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Wibowo DP, Chalid MT, Rasyak MR, El Khobar KE, Turyadi, Sjahril R, Wahyuni R, Setiady Y, Muljono DH. Characteristics of hepatitis B virus surface protein and occult hepatitis B infection in infants with immunoprophylaxis failure from Indonesia. Vaccine 2025; 56:127130. [PMID: 40305978 DOI: 10.1016/j.vaccine.2025.127130] [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: 07/15/2024] [Revised: 03/21/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025]
Abstract
Perinatal hepatitis B virus (HBV) infection carries a significant risk of chronicity and complications while making infected people reservoirs for further transmission. Hepatitis B immunization in infants, with or without hepatitis B immune globulin (HBIG), has proven effective in preventing mother-to-child transmission. Nevertheless, some newborns of mothers with high viremia testing positive for hepatitis B e antigen (HBeAg) may not benefit from HBV immunoprophylaxis. Nineteen (10.2 %) of 186 infants born to HBV-infected mothers were HBV DNA-positive. HBV genotypes, serotypes, and hepatitis B surface antigen (HBsAg) sequences were comparable in most mother-cord blood-infant sample pairings, indicating that the infants' HBV strains originated from their mothers. Three (15.3 %) infants had overt HBV infection, whereas 16 (84.2 %) had occult HBV infection (OBI). The HBV isolates from infants exhibited 26 mutations: 38.5 % in the 'a' determinant and 61.5 % in the rest of HBsAg. Mutations were identified in B-cell and T-cell epitopes, impairing humoral and cellular responses to detect or neutralize the virus. This rendered immunoprophylaxis and diagnostics ineffective while inducing tolerance to the infection. HBV strains with these mutations can persist and cause complications, but they can be transmitted undetected by HBsAg tests commonly used in community healthcare. This study reveals the risk of HBV transmission from HBsAg mutant-infected mothers to newborns despite having received the birth dose with HBIG and complete hepatitis B vaccination.
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Affiliation(s)
- Dhita Prabasari Wibowo
- Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia; Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Maisuri T Chalid
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Muhammad Rezki Rasyak
- Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia; Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Korri E El Khobar
- Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Turyadi
- Eijkman Research Centre for Molecular Biology, National Research and Innovation Agency, Bogor, West Java, Indonesia
| | - Rizalinda Sjahril
- Department of Microbiology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Ridha Wahyuni
- Department of Microbiology, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | | | - David H Muljono
- Department of Internal Medicine, Faculty of Medicine, Universitas Hasanuddin, Makassar, South Sulawesi, Indonesia; Indonesian Academy of Sciences (AIPI), Jakarta, Indonesia; Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.
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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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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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Qu W, Hua C, Wang Y, Wang Y, Zhang L, Wang Z, Shi W, Chen F, Wu Z, Wang Q, Lu L, Jiang S, Sui L, Li Y. Lineage Replacement and Genetic Changes of Four HR-HPV Types during the Period of Vaccine Coverage: A Six-Year Retrospective Study in Eastern China. Vaccines (Basel) 2024; 12:411. [PMID: 38675793 PMCID: PMC11053858 DOI: 10.3390/vaccines12040411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/31/2024] [Accepted: 04/07/2024] [Indexed: 04/28/2024] Open
Abstract
OBJECTIVE This study aimed to provide clinical evidence for lineage replacement and genetic changes of High-Risk Human Papillomavirus (HR-HPV) during the period of vaccine coverage and characterize those changes in eastern China. METHODS This study consisted of two stages. A total of 90,583 patients visiting the Obstetrics and Gynecology Hospital of Fudan University from March 2018 to March 2022 were included in the HPV typing analysis. Another 1076 patients who tested positive for HPV31, 33, 52, or 58 from November 2020 to August 2023 were further included for HPV sequencing. Vaccination records, especially vaccine types and the third dose administration time, medical history, and cervical cytology samples were collected. Viral DNA sequencing was then conducted, followed by phylogenetic analysis and sequence alignment. RESULTS The overall proportion of HPV31 and 58 infections increased by 1.23% and 0.51%, respectively, while infection by HPV33 and 52 decreased by 0.42% and 1.43%, respectively, within the four-year vaccination coverage period. The proportion of HPV31 C lineage infections showed a 22.17% increase in the vaccinated group, while that of the HPV58 A2 sublineage showed a 12.96% increase. T267A and T274N in the F-G loop of HPV31 L1 protein, L150F in the D-E loop, and T375N in the H-I loop of HPV58 L1 protein were identified as high-frequency escape-related mutations. CONCLUSIONS Differences in epidemic lineage changes and dominant mutation accumulation may result in a proportional difference in trends of HPV infection. New epidemic lineages and high-frequency escape-related mutations should be noted during the vaccine coverage period, and regional epidemic variants should be considered during the development of next-generation vaccines.
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Affiliation(s)
- Wenjie Qu
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
| | - Chen Hua
- Shanghai Institute of Infection Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China; (C.H.)
| | - Yaping Wang
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
| | - Yan Wang
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
- Qingpu Branch of the Yangtze River Delta Integrated Demonstration Zone, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China
| | - Lu Zhang
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
| | - Zhiheng Wang
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
- Qingpu Branch of the Yangtze River Delta Integrated Demonstration Zone, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China
| | - Wenqian Shi
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
| | - Fang Chen
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
| | - Zhiyong Wu
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
- Qingpu Branch of the Yangtze River Delta Integrated Demonstration Zone, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China
| | - Qian Wang
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai 201508, China
| | - Lu Lu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai 201508, China
| | - Shibo Jiang
- Shanghai Institute of Infection Disease and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China; (C.H.)
| | - Long Sui
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
| | - Yanyun Li
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China; (W.Q.)
- Qingpu Branch of the Yangtze River Delta Integrated Demonstration Zone, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China
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Al-Busafi SA, Alwassief A. Global Perspectives on the Hepatitis B Vaccination: Challenges, Achievements, and the Road to Elimination by 2030. Vaccines (Basel) 2024; 12:288. [PMID: 38543922 PMCID: PMC10975970 DOI: 10.3390/vaccines12030288] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 10/21/2024] Open
Abstract
Annually, more than 1.5 million preventable new hepatitis B (HBV) infections continue to occur, with an estimated global burden of 296 million individuals living with chronic hepatitis B infection. This substantial health challenge results in over 820,000 annual deaths being attributed to complications such as liver cirrhosis and hepatocellular carcinoma (HCC). The HBV vaccination remains the cornerstone of public health policy to prevent chronic hepatitis B and its related complications. It serves as a crucial element in the global effort to eliminate HBV, as established by the World Health Organization (WHO), with an ambitious 90% vaccination target by 2030. However, reports on global birth dose coverage reveal substantial variability, with an overall coverage rate of only 46%. This comprehensive review thoroughly examines global trends in HBV vaccination coverage, investigating the profound impact of vaccination on HBV prevalence and its consequences across diverse populations, including both high-risk and general demographics. Additionally, the review addresses the essential formidable challenges and facilitating factors for achieving WHO's HBV vaccination coverage objectives and elimination strategies in the coming decade and beyond.
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Affiliation(s)
- Said A. Al-Busafi
- Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
| | - Ahmed Alwassief
- Division of Gastroenterology and Hepatology, Department of Medicine, Sultan Qaboos University Hospital, Muscat 123, Oman
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Alemayehu T, Daba MD, Buonsenso D. Long-Term Hepatitis B Vaccine Immunity in Ethiopian Children That Received a Pentavalent Vaccine Series: A Retrospective Cohort Study. CHILDREN (BASEL, SWITZERLAND) 2024; 11:136. [PMID: 38275446 PMCID: PMC10814694 DOI: 10.3390/children11010136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024]
Abstract
BACKGROUND Chronic hepatitis B affects close to 300 million people globally with 1.5 million new infections per year. It causes the highest numbers of cirrhosis and liver cancer diagnoses each year. In children, perinatal transmission and contact with infected blood or body fluids remain the main methods of transmission. There are increasing reports of breakthrough hepatitis B infections in fully vaccinated children born to hepatitis B-negative mothers, especially in low- and middle-income countries. Our study aimed to measure the adequacy of hepatitis B surface antibody levels among children and adolescents who received three rounds of hepatitis B vaccination during infancy and delivered to hepatitis B-negative mothers in Addis Ababa, Ethiopia. METHOD This was a retrospective cohort study analyzing results of paired serology tests for hepatitis B surface antibody and antigen tests performed for children aged 1-18 years from July 2022 to June 2023. All recorded data were transferred to SPSS version 29.0. The prevalence of adequate hepatitis B surface antibody levels was determined and sub-group analysis conducted using descriptive statistics, frequencies and tables. The magnitude of association between different variables and vaccine-induced hepatitis B immunity was assessed using logistic regression. Statistically significant differences were taken at p < 0.05. RESULTS A total of 256 children were included in the study (mean age: 7.53 years). Six children (2.3%) had breakthrough hepatitis B infections. Overall, 37 children (14.4%) were categorized as having optimal hepatitis B surface antibody levels (vaccine-induced antibody titers of >10 IU/mL), while 219 (85.6%) had low titers of <10 IU/mL. Nearly all (97.4%) of the sub-group aged 10 years and above had below-par antibody levels, with adolescents (11-18 years) being ten times more likely to have low seroprotection than those aged less than 5 years. CONCLUSIONS Our study showed markedly low vaccine-induced hepatitis B surface antibody levels among the study population, especially adolescents. The presence of breakthrough infections may suggest a genuine lack of response and not just a mere drop in antibody titers and thus could highlight a significant public health problem in Ethiopia. Further immunologic studies and a thorough analysis of vaccine storage and administration should be conducted to inform prevention programs.
