBV carriers without anti-HBs as a control group. Recombinant HBsAg bearing the most frequent N-glycosylation mutations were expressed in CHO and HuH7 cells. After confirming N-glycosylation at the most frequent sites (129 and 131), together with inserted mutations, functional analysis were performed to study antigenicity and secretion capacity. RESULTS One hundred twenty-three patients had the wild-type HBs gene sequence, 93 patients (43%) had mutants in the major hydrophilic region (MHR), and 47 of the 93 patients had additional N-glycosylation mutations, which were transmitted horizontally to at least 2 patients, one of whom was efficiently vaccinated. The frequency of N-glycosylation mutation in the case group was much higher than that of the control group (47/216 vs. 1/182). Compared with wild-type HBsAg, HBsAg mutants reacted weakly with anti-HBs using a chemiluminescent microparticle enzyme immunoassay. Native gel analysis of secreted virion in supernatants of transfected HuH7 cells indicated that mutants had better virion enveloping and secretion capacity than wild-type HBV. CONCLUSIONS Our results suggest that specific HBsAg MHR N-glycosylation mutations are implicated in HBV immune escape in a high endemic area.
Collapse
Affiliation(s)
- De-Min Yu
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xin-Hua Li
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China; The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Vannary Mom
- INSERM, U1052, 151 cours Albert Thomas, 69424 Lyon cedex 03, France
| | - Zhong-Hua Lu
- Wu Xi Hospital of Infectious Diseases, People's Republic of China
| | - Xiang-Wei Liao
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yue Han
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | | | - Qi-Ming Gong
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Dong-Hua Zhang
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yan Zhang
- Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine (SCSB), Shanghai Jiao Tong University, People's Republic of China
| | - Paul Deny
- INSERM, U1052, 151 cours Albert Thomas, 69424 Lyon cedex 03, France; University Paris 13, Groupe des Hôpitaux Universitaires Paris Seine Saint Denis, Paris, France
| | - Fabien Zoulim
- INSERM, U1052, 151 cours Albert Thomas, 69424 Lyon cedex 03, France; Lyon University and Hospices Civils de Lyon, Lyon, France.
| | - Xin-Xin Zhang
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| |
Collapse
|
|
11
|
Naturally occurring hepatitis B virus B-cell and T-cell epitope mutants in hepatitis B vaccinated children. ScientificWorldJournal 2013; 2013:571875. [PMID: 24379746 PMCID: PMC3860134 DOI: 10.1155/2013/571875] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 09/24/2013] [Indexed: 12/17/2022] Open
Abstract
To control hepatitis B virus (HBV) infection, a universal HBV vaccination program for infants was launched in Taiwan in 1984. The aim of this study was to investigate the role of B-cell and T-cell epitope variations of HBsAg and polymerase in HBV infection in vaccinated children. One hundred sixty-three sera from vaccinated children were enrolled randomly. HBV serum markers, including hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and core antigen (anti-HBc), were detected by ELISA. Nucleotide sequences encoding the S and the pre-S regions of HBsAg were analyzed in all HBsAg positive sera. Five children were HBsAg positive. Sequence analysis of S, pre-S, and overlapped polymerase (P) genes showed that HBV isolates of HBsAg-positive vaccinees were variants; no G145R but G145A and other substitutions were found in the “a” determinant. Fifteen, six, and eight amino acid substitutions within B-cell and T-cell epitopes of S, pre-S, and P regions were detected, respectively. Several immune-epitope mutants, such as S45T/A, N131T, I194V, and S207N in S, were detected in all isolates. In conclusion, our results suggested that these naturally occurring immunoepitope mutants, which changed their immunogenicity leading to escape from immune response, might cause HBV infection.