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Affiliation(s)
- Tinsae Alemayehu
- Department of Pediatrics and Adolescent Health, University of Botswana, Private Bag UB, Gaborone 00713, Botswana;
- Department of Pediatrics and Adolescent Health, St. Paul’s Hospital Millennium Medical College, Addis Ababa P.O. Box 1271, Ethiopia;
| | - Million Dechassa Daba
- Department of Pediatrics and Adolescent Health, St. Paul’s Hospital Millennium Medical College, Addis Ababa P.O. Box 1271, Ethiopia;
| | - Danilo Buonsenso
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Centro di Salute Globale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Qu W, Sui L, Li Y. Vaccine escape challenges virus prevention: The example of two vaccine-preventable oncogenic viruses. J Med Virol 2023; 95:e29184. [PMID: 37943176 DOI: 10.1002/jmv.29184] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/06/2023] [Accepted: 10/09/2023] [Indexed: 11/10/2023]
Abstract
Over the years, the pace of developing vaccines for HBV and HPV has never stopped. After more than 30 years of application, the HBV vaccine has reduced 80% of hepatocellular carcinoma (HCC). However, vaccine escape variants occur under selective pressure induced by widespread vaccination and antiviral therapy, which results in fulminant infection and horizontal transmission. Several mechanisms have been studied to explain HBV vaccine escape, including vaccine escape mutations (VEMs) in the major hydrophilic region, which leads to a decrease in the binding ability to neutralize antibodies and is the primary escape mechanism, protein conformational and N-linked glycosylation sites changes caused by VEMs, differences in genotype distribution, gene recombination, and some temporarily unknown reasons. However, effective solutions are still being explored. The HPV vaccine has also been proven to prevent 70%-90% of cervical cancer worldwide. Cases of HPV infection after being vaccinated have been observed in clinical practice. However, few researchers have paid attention to the mechanism of HPV vaccine escape. Thus, we reviewed the literature on vaccine escape of both HBV and HPV to discuss the mechanism of the virus escaping from vaccine protection and possible solutions to this problem. We analyzed the gap between studies of HPV and HBV and made prospects for further research in HPV vaccine escape.
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Affiliation(s)
- Wenjie Qu
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Shanghai, China
| | - Long Sui
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yanyun Li
- Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
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di Filippo Villa D, Navas MC. Vertical Transmission of Hepatitis B Virus-An Update. Microorganisms 2023; 11:1140. [PMID: 37317114 DOI: 10.3390/microorganisms11051140] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 06/16/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major public health problem in the world. Approximately 296 million people are chronically infected. In endemic areas, vertical transmission is a common route of transmission. There are several strategies for the prevention of HBV vertical transmission, such as antiviral treatment during the third trimester of pregnancy and immunoprophylaxis to newborns that includes the administration of hepatitis B immune globulin (HBIG) and an HBV vaccine. Despite this, immunoprophylaxis failure can occur in up to 30% of infants born to HBeAg-positive mothers and/or with high viral load. Therefore, management and prevention of HBV vertical transmission is of paramount significance. In this article, we provided a review of the epidemiology, mechanisms of pathogenesis and risk factors of vertical transmission, as well as the strategies implemented to prevent the infection.
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Affiliation(s)
- Diana di Filippo Villa
- Gastrohepatology Group, Faculty of Medicine, Universidad de Antioquia (UdeA), Calle 70 No. 52-21, Medellin 050010, Colombia
| | - Maria-Cristina Navas
- Gastrohepatology Group, Faculty of Medicine, Universidad de Antioquia (UdeA), Calle 70 No. 52-21, Medellin 050010, Colombia
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Madhuravasal Krishnan J, Kong L, Karns R, Medvedovic M, Sherman KE, Blackard JT. The Synthetic Opioid Fentanyl Increases HIV Replication and Chemokine Co-Receptor Expression in Lymphocyte Cell Lines. Viruses 2023; 15:1027. [PMID: 37113007 PMCID: PMC10145664 DOI: 10.3390/v15041027] [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: 03/28/2023] [Revised: 04/11/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND In the United States, the illicit use of synthetic opioids such as fentanyl has led to a serious public health crisis. Synthetic opioids are known to enhance viral replication and to suppress immunologic responses, but their effects on HIV pathogenesis remain unclear. Thus, we examined the impact of fentanyl on HIV-susceptible and HIV-infected cell types. METHODS TZM-bl and HIV-infected lymphocyte cells were incubated with fentanyl at varying concentrations. Expression levels of the CXCR4 and CCR5 chemokine receptors and HIV p24 antigen were quantified with ELISA. HIV proviral DNA was quantified using SYBR RT-PCR. Cell viability was detected with the MTT assay. RNAseq was performed to characterize cellular gene regulation in the presence of fentanyl. RESULTS Fentanyl enhanced expression of both chemokine receptor levels in a dose-dependent manner in HIV-susceptible and infected cell lines. Similarly, fentanyl induced viral expression in HIV-exposed TZM-bl cells and in HIV-infected lymphocyte cell lines. Multiple genes associated with apoptosis, antiviral/interferon response, chemokine signaling, and NFκB signaling were differentially regulated. CONCLUSIONS Synthetic opioid fentanyl impacts HIV replication and chemokine co-receptor expression. Increased virus levels suggest that opioid use may increase the likelihood of transmission and accelerate disease progression.
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Affiliation(s)
- Janani Madhuravasal Krishnan
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
| | - Ling Kong
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
| | - Rebekah Karns
- Digestive Health Center, Cincinnati Children’s Hospital, Cincinnati, OH 45229, USA
| | - Mario Medvedovic
- Department of Environmental & Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Kenneth E. Sherman
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Jason T. Blackard
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (J.M.K.)
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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Post-Vaccination and Post-Infection Immunity to the Hepatitis B Virus and Circulation of Immune-Escape Variants in the Russian Federation 20 Years after the Start of Mass Vaccination. Vaccines (Basel) 2023; 11:vaccines11020430. [PMID: 36851307 PMCID: PMC9962567 DOI: 10.3390/vaccines11020430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/07/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
A neonatal vaccination against the Hepatitis B virus (HBV) infection was initiated in Russia 20 years ago, with catch-up immunization for adolescents and adults under the age of 60 years launched in 2006. Here, we have assessed the humoral immunity to HBV in different regions of Russia, as well as the infection frequency following 20 years of a nationwide vaccination campaign. We have also evaluated the role of immune-escape variants in continuing HBV circulation. A total of 36,149 healthy volunteers from nine regions spanning the Russian Federation from west to east were tested for HBV surface antigen (HBsAg), antibodies to HBV capsid protein (anti-HBc), and antibodies to HBsAg (anti-HBs). HBV sequences from 481 chronic Hepatitis B patients collected from 2018-2022 were analyzed for HBsAg immune-escape variants, compared with 205 sequences obtained prior to 2010. Overall, the HBsAg detection rate was 0.8%, with this level significantly exceeded only in one study region, the Republic of Dagestan (2.4%, p < 0.0001). Among the generation vaccinated at birth, the average HBsAg detection rate was below 0.3%, ranging from 0% to 0.7% depending on the region. The anti-HBc detection rate in subjects under 20 years was 7.4%, indicating ongoing HBV circulation. The overall proportion of participants under 20 years with vaccine-induced HBV immunity (anti-HBs positive, anti-HBc negative) was 41.7% but below 10% in the Tuva Republic and below 25% in the Sverdlovsk and Kaliningrad regions. The overall prevalence of immune-escape HBsAg variants was 25.2% in sequences obtained from 2018-2022, similar to the prevalence of 25.8% in sequences collected prior to 2010 (p > 0.05). The population dynamics of immune-escape variants predicted by Bayesian analysis have remained stable over the last 20 years, indicating the absence of vaccine-driven positive selection. In contrast, the wild-type HBV population size experienced a rapid decrease starting in the mid-1990s, following the introduction of mass immunization, but it subsequently began to recover, reaching pre-vaccination levels by 2020. Taken together, these data indicate that it is gaps in vaccination, and not virus evolution, that may be responsible for the continued virus circulation despite 20 years of mass vaccination.