Collapse
|
|
12
|
Eng NF, Bhardwaj N, Mulligan R, Diaz-Mitoma F. The potential of 1018 ISS adjuvant in hepatitis B vaccines: HEPLISAV™ review. Hum Vaccin Immunother 2013; 9:1661-72. [PMID: 23732907 PMCID: PMC3906263 DOI: 10.4161/hv.24715] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 04/08/2013] [Accepted: 04/16/2013] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B (HBV) virus infects the liver, and upon chronic infection, can cause liver cirrhosis and hepatocellular carcinoma. Despite universal vaccination programs against the virus, HBV still affects over 2 billion people worldwide, with over 240 million developing a chronic infection. While current alum-adjuvanted vaccines have shown efficacy in promoting seroprotection in healthy adults, 5-10% of immune-competent populations fail to achieve long-lasting seroprotection from these formulations. Furthermore, a large proportion of immunocompromised patients fail to achieve seroprotective antibody titers after receiving these vaccines. A novel vaccine candidate, HEPLISAV™, uses immunostimulatory sequences (ISS), in its formulation that helps induce a robust humoral and cell mediated immunity against HBV. In Phase III clinical trials, HEPLISAV™ has been shown to elicit seroprotective antibody titers with fewer immunizations. Similar safety profiles are demonstrated when compared with current HBV vaccines. For these reasons, HEPLISAV™ is an attractive vaccine to combat this global disease.
Collapse
Affiliation(s)
- Nelson F Eng
- Advanced Medical Research Institute of Canada; Sudbury, ON Canada
| | - Nitin Bhardwaj
- Advanced Medical Research Institute of Canada; Sudbury, ON Canada
| | - Rebecca Mulligan
- Advanced Medical Research Institute of Canada; Sudbury, ON Canada
| | | |
Collapse
|
|
13
|
Khedive A, Norouzi M, Ramezani F, Karimzadeh H, Alavian SM, Malekzadeh R, Montazeri G, Nejatizadeh A, Ziaee M, Abedi F, Ataei B, Yaran M, Sayad B, Somi MH, Sarizadeh G, Sanei-Moghaddam I, Mansour-Ghanaei F, Rafatpanah H, Pourhosseingholi MA, Keyvani H, Kalantari E, Saberifiroozi M, Judaki MA, Ghamari S, Daram M, Mahabadi M, Fazeli Z, Goodarzi Z, Poortahmasebi V, Jazayeri SM. Hepatitis B virus surface protein mutations clustered mainly in CTL immune epitopes in chronic carriers: results of an Iranian nationwide study. J Viral Hepat 2013; 20:494-501. [PMID: 23730843 DOI: 10.1111/jvh.12045] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 11/27/2012] [Indexed: 12/14/2022]
Abstract
Mutations within the coding region of hepatitis B surface antigen (HBsAg) have been found naturally in chronic carriers. To characterize the mutations of HBsAg from Iranian chronic carriers who were vaccine and/or medication naive. The surface genes from 360 patients were amplified and directly sequenced. The distribution of amino acid substitutions was classified according to different immune epitopes of the surface protein. All isolates belonged to genotype D. 222 (61.6%) of 360 patients contained at least one amino acid substitution. 404 (74.5%) of 542 amino acid changes occurred in different immune epitopes of HBsAg, of which 112 (27.7%) in 32 residues of B-cell epitopes (62 in the 'a' determinant); 111 (27.4%) in 32 residues of T helper; and 197 (48.7%) in 32 residues inside cytotoxic T lymphocyte (CTL) epitopes. One Th (186-197) and two CTL (28-51 and 206-215) epitopes were found to be hotspot motifs for the occurrence of 213 (52.7%) substitutions. 20 stop codons were identified in different epitopes. There was a significant association between amino acid substitutions and anti-HBe seropositivity; however, the correlation between such changes with viral load and ALT levels was not significant. In chronic hepatitis B virus(HBV) carriers, positive selection in particular outside the 'a' determinant appeared to exert influence on the surface proteins. These changes could be immune escape mutations naturally occurring due to the host immune surveillance especially at the T-cell level.
Collapse
Affiliation(s)
- A Khedive
- Hepatitis B Molecular Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Jeulin H, Velay A, Murray J, Schvoerer E. Clinical impact of hepatitis B and C virus envelope glycoproteins. World J Gastroenterol 2013; 19:654-664. [PMID: 23429668 PMCID: PMC3574591 DOI: 10.3748/wjg.v19.i5.654] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 12/17/2012] [Indexed: 02/06/2023] Open
Abstract
Chronic infection by either hepatitis B virus (HBV) or hepatitis C virus (HCV) share epidemiological characteristics with risks for development of severe complications such as liver cirrhosis and hepatocellular carcinoma. HBV and HCV also share a high genetic variability. Among highly variable regions, viral genes encoding surface proteins (hepatitis B surface antigen, E1/E2 HCV glycoproteins) play key roles in the stimulation of the host-related immune response and viral entry into hepatocytes. Specific segments of HBV envelope proteins (preS1, “a” determinant) are crucial in the entry process into permissive cells. HCV entry is a complex multistep process involving multiple cell cofactors (glycosaminoglycans, low density lipoprotein receptor, SR-B1, CD81, claudin-1, occludin, EGFR, EphA2) in the interaction with HCV E1/E2 envelope glycoproteins. In vitro both viruses can be controlled by antibody-mediated neutralization targeting viral envelope, also essential in preventing HBV infection in vivo as observed through successful vaccination using HBs antigen. But preventive vaccination and/or therapeutic pressure can influence HBV and HCV variability. For HBV, the patterns of antiviral drug resistance in chronic hepatitis are complex and the original pol/S gene overlap has to be taken into account. Treatment-induced HBV mutations in pol could indeed generate S mutants with subsequent modified antigenicity or increased cancer induction. Variability of HBV and HCV envelope proteins combining high exposure to selective pressures and crucial functional roles require investigation in the context of diagnostic, vaccination and treatment tools. In this editorial a synthesis is performed of HBV and HCV envelope properties at the entry step and as antigenic proteins, and the subsequent clinical impact.
Collapse
MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Drug Resistance, Viral
- Genotype
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepacivirus/metabolism
- Hepacivirus/pathogenicity
- Hepatitis B Vaccines
- Hepatitis B virus/drug effects
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B virus/metabolism
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/prevention & control
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/prevention & control
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions
- Humans
- Phenotype
- Prognosis
- Viral Envelope Proteins/genetics
- Viral Envelope Proteins/metabolism
Collapse
|
|
15
|
Abstract
During hepatitis B virus (HBV) infection, at least four antigen-antibody systems are observed: HBsAg and anti-HBs; preS antigen and anti-preS antibody; HBcAg and anti-HBc; and HBeAg and anti-HBe. Through the examination of these antigen-antibody systems, hepatitis B infection is diagnosed and the course of the disorder may be observed. Although the serologic findings that allow both the diagnosis of HBV infection as well as assessing of its clinical course are already well established, the dynamics of viral proteins expression and of the antibodies production may vary during the infection natural course. This causes the HBV infection to be occasionally associated with the presence of uncommon serological profiles, which could lead to doubts in the interpretation of results or suspicion of a serological result being incorrect. This paper is dedicated to the discussion of some of these profiles and their significance.
Collapse
|
|
16
|
Sueki R, Maekawa S, Miura M, Kadokura M, Komase K, Shindo H, Kanayama A, Ohmori T, Shindo K, Amemiya F, Nakayama Y, Uetake T, Inoue T, Sakamoto M, Enomoto N. Correlation between pretreatment viral sequences and the emergence of lamivudine resistance in hepatitis B virus infection. J Med Virol 2012; 84:1360-8. [PMID: 22825814 DOI: 10.1002/jmv.23314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The emergence of amino acid or nucleotide substitutions leads to lamivudine resistance in hepatitis B virus (HBV) infected patients. The aim of this study was to investigate whether viral sequences help predict the emergence of lamivudine resistance. The study subjects comprised 59 consecutive patients infected with HBV treated with daily therapy of 100 mg lamivudine. Among those, 32 patients with adequate pretreatment serum preservation were investigated for the correlation between viral amino acid substitutions and the appearance of lamivudine resistance with consideration of clinical background by determining dominant HBV full open reading frames. Viral resistance to lamivudine emerged in 28 of 59 patients (47%) in a median period of 2.45 years. Sequence comparisons of HBV genomes between patients who later developed lamivudine resistance and patients who did not revealed the existence of significant differences between the two groups in the pre-S1 84 (P = 0.042), pre-S2 1 (P = 0.017) and 22 (P = 0.015), and polymerase tp 95 (P = 0.046), judged by a log-rank test. Viral sequence analyses revealed the presence of amino acid substitutions in HBV pre-S1 and pre-S2 that may be associated with the emergence of lamivudine resistance during chronic HBV infection.