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Cheng TW, Yang JF, Chen YY, Wu KT, Lee MS, Kuo HJ, Lin TC, Wang CL, Hsieh MH, Lin CY, Batsaikhan B, Ho CK, Dai CY. Epidemiology of Chronic Hepatitis B Infection in the Cohort of College Students with Vaccination in Taiwan. Vaccines (Basel) 2023; 11:vaccines11020348. [PMID: 36851225 PMCID: PMC9964940 DOI: 10.3390/vaccines11020348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/28/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
After the mass vaccination project in Taiwan, the prevalence of the hepatitis B virus (HBV) infection for the college-aged population of 18 to 21 years is uncertain. We aimed to investigate the prevalence of hepatitis B markers in different birth cohorts. A total of 38,075 students in universities in Kaohsiung area undergoing entrance examinations between July 2006 to September 2020 were included. Seroprevalence of the hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) status and laboratory data were collected. The seropositive rate of HBsAg was less than 1% for students born after 1991. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly higher, and body mass index (BMI) was significantly lower in HBV carriers compared to those who were not carriers (all p < 0.001). Multivariate logistic regression showed that age, male, higher BMI, and positive HBsAg were risk factors of abnormal ALT value. A decrease in the positive rate of anti-HBs which was significantly higher in the cohort of plasma-derived vaccines than recombinant vaccines was found. We concluded that there were decreasing trends in seropositive rates of HBsAg and anti-HBs for students of the college-aged population in the Kaohsiung area. The status of HBsAg was a predictive factor of abnormal ALT levels. The period effect on anti-HBs seropositivity for DNA recombinant vaccine somehow existed.
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Affiliation(s)
- Te-Wei Cheng
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Jeng-Fu Yang
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Yi-Yu Chen
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Kuan-Ta Wu
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Meng-Szu Lee
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Department of Public Health, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Hsiang-Ju Kuo
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Tzu-Chun Lin
- Executive Master of Healthcare Administration, Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Chao-Ling Wang
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Meng-Hsuan Hsieh
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Chia-Yi Lin
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Batbold Batsaikhan
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia
| | - Chi-Kung Ho
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
| | - Chia-Yen Dai
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Health Management Center, Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80756, Taiwan
- Correspondence:
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12
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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: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Kong L, Shata MTM, Brown JL, Lyons MS, Sherman KE, Blackard JT. The synthetic opioid fentanyl increases HIV replication and chemokine co-receptor expression in vitro. J Neurovirol 2022; 28:583-594. [PMID: 35976538 PMCID: PMC11135282 DOI: 10.1007/s13365-022-01090-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 07/19/2022] [Accepted: 07/27/2022] [Indexed: 01/13/2023]
Abstract
The US is experiencing a major public health crisis that is fueled by the illicit use of synthetic opioids including fentanyl. While several drugs of abuse can enhance viral replication and/or antagonize immune responses, the impact of specific synthetic opioids on HIV pathogenesis is poorly understood. Thus, we evaluated the effects of fentanyl on HIV replication in vitro. HIV-susceptible or HIV-expressing cell lines were incubated with fentanyl. HIV p24 synthesis and chemokine receptor levels were quantified by ELISA in culture supernatants and cell lysates, respectively. Addition of fentanyl resulted in a dose-dependent increase in HIV replication. Fentanyl enhanced expression of the HIV chemokine co-receptors CXCR4 and CCR5 and caused a dose-dependent decrease in cell viability. The opioid antagonist naltrexone blocked the effect of fentanyl on HIV replication and CCR5 receptor levels but not CXCR4 receptor levels. TLR9 expression was induced by HIV; however, fentanyl inhibited TLR9 expression in a dose-dependent manner. These data demonstrate that the synthetic opioid fentanyl can promote HIV replication in vitro. As increased HIV levels are associated with accelerated disease progression and higher likelihood of transmission, additional research is required to enhance the understanding of opioid-virus interactions and to develop new and/or optimized treatment strategies for persons with HIV and opioid use disorder.
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Affiliation(s)
- Ling Kong
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, ML 0595, 231 Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Mohamed Tarek M Shata
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, ML 0595, 231 Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Jennifer L Brown
- Addiction Sciences Division, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Department of Psychology, University of Cincinnati, Cincinnati, OH, USA
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michael S Lyons
- Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kenneth E Sherman
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, ML 0595, 231 Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jason T Blackard
- Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, ML 0595, 231 Albert Sabin Way, Cincinnati, OH, 45267-0595, USA.
- Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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14
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Yamada R, Morikawa K, Hotta K, Iwami D, Tanabe T, Murai S, Shinohara N, Yoshida S, Hosoda S, Kubo A, Tokuchi Y, Kitagataya T, Kimura M, Yamamoto K, Nakai M, Sho T, Suda G, Natsuizaka M, Ogawa K, Sakamoto N. Incidence of post-transplant hepatitis B virus reactivation with the use of kidneys from donors with resolved hepatitis B virus infection. J Viral Hepat 2022; 29:976-985. [PMID: 36031873 DOI: 10.1111/jvh.13740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/11/2022] [Accepted: 07/19/2022] [Indexed: 12/09/2022]
Abstract
Donors with resolved hepatitis B virus (HBV) infection may be a solution for the organ shortage for kidney transplantation (KT). The purpose of this study was to clarify the current state of HBV markers after KT from donors with resolved HBV infection to HBV naïve recipients and the rate of HBV reactivation in recipients with resolved HBV infection. Furthermore, we investigated HBV covalently closed circular DNA (cccDNA) in transplanted organs from donors with resolved HBV infection and the capability of HBV replication in kidney cell lines. We retrospectively analysed the HBV status of 340 consecutive donors and recipients who underwent KT in a single centre. We prospectively measured cccDNA by real-time polymerase chain reaction in kidney biopsy specimens of 32 donors with resolved HBV infection. HBV reactivation was found in three recipients with resolved HBV infection (4.8%, 3/63) after KT. We analysed 45 cases of transplantation from donors with resolved HBV infection to HBV-naive recipients. One case (2.2%, 1/45) became seropositive for hepatitis B core antibody (anti-HBc) and in another case (2.2%, 1/45), HBV-DNA was detected qualitatively in an HBV naive recipient with a donor with resolved HBV infection. In the latter case, cccDNA was measured in the donor kidney during KT. HBV replication was observed in kidney cell lines with HBV plasmid transfection. In conclusion, the risk of reactivation in anti-HBc-positive donors is relatively low. However, post-transplant HBV monitoring should be conducted in all at-risk cases.
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Affiliation(s)
- Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Kiyohiko Hotta
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Daiki Iwami
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan.,Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Tatsu Tanabe
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Sachiyo Murai
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Nobuo Shinohara
- Department of Renal and Genitourinary Surgery, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Koji Yamamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan
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15
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Pantazica AM, Dobrica MO, Lazar C, Scurtu C, Tucureanu C, Caras I, Ionescu I, Costache A, Onu A, Clarke JL, Stavaru C, Branza-Nichita N. Efficient cellular and humoral immune response and production of virus-neutralizing antibodies by the Hepatitis B Virus S/preS116-42 antigen. Front Immunol 2022; 13:941243. [PMID: 35935966 PMCID: PMC9354405 DOI: 10.3389/fimmu.2022.941243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Despite the availability of improved antiviral therapies, infection with Hepatitis B virus (HBV) remains a3 significant health issue, as a curable treatment is yet to be discovered. Current HBV vaccines relaying on the efficient expression of the small (S) envelope protein in yeast and the implementation of mass vaccination programs have clearly contributed to containment of the disease. However, the lack of an efficient immune response in up to 10% of vaccinated adults, the controversies regarding the seroprotection persistence in vaccine responders and the emergence of vaccine escape virus mutations urge for the development of better HBV immunogens. Due to the critical role played by the preS1 domain of the large (L) envelope protein in HBV infection and its ability to trigger virus neutralizing antibodies, including this protein in novel vaccine formulations has been considered a promising strategy to overcome the limitations of S only-based vaccines. In this work we aimed to combine relevant L and S epitopes in chimeric antigens, by inserting preS1 sequences within the external antigenic loop of S, followed by production in mammalian cells and detailed analysis of their antigenic and immunogenic properties. Of the newly designed antigens, the S/preS116–42 protein assembled in subviral particles (SVP) showed the highest expression and secretion levels, therefore, it was selected for further studies in vivo. Analysis of the immune response induced in mice vaccinated with S/preS116–42- and S-SVPs, respectively, demonstrated enhanced immunogenicity of the former and its ability to activate both humoral and cellular immune responses. This combined activation resulted in production of neutralizing antibodies against both wild-type and vaccine-escape HBV variants. Our results validate the design of chimeric HBV antigens and promote the novel S/preS1 protein as a potential vaccine candidate for administration in poor-responders to current HBV vaccines.