Collapse
Affiliation(s)
- Ryota Sueki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
|
|
18
|
Lai MW, Lin TY, Tsao KC, Huang CG, Hsiao MJ, Liang KH, Yeh CT. Increased seroprevalence of HBV DNA with mutations in the s gene among individuals greater than 18 years old after complete vaccination. Gastroenterology 2012; 143:400-7. [PMID: 22580098 DOI: 10.1053/j.gastro.2012.05.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 04/04/2012] [Accepted: 05/04/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Despite the success of a universal vaccination program against hepatitis B virus (HBV) in Taiwan, a small but substantial proportion of individuals remain infected by mutant viruses that escape the vaccine. We investigated the seroepidemiology and genotypic characteristic of HBV for long periods after neonatal vaccination. METHODS We measured hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B surface antigen (anti-HBs) in 1214 serum samples collected throughout Taiwan from individuals 0.6-87.8 years old in 2007. HBV DNA was detected using polymerase chain reaction and sequence analysis in vaccine recipients who tested positive for anti-HBc and/or HBsAg. RESULTS The overall seroprevalence of HBsAg and anti-HBc was significantly lower among individuals born after the initiation of the nationwide vaccination program (P < .001). However, we observed increasing seroprevalence of anti-HBc and isolated anti-HBs when subjects were grouped by age: at 10-14, 14-18, to 18-21 years of age, values were 0.4%, 1.9%, and 8.1% (P = .0135) and 43.7%, 55.4%, and 59.6% (P = .0093), respectively (χ(2) test for trend). A large increase was observed in the percentage of patients who tested positive for HBV DNA at 18-21 years of age (3.0% vs 0.2% [P = .002] for all eligible subjects and 5.7% vs 0.3% [P < .001] for subjects vaccinated with ≥3 doses). Five of 8 completely vaccinated individuals who were seropositive for HBV DNA carried variants with mutations in the S gene. CONCLUSIONS Universal vaccination effectively controls HBV infection in children and adolescents. However, after adolescence, there is a significant increase in the seroprevalence of anti-HBs, anti-HBc, and HBV DNA, indicating that new preventative strategies are needed for adults.
Collapse
Affiliation(s)
- Ming-Wei Lai
- Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Alavian SM, Carman WF, Jazayeri SM. HBsAg variants: diagnostic-escape and diagnostic dilemma. J Clin Virol 2012; 57:201-8. [PMID: 22789139 DOI: 10.1016/j.jcv.2012.04.027] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Revised: 01/23/2012] [Accepted: 04/18/2012] [Indexed: 12/11/2022]
Abstract
A wide variety of commercial assays is available for the detection of hepatitis B surface antigen (HBsAg). Clearly, the sensitivity of an assay to detect a variant is dependent on the anti-HBs usage. Thus, it is not surprising that there are examples of variants that cannot be detected by all assays. Data from Europe, Asia and Africa about HBsAg variants which are not recognized by either monoclonal or polyclonal antibodies specific for wild-type group 'a' determinant, but positive by DNA polymerase chain reaction (PCR) in chronic patients and from vaccinated children are increasing. This would impose a challenge for public health issues of hepatitis B virus. In this review we tried to summarize the discrepancies between results of HBsAg assays and to explain some rationales for these inconsistencies.
Collapse
Affiliation(s)
- Seyed Moayed Alavian
- Baqiyatallah University of Medical Sciences, Baqiyatallah Research Centre for Gastroenterology and Liver Disease, Tehran, Iran
| | | | | |
Collapse
|
|
20
|
Effectiveness of a bivalent Haemophilus influenzae type B-hepatitis B vaccine in preventing hepatitis B virus infection among children born to hepatitis B e antigen-positive carrier mothers. Pediatr Infect Dis J 2009; 28:777-81. [PMID: 19636283 DOI: 10.1097/inf.0b013e3181a06fad] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND This observational study evaluated a modified immunoprophylactic regimen (hepatitis B immune globulin [HBIG]) and a dose of thimerosal-free monovalent hepatitis B (HB) vaccine shortly after birth followed by doses of thimerosal-free bivalent Haemophilus influenzae type b (Hib)-HB vaccine at 2 and 4 months of age, and a booster at 12 months of age) in infants at high risk of hepatitis B virus (HBV) infection (mothers HBeAg+). METHODS Children >or=6 months of age vaccinated in routine clinical practice were tested twice (>or=6 months apart) for HBV antigens surface antigen (HBsAg) and "e" antigen, and for antibody to HBsAg. Partial nucleotide sequence analysis was performed on HBV DNA isolated from infants identified with a breakthrough chronic HBV infection. A fully sequential statistical design was used to maximize patient safety and study efficiency. RESULTS Four of 60 children developed chronic HBV infection despite vaccination, but at no point did the cumulative number of cases reach the boundary of statistical significance. Overall, the analysis adjusted for sequential testing yielded an estimated breakthrough rate of 6.7% (90% CI: 2.3%-14.6%). In a subset of uninfected children tested for antibody to HBsAg 1 to 4 months after the second dose of Hib-HB vaccine, 90% (9/10) had >or=10 milli-International Units per milliliter (mIU/mL). The third dose of Hib-HB vaccine induced a secondary increase in the level of antibody; 94.7% (18/19) of a second group developed >or=100 mIU/mL, with a geometric mean concentration of 771 mIU/mL (95% CI: 351.4-1692.1 mIU/mL). CONCLUSION The tested regimen is comparably effective to historical experience with a standard one employing HBIG plus monovalent thimerosal-containing HB vaccine given at 0, 1, and 6 months of age.
Collapse
|
|
21
|
Malmassari SL, Deng Q, Fontaine H, Houitte D, Rimlinger F, Thiers V, Maillere B, Pol S, Michel ML. Impact of hepatitis B virus basic core promoter mutations on T cell response to an immunodominant HBx-derived epitope. Hepatology 2007; 45:1199-209. [PMID: 17465004 DOI: 10.1002/hep.21594] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
UNLABELLED The hepatitis B X (HBx) protein is a crucial component in HBV infection in vivo and has been implicated in HCC. In this study, we aimed to detect and characterize peripheral HBx-specific T cells in chronically infected patients at the inactive carrier state of the disease. HBx-specific IFN-gamma-secreting T cells were found in 36 of 52 patients (69%), and 78% (28/36) of responding patients had T cells targeting epitopes in the carboxy-terminal part of HBx. IL-10 secretion after the stimulation of T cells with HBx-derived peptides was weak or undetectable. IFN-gamma-secreting T cells recognized a previously unknown immunodominant CD4+ T cell epitope, HBx 126-140 (EIRLKVFVLGGCRHK), in 86% (24 of 28) of patients. This peptide bound several HLA-DR molecules (HLA-DRB1*0101, HLA-DRB1*0401, HLA-DRB1*1301, and HLA-DRB5*0101). Its coding sequence overlaps a domain of the HBV genome encompassing the basic core promoter (BCP) region. Taking into account the selection of viral core promoter mutants during HBV infection, we found that HBV variants with BCP mutations were present in patient sera. We further demonstrated that these viral mutant sequences activated T cells specific for the immunodominant epitope only weakly, if at all. This is the first study linking BCP mutations and HBx-specific T cell responses. CONCLUSION Wild-type and variant peptides may represent potential tools for monitoring the HBV-specific T cell responses involved in sequence evolution during disease progression. Finally, the degenerate HLA-DR binding of this promiscuous, immunodominant peptide would make it a valuable component of vaccines for protecting large and ethnically diverse patient populations.
Collapse
|
|
22
|
Abstract
Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.
Collapse
Affiliation(s)
- Thomas F Baumert
- Department of Medicine I, Schlosspark Klinik, Teaching Hospital of the Charite, Humboldt University, Heubnerweg 2, D-14059 Berlin, Germany
| | | | | |
Collapse
|
|
23
|
Affiliation(s)
- Stephan Günther
- Bernhard-Nocht-Institute of Tropical Medicine, Hamburg, Germany.