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Affiliation(s)
- Ana-Maria Pantazica
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Mihaela-Olivia Dobrica
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Catalin Lazar
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Cristina Scurtu
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
| | - Catalin Tucureanu
- Immunology Laboratory, “Cantacuzino” Medico-Military National Research Institute, Bucharest, Romania
| | - Iuliana Caras
- Immunology Laboratory, “Cantacuzino” Medico-Military National Research Institute, Bucharest, Romania
| | - Irina Ionescu
- Immunology Laboratory, “Cantacuzino” Medico-Military National Research Institute, Bucharest, Romania
| | - Adriana Costache
- Immunology Laboratory, “Cantacuzino” Medico-Military National Research Institute, Bucharest, Romania
| | - Adrian Onu
- Immunology Laboratory, “Cantacuzino” Medico-Military National Research Institute, Bucharest, Romania
| | - Jihong Liu Clarke
- Division of Biotechnology and Plant Health, NIBIO - Norwegian Institute for Bioeconomy Research, Ås, Norway
| | - Crina Stavaru
- Immunology Laboratory, “Cantacuzino” Medico-Military National Research Institute, Bucharest, Romania
- *Correspondence: Norica Branza-Nichita, ; Crina Stavaru,
| | - Norica Branza-Nichita
- Department of Viral Glycoproteins, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania
- *Correspondence: Norica Branza-Nichita, ; Crina Stavaru,
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16
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Lai MW, Chang YL, Cheng PJ, Chueh HY, Chang SC, Yeh CT. Absence of chronicity in infants born to immunized mothers with occult HBV infection in Taiwan. J Hepatol 2022; 77:63-70. [PMID: 35176439 DOI: 10.1016/j.jhep.2022.01.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 01/06/2022] [Accepted: 01/28/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS In the Taiwanese population born in the universal vaccination era, HBsAg carrier rates have fallen below 2%, while approximately 5% develop occult hepatitis B infection (OBI). However, the potential for transmission from mothers with OBI to their infants has not been well studied. We aimed to investigate whether mothers with OBI could transmit HBV to their babies. METHODS A total of 253 pregnant women who were born after July 1986 and had been fully vaccinated against HBV during infancy were recruited from a tertiary hospital in Northern Taiwan. HBV serology and DNA levels were determined. Babies born to mothers with OBI were followed-up until 1 year of age. The surface genes were sequenced. RESULTS HBV infection was documented in 18 vaccinated mothers, 2 of whom were HBsAg-reactive (0.79 %). Seventeen were positive for HBV DNA, among whom 16 (6.32%) presented with OBI with a median DNA level of 145 IU/ml (interquartile range: 37.8-657.3 IU/ml). Eleven babies born to 10 mothers with OBI were recruited. Three babies were HBsAg-reactive, and 2 were positive for HBV DNA (17.0 and 212.0 IU/ml). Seven mothers with OBI carried multiple surface gene variants. Two transiently infected babies harbored variants originating from their mother's HBV quasi-species. All infants received complete hepatitis B vaccines. At 12 months of age, none of the babies were positive for HBsAg or HBV DNA. CONCLUSIONS It was possible for mothers with OBI to transmit HBV to their babies, who consequently harbored surface gene variants originating from their mothers' minor variants. Viremia was cleared 1 year after completing the hepatitis B vaccination series. LAY SUMMARY Since initiating the hepatitis B vaccination program in Taiwan, the rate of young individuals (i.e. born after 1986) carrying the HBV surface antigen has fallen below 2%, although around 5% of vaccinated individuals develop occult HBV infections. Herein, we show that pregnant mothers with occult HBV infections can transmit HBV to their offspring. However, no infant had sustained infection at 1 year of age having completed a full HBV vaccination series.
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Affiliation(s)
- Ming-Wei Lai
- Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - Yao-Lung Chang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Po-Jen Cheng
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ho-Yen Chueh
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Shun-Chih Chang
- Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Department of Hepatogastroenterology, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan.
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17
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Genetic variants of NTCP gene and hepatitis B vaccine failure in Taiwanese children of hepatitis B e antigen positive mothers. Hepatol Int 2022; 16:789-798. [PMID: 35635688 DOI: 10.1007/s12072-022-10350-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/25/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV) vaccine failure remains a hurdle to the global elimination of HBV infections in the vaccination era. We aimed to elucidate the relationships between HBV entry receptor sodium taurocholate co-transporting polypeptide (NTCP) and vaccine failure in children born to highly infectious mothers. METHODS The genetic variants rs7154439, rs4646285, rs4646287, and rs2296651 were genotyped in 170 children with chronic HBV infections and 138 control children of mothers positive for hepatitis B e antigen (HBeAg). All children received hepatitis B immunoglobulin and complete HBV vaccination. Total RNAs from 82 adult non-tumor liver tissues were quantified for NTCP, type I interferons and interferon-induced transmembrane protein 3 (IFITM3) levels. RESULTS A higher rate of the GA/AA genotype (28.3% vs. 15.3%, p = 0.006) of the genetic variant rs4646287 in intron 1 of the NTCP gene was detected in control children compared to the carrier children. The rs4646287 G > A genotype was associated with younger ages at which spontaneous HBeAg seroconversion occurred (10.8 ± 8.4 vs. 14.6 ± 8.7 years, p = 0.003) in chronic HBV-infected children. Unique correlation patterns of NTCP and innate immunity-related genes (type I interferons and IFITM3) were found in HBV-infected liver tissues with the rs4646287 G > A genotype. CONCLUSION The rs4646287 G > A genotype of the NTCP gene may be associated with lower risk for HBV vaccine failure in children born to highly infectious mothers. The protective effect of rs4646287 G > A was also present in carrier children, evidenced by earlier spontaneous HBeAg seroconversion.
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Konopleva MV, Feldsherova AA, Elgort DA, Tupoleva TA, Kokhanovskaya NA, Pankratova VN, Semenenko TA, Suslov AP. [Identification by enzyme immunoassay of escape mutants S143L and G145R of hepatitis B virus ( Hepadnaviridae: Orthohepadnavirus: Hepatitis B virus)]. Vopr Virusol 2022; 67:48-58. [PMID: 35293188 DOI: 10.36233/0507-4088-91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 03/15/2022] [Indexed: 11/05/2022]
Abstract
INTRODUCTION The achievement of the goal of the World Health Organization to eliminate viral hepatitis B by 2030 seems to be problematic partly due to the presence of escape mutants of its etiological agent, hepatitis B virus (HBV) (<i>Hepadnaviridae: Orthohepadnavirus: Hepatitis B virus</i>), that are spreading mainly in the risk groups. Specific routine diagnostic assays aimed at identification of HBV escape mutants do not exist.The study aimed the evaluation of the serological fingerprinting method adapted for routine detection of escape mutations in 143 and 145 aa positions of HBV surface antigen (HBsAg). MATERIAL AND METHODS HBV DNA from 56 samples of HBsAg-positive blood sera obtained from donors, chronic HBsAg carriers and oncohematology patients has been sequenced. After the identification of mutations in HBsAg, the samples were tested in the enzyme-linked immunosorbent assay (ELISA) kit «Hepastrip-mutant-3K». RESULTS AND DISCUSSION Escape mutations were detected mainly in patients with hematologic malignancies. Substitutions in 143 and 145 aa were found in 10.81% and in 8.11% of such patients, respectively. The G145R mutation was recognized using ELISA kit in almost all cases. The kit specifically recognized the S143L substitution in contrast to the S143T variant. The presence of neighbor mutation D144E can be assumed due to it special serological fingerprint. CONCLUSION ELISA-based detection of escape mutations S143L, D144E and G145R can be used for routine diagnostics, especially in the risk groups. The diagnostic parameters of the kit can be refined in additional studies. This immunoassay and methodology are applicable for the development and quality control of vaccines against escape mutants.
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Affiliation(s)
- M V Konopleva
- FSBI «National Research Centre for Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
| | - A A Feldsherova
- FSBI «National Research Centre for Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
| | - D A Elgort
- FSBI «National Research Centre for Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
| | - T A Tupoleva
- FSBI «National Medical Research Center for Hematology» of the Ministry of Health of Russia
| | - N A Kokhanovskaya
- FSBI «National Research Centre for Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
| | - V N Pankratova
- FSBI «National Research Centre for Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
| | - T A Semenenko
- FSBI «National Research Centre for Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
| | - A P Suslov
- FSBI «National Research Centre for Epidemiology and Microbiology named after honorary academician N.F. Gamaleya» of the Ministry of Health of Russia
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19
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Konopleva MV, Borisova VN, Sokolova MV, Semenenko TA, Suslov AP. Recombinant HBsAg of the Wild-Type and the G145R Escape Mutant, included in the New Multivalent Vaccine against Hepatitis B Virus, Dramatically Differ in their Effects on Leukocytes from Healthy Donors In Vitro. Vaccines (Basel) 2022; 10:235. [PMID: 35214692 PMCID: PMC8880183 DOI: 10.3390/vaccines10020235] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/20/2022] [Accepted: 01/25/2022] [Indexed: 12/14/2022] Open
Abstract
Immune-escape hepatitis B virus (HBV) mutants play an important role in HBV spread. Recently, the multivalent vaccine Bubo®-Unigep has been developed to protect against both wild-type HBV and the most significant G145R mutant. Here, we compared the effects of recombinant HBsAg antigens, wild-type and mutated at G145R, both included in the new vaccine, on activation of a human high-density culture of peripheral blood mononuclear cells (PBMC) in vitro. The antigens were used either alone or in combination with phytohemagglutinin (PHA). None of the antigens alone affected the expression of CD40, HLA-DR or CD279. Wild-type HBsAg enhanced CD86 and CD69 expression, and induced TNF-α, IL-10, and IFN-γ, regardless of the anti-HBsAg status of donor. In the presence of PHA, wild-type HBsAg had no effect on either of the tested surface markers, but increased IFN-γ and IL-10 and inhibited IL-2. In contrast, the G145R mutant alone did not affect CD86 expression, it induced less CD69, and stimulated IL-2 along with lowering levels of TNF-α, IL-10, and IFN-γ. The G145R mutant also suppressed PHA-induced activation of CD69. The dramatic differences in the immune responses elicited by wild-type HBsAg and the G145R mutant HBsAg suggest distinct adaptive capabilities of the G145R mutant HBV.
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Affiliation(s)
- Maria V. Konopleva
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
| | | | - Maria V. Sokolova
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
| | - Tatyana A. Semenenko
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
| | - Anatoly P. Suslov
- Federal State Budget Institution “National Research Center for Epidemiology and Microbiology Named after Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.S.); (T.A.S.); (A.P.S.)
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20
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Drugs of Abuse and Their Impact on Viral Pathogenesis. Viruses 2021; 13:v13122387. [PMID: 34960656 PMCID: PMC8707190 DOI: 10.3390/v13122387] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/23/2021] [Accepted: 11/27/2021] [Indexed: 02/07/2023] Open
Abstract
Commonly misused substances such as alcohol, cocaine, heroin, methamphetamine, and opioids suppress immune responses and may impact viral pathogenesis. In recent years, illicit use of opioids has fueled outbreaks of several viral pathogens, including the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). This review focuses on the myriad of mechanisms by which drugs of abuse impact viral replication and disease progression. Virus–drug interactions can accelerate viral disease progression and lead to increased risk of virus transmission.
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21
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Shah AS, Civelli VF, Bali V, Johnson RH, Heidari A. A Case of S-Variant Hepatitis B Virus: An Immune System Escape Artist. J Investig Med High Impact Case Rep 2021; 9:23247096211045450. [PMID: 34521227 PMCID: PMC8447092 DOI: 10.1177/23247096211045450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Genomic variants of the hepatitis B virus (HBV) preS/S protein are well-known to
occur. Typically, immunity is gained through recovered HBV infection or by
immunization. Very rarely, there are certain mutations that may enable HBV
escape from the immune detection. PreS/S mutants may present with unpredictable
pathobiologic, clinical, and transmittable implications. Standard laboratory
testing for genomic HBV variants is not routinely performed by reference
guidelines. s-variant HBV management remains challenging. Herein is a case of
s-variant chronic HBV infection in a 55-year-old man. Diagnosis and treatment
are described.
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Affiliation(s)
- Amar S Shah
- UCLA at Kern Medical Center, Bakersfield, CA, USA
| | | | - Varun Bali
- UCLA at Kern Medical Center, Bakersfield, CA, USA
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22
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Ohta T, Ito K, Sugiura T, Koyama N, Saitoh S, Murakami S, Tanaka Y. Breakthrough HBV infection in a vaccinated child due to vaccine escape mutant. KANZO 2021; 62:403-412. [DOI: 10.2957/kanzo.62.403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Affiliation(s)
- Takanori Ohta
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University
| | - Koichi Ito
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University
| | - Tokio Sugiura
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University
- Sugiura Kids Clinic, Hekinan
| | | | - Shinji Saitoh
- Department of Pediatrics and Neonatology, Graduate School of Medical Sciences, Nagoya City University
| | - Shuko Murakami
- Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Graduate School of Medical Sciences, Nagoya City University
- Department of Gastroenterology and Hepatology, Kumamoto University
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23
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Konopleva MV, Belenikin MS, Shanko AV, Bazhenov AI, Kiryanov SA, Tupoleva TA, Sokolova MV, Pronin AV, Semenenko TA, Suslov AP. Detection of S-HBsAg Mutations in Patients with Hematologic Malignancies. Diagnostics (Basel) 2021; 11:diagnostics11060969. [PMID: 34072185 PMCID: PMC8228241 DOI: 10.3390/diagnostics11060969] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/21/2021] [Accepted: 05/24/2021] [Indexed: 01/04/2023] Open
Abstract
Multiple studies of hepatitis B virus (HBV) genetic variability and its relationship with the disease pathogenesis are currently ongoing, stemming from growing evidence of the clinical significance of HBV mutations. It is becoming increasingly evident that patients with hematologic malignancies may be particularly prone to a higher frequency of such mutations. The present report is the first extensive study of the prevalence of escape mutations in S-HBsAg, performed using isolates from 59 patients from hospital hematology departments with diagnoses of leukemia (n = 32), lymphoma (n = 20), multiple myeloma (n = 3), and non-tumor blood diseases (n = 4). The isolates were serologically examined for the presence of HBV markers and sequenced using either next-generation sequencing (NGS) or Sanger sequencing. Occult hepatitis B was found in 5.1% of cases. Genetic analysis of the region corresponding to S-HBsAg demonstrated an exceptionally high mutation frequency in patients with leukemias (93.4%) and lymphomas (85.0%), along with the prominent mutation heterogeneity. Additionally, more than 15 mutations in one sample were found in patients with leukemias (6.3% of cases) and lymphomas (5.0% of cases). Most of the mutations were clinically significant. The study analyzes the mutation profile of HBV in different oncohematological diseases and the frequency of individual mutations. The data strongly suggest that the NGS method, capable of detecting minor populations of HBV mutations, provides a diagnostic advantage, lays the foundation for the development of screening methods, and allows for the study of the virological and pathogenetic aspects of hepatitis B.
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Affiliation(s)
- Maria V. Konopleva
- Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.K.); (A.V.S.); (S.A.K.); (M.V.S.); (A.V.P.); (T.A.S.)
| | - Maxim S. Belenikin
- Laboratory of Molecular Medical Diagnostics, Moscow Institute of Physics and Technology, State University, 141701 Dolgoprudny, Russia;
| | - Andrei V. Shanko
- Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.K.); (A.V.S.); (S.A.K.); (M.V.S.); (A.V.P.); (T.A.S.)
| | - Alexey I. Bazhenov
- State Budget Institution “Research Institute of Emergency Medicine Named After N.V. Sklifosovsky” of the Moscow Department of Healthcare, 129010 Moscow, Russia;
| | - Sergei A. Kiryanov
- Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.K.); (A.V.S.); (S.A.K.); (M.V.S.); (A.V.P.); (T.A.S.)
| | | | - Maria V. Sokolova
- Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.K.); (A.V.S.); (S.A.K.); (M.V.S.); (A.V.P.); (T.A.S.)
| | - Alexander V. Pronin
- Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.K.); (A.V.S.); (S.A.K.); (M.V.S.); (A.V.P.); (T.A.S.)
| | - Tatyana A. Semenenko
- Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.K.); (A.V.S.); (S.A.K.); (M.V.S.); (A.V.P.); (T.A.S.)
| | - Anatoly P. Suslov
- Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N.F. Gamaleya” of the Ministry of Health of the Russian Federation, 123098 Moscow, Russia; (M.V.K.); (A.V.S.); (S.A.K.); (M.V.S.); (A.V.P.); (T.A.S.)