| |
Collapse
|
|
24
|
Cuestas ML, Mathet VL, Ruiz V, Minassian ML, Rivero C, Sala A, Corach D, Alessio A, Pozzati M, Frider B, Oubiña JR. Unusual naturally occurring humoral and cellular mutated epitopes of hepatitis B virus in a chronically infected argentine patient with anti-HBs antibodies. J Clin Microbiol 2006; 44:2191-8. [PMID: 16757620 PMCID: PMC1489447 DOI: 10.1128/jcm.00057-06] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Serum hepatitis B virus (HBV) DNA was extracted from a chronically infected patient with cocirculation of hepatitis B surface antigen (HBsAg) and anti-HBs antibodies. Direct PCR and clone-derived sequences of the S and overlapped P genes were obtained. DNA sequences and phylogenetic analysis ascribed this isolate to genotype A (serotype adw2). Five of six HBV DNA clones exhibited point mutations inside and outside the major hydrophilic region, while the sixth clone exhibited a genotype A "wild-type" amino acid sequence. Observed replacements included both humoral and/or cellular (major histocompatibility complex class I [MHC-I] and MHC-II) HBV mutated epitopes, such as S45A, P46H, L49H, C107R, T125A, M133K, I152F, P153T, T161S, G185E, A194T, G202R, and I213L. None of these mutants were individually present within a given clone. The I213L replacement was the only one observed in the five clones carrying nonsynonymous mutations in the S gene. Some of the amino acid substitutions are reportedly known to be responsible for the emergence of immune escape mutants. C107R replacement prevents disulfide bonding, thus disrupting the first loop of the HBsAg. Circulation of some of these mutants may represent a potential risk for the community, since neither current hepatitis B vaccines nor hyperimmune hepatitis B immune globulin are effectively prevent the liver disease thereto associated. Moreover, some of the recorded HBsAg variants may influence the accuracy of the results obtained with currently used diagnostic tests.
Collapse
Affiliation(s)
- María L Cuestas
- Departamento Microbiología, Facultad de Medicina, UBA, Buenos Aires, Argentina
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Welschinger R, Cossart Y, Pouliopoulos J, Dixon R, Vickery K. Identification of T-cell epitopes associated with immunity within the surface protein of duck hepatitis B virus. J Viral Hepat 2006; 13:515-22. [PMID: 16901281 DOI: 10.1111/j.1365-2893.2005.00717.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Duck hepatitis is a convenient model of hepatitis B virus (HBV) infection, but the lack of immunological reagents hampers investigation of pathogenesis and vaccine development. The aim of this study was to define T-cell epitopes in the surface peptide recognized by vaccinated immune birds. Blastogenesis assays were used to test the proliferative response of spleen mononuclear cells to synthetic peptides spanning the pre-S/S region in 22 naïve and 13 immunized and challenged immune ducks. Roughly > or = 50% of the immune ducks responded to five immunodominant peptides eliciting a statistically greater proliferative response than in naïve birds. Fewer ducks responded to an additional six peptides. No statistically significant difference could be shown for the response to 11 peptides between the immune ducks and the naïve ducks. There was no clustering of the immunodominant peptides which were located throughout the surface antigen at sites of major swings in hydrophobicity. A number of peptides which induce lymphoblastogenesis in vaccinated immune ducks have been identified. Their role in spontaneous recovery from duck hepatitis B infection merits investigation.
Collapse
Affiliation(s)
- R Welschinger
- Department of Infectious Diseases and Immunology, Central Clinical School, University of Sydney, Sydney, NSW, Australia
| | | | | | | | | |
Collapse
|
|
26
|
Lada O, Benhamou Y, Poynard T, Thibault V. Coexistence of hepatitis B surface antigen (HBs Ag) and anti-HBs antibodies in chronic hepatitis B virus carriers: influence of "a" determinant variants. J Virol 2006; 80:2968-75. [PMID: 16501106 PMCID: PMC1395421 DOI: 10.1128/jvi.80.6.2968-2975.2006] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2005] [Accepted: 12/02/2005] [Indexed: 12/11/2022] Open
Abstract
In chronic hepatitis B (CHB), the persistence of hepatitis B surface antigen (HBs Ag) is sometimes associated with antibodies (Ab) to HBs (anti-HBs). To assess the hypothesis of the selection of HBs Ag immune escape variants in CHB patients, the variability of the HBV S gene was determined for patients persistently carrying both HBs Ag and anti-HBs antibodies and patients solely positive for HBs Ag. We selected 14 patients who presented both markers (group I) in several consecutive samples and 12 patients positive for HBs Ag only (group II). The HBs Ag-encoding gene was amplified and cloned, and at least 15 clones per patient were sequenced and analyzed. The number of residue changes within the S protein was 2.7 times more frequent for group I than for group II patients and occurred mostly in the "a" determinant of the major hydrophilic region (MHR), with 9.52 versus 2.43 changes per 100 residues (P = 0.009), respectively. Ten patients (71%) from group I, but only three (25%) from group II, presented at least two residue changes in the MHR. The most frequent changes in group I patients were located at positions s145, s129, s126, s144, and s123, as described for immune escape variants. In CHB patients, the coexistence of HBs Ag and anti-HBs Ab is associated with an increase of "a" determinant variability, suggesting a selection of HBV immune escape mutants during chronic carriage. The consequences of this selection process with regard to vaccine efficacy, diagnosis, and clinical evolution remain partially unknown.
Collapse
Affiliation(s)
- Olivier Lada
- Departments of Virology, Hepato-Gastro-Enterology, AP-HP Pitie-Salpetriere Hospital, Paris, France
| | | | | | | |
Collapse
|
|
27
|
Kazim SN, Sarin SK, Sharma BC, Khan LA, Hasnain SE. Characterization of naturally occurring and Lamivudine-induced surface gene mutants of hepatitis B virus in patients with chronic hepatitis B in India. Intervirology 2006; 49:152-60. [PMID: 16428891 DOI: 10.1159/000089376] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2004] [Accepted: 05/23/2005] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Besides vaccine escape or immune escape hepatitis B virus (HBV) mutants, naturally occurring and drug-induced mutations have been reported in the surface gene (S-gene) of HBV. AIM To investigate the frequency and profile of naturally occurring S-gene mutants and the influence of long-term lamivudine therapy in patients with chronic hepatitis B (CHB). MATERIALS AND METHODS 57 patients with histologically proven CHB, on lamivudine 100 mg/day for more than 24 months, were included. Viral DNA was extracted at baseline and from on-therapy serum samples. The region encoding the complete major hydrophilic region (MHR) and flanking regions (nucleotides 425-840) of major S-gene that overlapped with the viral polymerase was PCR amplified and sequenced. End-of-therapy response (ETR) was assessed. RESULTS Two (3.5%) patients had naturally occurring HBV mutants, sP127S and sS143L seen in the 'a' determinant of the S-gene. Following lamivudine therapy, 14 of 57 (24.5%) patients developed 16 types of S-gene mutations (sP120S, sA128V, sS143L, sW182St., sT189I, sV190A, sS193L, sI195M, sW196L, sW196St., sS207R, sI208T, sS210E, sF219S, sF220L and sC221G). Thirteen (81.2%) of these mutations emerged downstream to the MHR. Nine of 16 types of S-gene mutations observed with lamivudine therapy were also associated with the corresponding changes in the polymerase gene. Baseline viral DNA was significantly higher (2,093 vs. 336 pg/ml; p < 0.05) among patients developing S-gene mutants and the ETR in them was significantly lower [3 of 16 (18.8%) vs. 17 of 41 (41.5%); p < 0.05]. CONCLUSIONS Naturally occurring S-gene mutations are uncommon and are restricted to the 'a' determinant region. Mutations develop in about a quarter of the patients on lamivudine therapy, mostly downstream to the MHR. They may contribute to non-response to the antiviral therapy.
Collapse
Affiliation(s)
- Syed Naqui Kazim
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India
| | | | | | | | | |
Collapse
|
|
28
|
Eckert V, Struff WG. Hepatitis B: Where Are We Today? Transfus Med Hemother 2006. [DOI: 10.1159/000093298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
|
|
29
|
Umemura T, Wang RYH, Schechterly C, Shih JWK, Kiyosawa K, Alter HJ. Quantitative analysis of anti-hepatitis C virus antibody-secreting B cells in patients with chronic hepatitis C. Hepatology 2006; 43:91-9. [PMID: 16323211 DOI: 10.1002/hep.20917] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
To investigate the quantitative characteristics of humoral immunity in patients with hepatitis C, we established an enzyme-linked immunosorbent spot (ELISpot) assay for detection of anti-hepatitis C virus (HCV)-secreting B cells. Receiver operating characteristic curve analysis demonstrated 100% specificity and 58% to 92% sensitivity for detecting B-cell responses to NS5b, NS3, E2, and core antigens. The median sum of anti-HCV-secreting B cells to all HCV antigens tested was significantly higher in 39 patients with chronic hepatitis C (47.3 spot forming cells [SFCs]/10(6) peripheral blood mononuclear cells [PBMCs]) than in 9 recovered subjects (15.3 SFCs/10(6) PBMCs; P = .05) or 11 uninfected controls (5.3 SFCs/10(6) PBMCs; P < .001); the significant difference (P = .018) in chronic versus recovered patients was in reactivity to nonstructural antigens NS3 and NS5b. Anti-HCV immunoglubulin M (IgM)-secreting B cells were also readily detected and persisted decades into HCV infection; there was no difference in IgM-positive cells between chronic and recovered patients. ELISpot reactivity to genotype 1-derived antigens was equivalent in patients of genotypes 1, 2, and 3. There was significant correlation between the numbers of anti-HCV IgG-secreting B cells and serum aminotransferase and to the level of circulating antibody. In conclusion, ELISpot assays can be adapted to study B-cell as well as T-cell responses to HCV. Measurement at the single-cell level suggests that humoral immunity plays a minor role in recovery from HCV infection and that B-cell immunity is strongest in those with persistent infection.