- Correspondence:
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24
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Identification of Two Critical Neutralizing Epitopes in the Receptor Binding Domain of Hepatitis B Virus preS1. J Virol 2021; 95:JVI.01680-20. [PMID: 33298539 PMCID: PMC8092832 DOI: 10.1128/jvi.01680-20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major public health problem. Human hepatocytes are infected with HBV via binding between the preS1 region in the large envelope protein of HBV and sodium taurocholate cotransporting polypeptide. Although several monoclonal antibodies (MAbs) that recognize the receptor binding domain in preS1 and neutralize HBV infection have been isolated, details of neutralizing epitopes are not understood. In this study, we generated 13 MAbs targeting the preS1 receptor binding domain from preS1-specific memory B cells derived from DNA immunized mice. The MAbs were classified into three groups according to the epitope regions, designated epitopes I-III. A virus neutralization assay revealed that MAbs recognizing epitopes I and III neutralized HBV infection, suggesting that these domains are critical epitopes for viral neutralization. In addition, a neutralization assay against multiple genotypes of HBV revealed that epitope I is a semi-pangenotypic neutralizing epitope, whereas epitope III is a genotype-specific epitope. We also showed that neutralizing MAbs against preS1 could neutralize HBV bearing vaccine-induced escape mutation. These findings provide insight into novel immunoprophylaxis for the prevention and treatment of HBV infection.IMPORTANCE The HBV preS1 2-47 aa region (preS1/2-47) is essential for virus binding with sodium taurocholate cotransporting polypeptide. Several MAbs targeting preS1/2-47 have been reported to neutralize HBV infection; however, which region in preS1/2-47 contains the critical neutralizing epitope for HBV infection is unclear. Here, we generated several MAbs targeting preS1/2-47 and found that MAbs recognizing the N- or C-terminus of preS1/2-47 remarkably neutralized HBV infection. We further confirmed the neutralizing activity of anti-preS1 MAbs against HBV with vaccine escape mutation. These data clarified the relationship between the antibody epitope and the virus neutralizing activity and also suggested the potential ability of a vaccine antigen containing the preS1 region to overcome the weakness of current HB vaccines comprising the small S protein.
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25
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Abstract
Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population starting from birth dose, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective, the cancer preventive efficacy support it as the first successful example of cancer preventive vaccine in human. Addition of hepatitis B immunoglobulin immediately after birth and antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are existing or possible emerging strategies to enhance the prevention efficacy of HBV infection and its related liver cancer. Secondary prevention with current antiviral agents may reduce the risk or delay the onset of HCC development, but could not eradicate HBV infection and HCC. Better antiviral therapeutic agents are needed for better secondary prevention.
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Affiliation(s)
- Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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26
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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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27
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The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol 2020; 17:618-634. [PMID: 32467580 DOI: 10.1038/s41575-020-0296-6] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2020] [Indexed: 02/06/2023]
Abstract
The global burden of hepatitis B virus (HBV) is enormous, with 257 million persons chronically infected, resulting in more than 880,000 deaths per year worldwide. HBV exists as nine different genotypes, which differ in disease progression, natural history and response to therapy. HBV is an ancient virus, with the latest reports greatly expanding the host range of the Hepadnaviridae (to include fish and reptiles) and casting new light on the origins and evolution of this viral family. Although there is an effective preventive vaccine, there is no cure for chronic hepatitis B, largely owing to the persistence of a viral minichromosome that is not targeted by current therapies. HBV persistence is also facilitated through aberrant host immune responses, possibly due to the diverse intra-host viral populations that can respond to host-mounted and therapeutic selection pressures. This Review summarizes current knowledge on the influence of HBV diversity on disease progression and treatment response and the potential effect on new HBV therapies in the pipeline. The mechanisms by which HBV diversity can occur both within the individual host and at a population level are also discussed.
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28
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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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29
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Abstract
Enhancing host immunity by vaccination to prevent hepatitis B virus (HBV) infection remains the most important strategy for global control of hepatitis B. Currently, 187 countries have in place infant hepatitis B vaccination programs. Hepatitis B surface antigen prevalence has decreased to less than 1% in children after successful implementation of universal HBV vaccination in newborns. The incidence of primary liver cancer in children, adolescents, and young adults has drastically decreased to near zero in birth cohorts receiving hepatitis B vaccination. Elimination of chronic hepatitis B by 2030 is not a mission impossible.
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30
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No evidence of occult HBV infection in population born after mass vaccination. Wien Med Wochenschr 2020; 170:218-223. [PMID: 32274600 DOI: 10.1007/s10354-020-00748-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 03/16/2020] [Indexed: 12/13/2022]
Abstract
Despite access to efficient hepatitis B virus (HBV) vaccine and universal immunization schedules, HBV infection remains a global health concern. HBV infection has decreased by this program. Nevertheless, breakthrough infections occur due to generation of occult HBV infection (OBI) and surface gene mutants in the immunized population. We aimed to determine the presence of OBI in a population born after initiation of nationwide HBV vaccination in Tehran, Iran. A HBV mass vaccination schedule was launched in Iran in 1993. For this study, we enrolled 1120 cases younger than 24 years. ELISA was applied to evaluate the presence of HBsAg, anti-HBs and anti-HBc. HBV-DNA presence was determined in all HBsAg-negative cases using nested polymerase chain reaction. The prevalence of HBsAg, anti-HBc and anti-HBs was 0.1, 0.54 and 39.9% respectively. Out of 6 anti-HBc-positive individuals, 4 cases also had anti-HBs. One case revealed HBsAg co-existence and the other one showed isolated anti-HBc. HBV-DNA was not detected in HBsAg-negative specimens. A very low prevalence of HBsAg and isolated anti-HBc was observed and no occult HBV infection was detected. It seems that evasion mutants are not a potential threat for HBV universal immunization efficacy in the vaccinated population.
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31
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Das S, Ramakrishnan K, Behera SK, Ganesapandian M, Xavier AS, Selvarajan S. Hepatitis B Vaccine and Immunoglobulin: Key Concepts. J Clin Transl Hepatol 2019; 7:165-171. [PMID: 31293917 PMCID: PMC6609845 DOI: 10.14218/jcth.2018.00037] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 11/16/2018] [Accepted: 05/11/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) immunization is safe and has been accepted worldwide as a routine practice. The target of such vaccination is to induce the immune response in the host, resulting in the prevention of replication of HBV. There are several immunological and clinical factors which determine the clinical efficacy and safety of the HBV vaccine. In this article we have highlighted the response of the host immune system to HBV vaccination (immunogenicity), efficacy, and safety of the vaccine, issues with booster dosing, paths of development (preclinical and clinical) of the HBV vaccine, novel and upcoming strategies for improvement of HBV vaccination, and the concept of therapeutic HBV vaccination. The different aspects and regulatory recommendations pertaining to HBV vaccine development are also discussed. The new strategies for improvement of HBV vaccination include pre-S1 and pre-S2 portions of the HBV surface antigen, increasing the antigen dose, accelerated vaccination schedules, alternative vaccination route, use of adjuvants like immunostimulatory DNA sequences, etc. Therapeutic vaccination is being explored for initiation of a multifunctional and multispecific T cell response against the major HBV antigens and also effective activation of humoral immunity for viral control.
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Affiliation(s)
- Saibal Das
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Kirubakaran Ramakrishnan
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Sapan Kumar Behera
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Mahalakshmi Ganesapandian
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Alphienes Stanley Xavier
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Sandhiya Selvarajan
- Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
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32
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Hung WL, Wu JF, Ni YH, Chen HL, Chiang CL, Chang MH, Hsu HY. Occult hepatitis B virus and surface antigen mutant infection in healthy vaccinated cohorts and children with various forms of hepatitis and multiple transfusions. Liver Int 2019; 39:1052-1061. [PMID: 30790411 DOI: 10.1111/liv.14076] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/29/2019] [Accepted: 02/01/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Despite the success of universal infant immunization initiated in Taiwan in 1984, occult hepatitis B virus infection (OBI) and circulating surface antigen mutants remain potential obstacles for eventual eradication of HBV infection. METHODS From 3299 apparently healthy, neonatally-vaccinated subjects (<30 years of age ) enrolled during 2014 serosurvey, we recruited all HBsAg-positive (n = 17), all HBsAg-negative but anti-HBc-positive (n = 132) and randomly selected HBsAg-negative and anti-HBc-negative subjects (n = 411). These recruited subjects and 81 HBsAg-negative children with various forms of hepatitis and multiple transfusions were analysed for serum HBV DNA. RESULTS In healthy, HBsAg-negative subjects, OBI frequency was higher in anti-HBc-positive than anti-HBc-negative individuals (8/90[8.9%] vs 8/301[2.7%], P = 0.0192) aged <18-years, but was not different between anti-HBc-positive and anti-HBc-negative individuals (0/11[0%] vs 3/110[2.7%], P > 0.05) aged 18 to 30 years. OBI occurred more frequently in children of HBsAg-positive mothers than in children of HBsAg-negative mothers (10/101 [9.9%] vs 1/75 [1.3%], P = 0.025). The prevalence of surface 'a' determinant (aa110-160) mutants was 13.3% (2/15) in OBI subjects compared to 36.4% (4/11) in HBsAg-positive subjects (P > 0.05). OBI was found in 30% (3/10) of serologic 'non-A to E' viral hepatitis, 14.3% (3/21) of chronic hepatitis C and 2.0% (1/50) of multitransfused, thalassemic children. CONCLUSIONS In this highly immunized population, surface antigen mutant infection is uncommon and has low contribution to OBI development. HBsAg screening plus highly sensitive HBV DNA assays are needed for assurance of blood supply safety. Multiple transfusions from HBsAg-negative blood donors rarely result in persistent HBV infection. HBV might be related to some of serologic 'non-A to E' viral hepatitis.
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Affiliation(s)
- Wei-Li Hung
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Cheng-Lun Chiang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
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33
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Di Lello FA, Ridruejo E, Martínez AP, Pérez PS, Campos RH, Flichman DM. Molecular epidemiology of hepatitis B virus mutants associated with vaccine escape, drug resistance and diagnosis failure. J Viral Hepat 2019; 26:552-560. [PMID: 30576055 DOI: 10.1111/jvh.13052] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 11/21/2018] [Indexed: 12/27/2022]
Abstract
The massive implementation of the vaccine and antiviral agents against hepatitis B virus (HBV), targeting the envelope and viral polymerase genes, induces a selection pressure that might lead to the emergence of variants that impair the effectiveness of the vaccine, diagnostic methods and antiviral therapy. The aim of this study was to evaluate the prevalence of HBV vaccine escape mutants (VEMs), diagnostic failure mutants (DFMs) and treatment resistance mutants (ARMs) among individuals from Buenos Aires, Argentina. HBV surface antigen and polymerase sequences obtained from serum samples of 530 HBV-infected individuals were analysed. Samples belonged to genotypes A (28.1%), D (13.6%) and F (58.3%). VEMs, DMFs and ARMs were present in 40 (7.5%), 57 (10.7%) and 27 (5.1%) samples within the studied population. Additionally, eight nonpreviously reported VEMs and nine DFMs were identified. VEMs and DFMs were biased by genotype, being higher in genotype D (33.3% and 33.3%) compared to genotype A (6% and 17.4%) and genotype F (2.3% and 2.3%) (P > 0.001). On the contrary, there was no association between the presence of ARMs and HBV genotype (P = 0.324). VEMs, DFMs and ARMs create public health concerns. The current study provided valuable information about mutants in surface antigen and polymerase in HBV-infected patients from Argentina where HBV-F is the most prevalent genotype. Consequently, it constitutes an important reference for Latin American clinicians in order to optimize the management of HBV-infected patients.
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Affiliation(s)
- Federico A Di Lello
- Facultad de Farmacia y Bioquímica, Cátedra de Virología, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Ezequiel Ridruejo
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas, Norberto Quirno "CEMIC", Buenos Aires, Argentina
| | - Alfredo P Martínez
- Virology Section, Centro de Educación Médica e Investigaciones Clínicas, Norberto Quirno "CEMIC", Buenos Aires, Argentina
| | - Paula S Pérez
- Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida (INBIRS)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Rodolfo H Campos
- Facultad de Farmacia y Bioquímica, Cátedra de Virología, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Diego M Flichman
- Facultad de Farmacia y Bioquímica, Cátedra de Virología, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Ababneh NA, Sallam M, Kaddomi D, Attili AM, Bsisu I, Khamees N, Khatib A, Mahafzah A. Patterns of hepatitis B virus S gene escape mutants and reverse transcriptase mutations among genotype D isolates in Jordan. PeerJ 2019; 7:e6583. [PMID: 30867996 PMCID: PMC6410685 DOI: 10.7717/peerj.6583] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 02/08/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is an important infectious cause of morbidity and mortality in Jordan. HBV genotype D is the most prevalent in the country. Virus escape mutants in the HBV S region is an important public health problem halting preventive efforts. The aim of the current study was to investigate patterns of HBV escape and resistance mutations and to assess domestic transmission of the virus. METHODS Patients infected with HBV were recruited at Jordan University Hospital (n = 56) and were diagnosed during (1984-2012). A total of 37 partial HBV S sequences were generated using Sanger's method. Mutation analysis was done using the HIV grade HBV drug resistance interpretation online tool and Geno2pheno (HBV) online tools. Domestic transmission of HBV was assessed using maximum likelihood phylogenetic inference with similar GenBank sequences. RESULTS Genotyping revealed an exclusive presence of sub-genotype D1. Typical HBV escape mutants were identified in seven patients. These mutations included: L109R, Q129R, M133L, S143L and D144E with overall prevalence of 18.9% (95% CI [9.5-34.2]). Reverse transcriptase (RT) sequence analysis showed mutations in three patients with overall prevalence of 8.1% (95% CI [2.8-21.3]). RT mutations included: V173L, S202I, L180M, M204V and T184A. Transmission cluster analysis revealed a relatively high proportion of infections taking place as a result of domestic spread (29.7%). CONCLUSIONS Based on our findings, RT mutation analysis appears to be of high value before the initiation of therapy in patients with chronic HBV infection in Jordan. Phylogenetic analyses revealed a considerable proportion of local spread in the country which should be considered in the preventive infection control efforts.
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Affiliation(s)
| | - Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, Amman, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman, Jordan
- Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden
| | - Doaa Kaddomi
- Gastroenterology and Liver Division, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan
| | | | - Isam Bsisu
- School of Medicine, University of Jordan, Amman, Jordan
| | - Nadia Khamees
- Gastroenterology and Liver Division, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan
| | - Amer Khatib
- Gastroenterology and Liver Division, Department of Internal Medicine, Jordan University Hospital, Amman, Jordan
| | - Azmi Mahafzah
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, Amman, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman, Jordan
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35
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Huang Y, Wang B, Peng Z, Tang N, Chen W. Hepatitis B virus surface gene mutants in immunoprophylaxis-failed infants from Southern China. J Med Virol 2019; 91:1069-1075. [PMID: 30761578 DOI: 10.1002/jmv.25430] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 01/17/2023]
Abstract
Hepatitis B virus (HBV) vaccination was considered the most powerful tool for prevention of HBV transmission from mother to infant. In 1992, a universal HBV vaccination program for infants was launched in China. The aim of this study was to investigate the HBV surface antigen (HBsAg) variations in immunoprophylaxis-failed infants, vaccine free infant patients and adult chronic hepatitis B (CHB) patients (without nucleoside analog treatment). Immunoprophylaxis-failed infants were recruited from two centers (Guangdong and Chongqing, representing Southern China). HBV serum markers, including HBsAg, hepatitis e antigen (HBeAg), and core antigen, were detected by the enzyme-linked immunosorbent assay. HBV DNA load was detected by quantitative polymerase chain reaction. Nucleotide sequences encoding HBsAg were amplified and analyzed. Frequencies of amino acid substitutions within the second loop of "a" determinant (region with greater local hydrophilicity) in immunoprophylaxis-failed infants were clearly higher than the unvaccinated infant patients and adult CHB patients (9.6% vs 0% vs 3.8%; χ 2 = 7.454; P = 0.024). More than 50% (52.8%) aa substitutions in immunoprophylaxis-failed infants were located in B cell epitopes, while 64.6% aa substitutions in adult CHB patients were located in CTL cell epitopes. HBeAg negative patients had higher substitution frequency in CTL and Th cell epitopes, and in immunoprophylaxis-failed infant patients with substitution in major hydrophilic region region had a higher alanine aminotransferase level (68.6 ± 111.5 vs 62.1 ± 132.2; P = 0.026), and lower DNA load (7.03 ± 1.72 vs 7.82 ± 1.73; P < 0.001). In conclusion, our results observed vaccine-induced immune selection pressure in vaccine failed infants, substitutions in "a" determinant, especially the G145 substitution was still the most stable and remarkable site of vaccine escape.