Collapse
Affiliation(s)
- Takeji Umemura
- Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892-1184, USA
| | | | | | | | | | | |
Collapse
|
|
30
|
Hartmann G, Marschner A, Viveros PR, Stahl-Hennig C, Eisenblätter M, Suh YS, Endres S, Tenner-Racz K, Uberla K, Racz P, Steinman RM, Ignatius R. CpG oligonucleotides induce strong humoral but only weak CD4+ T cell responses to protein antigens in rhesus macaques in vivo. Vaccine 2005; 23:3310-7. [PMID: 15837237 DOI: 10.1016/j.vaccine.2005.01.077] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2004] [Revised: 11/29/2004] [Accepted: 01/05/2005] [Indexed: 11/28/2022]
Abstract
Oligonucleotides containing CpG motifs (CpG ODN) are strong adjuvants for humoral immune responses but data on cellular immune responses in primates are scarce. Rhesus macaque blood contained similar numbers of plasmacytoid dendritic cells and B cells, the key sensors of CpG ODN, as human blood, and these cells were activated by CpG-A and CpG-B in vitro. In vivo, both ODNs induced equal plasma levels of interferon-inducible protein 10 and similarly enhanced antibody responses following i.m. injections of the ODNs, protein antigen, and aluminium hydroxide into rhesus macaques, whereas antigen-specific CD4(+) T cell responses were only slightly increased by CpG ODN.
Collapse
Affiliation(s)
- Gunther Hartmann
- Department of Internal Medicine, Division of Clinical Pharmacology, Ludwig-Maximilians-University of Munich, Germany
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
Despite the availability of hepatitis A vaccines that might provide protection for decades, hepatitis B vaccines that provides protection for at least 15 years and the recent introduction of a combined hepatitis A and B vaccine, these infections continue to spread in both the developed and developing world. Hepatitis A vaccine coverage has been limited to high-risk groups: such a selective immunisation policy is unlikely to have a major impact. If adequate immunogenicity in infants is confirmed, dosing schedules can be improved and the costs of vaccination reduced, universal paediatric immunisation with combined hepatitis A and B products is likely to result in the eventual eradication of these infections. In the interim, novel hepatitis A vaccines are being investigated and additional studies on hepatitis A vaccine immunogenicity in infants are in progress. Worldwide use of hepatitis B vaccines for the newborn, young children and high-risk groups should control this infection and obviate the need for a vaccine against hepatitis D. Newer hepatitis B vaccines that may reduce the likelihood of non-responsiveness and have immunotherapeutic value are under study. A recombinant hepatitis E vaccine for use in endemic regions is currently in clinical trials. The development of an effective hepatitis C vaccine has been agonisingly slow and many impediments have been recognised. These include the lack of a susceptible small animal, a high degree of hepatitis C virus (HCV) genomic diversity and failure to produce high quantities of HCV in tissue culture. The development of a novel HCV replicon system may be a major breakthrough. Nonetheless, it may still be exceedingly difficult to produce a vaccine that uniformly provides sterilising immunity; the possibility of developing a hepatitis C vaccine that can prevent chronic infection is an exciting concept that requires further investigation. Advances in recombinant technology, the use of novel genetic (DNA-based) vaccines, expression of hepatitis antigens in plants and improved adjuvants also hold considerable promise.
Collapse
Affiliation(s)
- Raymond S Koff
- Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.
| |
Collapse
|