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Affiliation(s)
- Yong Huang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi Peng
- Department of Infectious Disease, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ni Tang
- Department of Infectious Disease, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weixian Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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36
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Kennedy DA, Read AF. Why the evolution of vaccine resistance is less of a concern than the evolution of drug resistance. Proc Natl Acad Sci U S A 2018; 115:12878-12886. [PMID: 30559199 PMCID: PMC6304978 DOI: 10.1073/pnas.1717159115] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Vaccines and antimicrobial drugs both impose strong selection for resistance. Yet only drug resistance is a major challenge for 21st century medicine. Why is drug resistance ubiquitous and not vaccine resistance? Part of the answer is that vaccine resistance is far less likely to evolve than drug resistance. But what happens when vaccine resistance does evolve? We review six putative cases. We find that in contrast to drug resistance, vaccine resistance is harder to detect and harder to confirm and that the mechanistic basis is less well understood. Nevertheless, in the cases we examined, the pronounced health benefits associated with vaccination have largely been sustained. Thus, we contend that vaccine resistance is less of a concern than drug resistance because it is less likely to evolve and when it does, it is less harmful to human and animal health and well-being. Studies of pathogen strains that evolve the capacity to replicate and transmit from vaccinated hosts will enhance our ability to develop next-generation vaccines that minimize the risk of harmful pathogen evolution.
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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 16802
| | - Andrew F Read
- Center for Infectious Disease Dynamics, Departments of Biology and Entomology, The Pennsylvania State University, University Park, PA 16802
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37
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Kang Y, Li F, Guo H, Yang S, Zhang Y, Zhu H, Wang J, Mao R, Qin Y, Xu J, Chen X, Wu C, Zhang J. Amino acid substitutions Q129N and T131N/M133T in hepatitis B surface antigen (HBsAg) interfere with the immunogenicity of the corresponding HBsAg or viral replication ability. Virus Res 2018; 257:33-39. [PMID: 30179704 DOI: 10.1016/j.virusres.2018.08.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/27/2018] [Accepted: 08/28/2018] [Indexed: 12/21/2022]
Abstract
Variants of hepatitis B surface antigen (HBsAg) influenced its antigenicity and immunogenicity. In our study, we aim to investigate biological significance of amino acid (aa) substitutions in HBsAg, Q129 N and T131 N/M133 T, for glycosylation, antigenicity and immunogenicity of variant HBsAg (vtHBsAg) and viral replication. Expression plasmids of vtHBsAg with aa substitutions Q129 L, T123 N, Q129 N and T131 N/M133 T were constructed. Immunofluorescence (IF) staining and Western blot were simultaneously utilized to examine expression of vtHBsAg proteins in Huh7 cells transfected with vtHBsAg constructs. vtHBsAg of Q129 N and T131 N/M133 T created new N-glycosylation and displayed perinuclear distribution by IF staining with the anti-HA. Antigenicity of vtHBsAg of Q129 N and T131 N/M133 T was reduced compared with wild type (wt) HBsAg. In addition, we discovered impaired ability to induce anti-HBs responses against wtHBsAg in mice immunized with plasmids pHBsAg- Q129 N and T131 N/M133 T. Even so, efficient protective response toward wild type HBV can be primed by the two vtHBsAgs in mice. Further, we discovered that vtHBsAg with Q129 N distinctly impaired HBV replication capacity, but vtHBsAg with T131 N/M133 T had no impact on viral replication. Thus, we conclude that vtHBsAg with Q129 N or T131 N/M133 T creates new N-glycosylation and interferes with both the antigenicity and immunogenicity of vtHBsAg. And vtHBsAg with Q129 N impaired HBV replication ability.
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Affiliation(s)
- Yaoyue Kang
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Department of Infectious Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Hongying Guo
- Department of Hepatitis Diseases, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Sisi Yang
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Yongmei Zhang
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Jinyu Wang
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Richeng Mao
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Yanli Qin
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Jie Xu
- Department of Infectious Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinwen Chen
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
| | - Chunchen Wu
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China.
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; Key laboratory of Medical Molecular Virology of the Ministries of Education and Health (MOH&MOE), Fudan University, Shanghai, China.
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38
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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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39
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Quasispecies characters of hepatitis B virus in immunoprophylaxis failure infants. Eur J Clin Microbiol Infect Dis 2018; 37:1153-1162. [PMID: 29629487 DOI: 10.1007/s10096-018-3235-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 03/13/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis B vaccination prevents 80-95% of transmission and reduces the incidence of HBV in children. The variations in the a determinant of HBV surface antigen (HBsAg) have been reported to be the most prevalent cause for vaccine or antibody escape. There is a conflicting evidence on as to whether escape mutants arise de novo in infected infants or whether the mutants, that have preexisted maternally, subsequently undergo selective replication in the infant under immune pressure. Here, we report that nearly 65% (55 of 85) vaccination failure in child patients has no amino acid substitution in a determinant as seen by Sanger sequencing. We further employed an Illumina sequencing platform-based method to detect HBV quasispecies in four immunoprophylaxis failure infants and their mothers. In our data, the substitution rate of amino acid located at a determinant is relatively low (< 10%), I/T126A, C124S, F134Y, K141Q, Q129H, D144A, G145V, and N146K, which showed no statistical difference to their mothers, proving that these vaccine escape mutants preexist maternally as minor variants. Besides that, bioinformatical analysis showed that the binding affinity of high variation epitopes (amino acid divergence in mother and their infants > 20%) to related HLA molecules was generally decreased, these traces of immune escape suggesting that immune pressure was present and was effective in all samples.
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40
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Bi X, Tong S. Impact of immune escape mutations and N-linked glycosylation on the secretion of hepatitis B virus virions and subviral particles: Role of the small envelope protein. Virology 2018; 518:358-368. [PMID: 29604477 DOI: 10.1016/j.virol.2018.03.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/08/2018] [Accepted: 03/14/2018] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus (HBV) expresses three co-terminal envelope proteins: large (L), middle (M), and small (S), with the S protein driving the secretion of both virions and subviral particles. Virion secretion requires N-linked glycosylation at N146 in the S domain but can be impaired by immune escape mutations. An M133T mutation creating a novel glycosylation site at N131could rescue virion secretion of N146Q mutant (loss of original glycosylation site) and immune escape mutants such as G145R. Here we demonstrate that other novel N-linked glycosylation sites could rescue virion secretion of the G145R and N146Q mutants to variable extents. Both G145R and N146Q mutations impaired virion secretion through the S protein. The M133T mutation restored virion secretion through the S protein, and could work in trans. Impaired virion secretion was not necessarily associated with a similar block in the secretion of subviral particles.
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Affiliation(s)
- Xiaohui Bi
- Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Shuping Tong
- Key Lab of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Liver Research Center, Rhode Island Hospital, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
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41
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42
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Stevens CE, Toy P, Kamili S, Taylor PE, Tong MJ, Xia GL, Vyas GN. Eradicating hepatitis B virus: The critical role of preventing perinatal transmission. Biologicals 2017; 50:3-19. [DOI: 10.1016/j.biologicals.2017.08.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Revised: 08/12/2017] [Accepted: 08/14/2017] [Indexed: 12/19/2022] Open
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43
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Jaramillo CM, de La Hoz F, Porras A, di Filippo D, Choconta-Piraquive LA, Payares E, Montes N, Navas MC. Characterization of hepatitis B virus in Amerindian children and mothers from Amazonas State, Colombia. PLoS One 2017; 12:e0181643. [PMID: 29016603 PMCID: PMC5634536 DOI: 10.1371/journal.pone.0181643] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 07/05/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Hepatitis B Virus (HBV) infection is a worldwide public health problem. In the 1980's a highly effective and safe vaccine against HBV was developed, although breakthrough infection still occasionally occurs because of the emergence of escape mutants. The aim of this study was to identify HBV genotypes and escape mutants in children and their mothers in Amerindian communities of the Amazonas State, Southern Colombia. METHODS Blood specimens collected from children and mothers belonging to 37 Amerindian communities in Amazonas state, were screened for HBsAg and anti-HBc using ELISA. The partial region containing the S ORF was amplified by nested PCR, and amplicons were sequenced. The phylogenetic analysis was performed using the MEGA 5.05 software. RESULTS Forty-six children (46/1275, 3.6%) and one hundred and seventy-seven mothers (177/572, 30.9%) were tested positive for the anti-HBc serological marker. Among them, 190 samples were tested for viral genome detection; 8.3% (2/31) serum samples obtained from children and 3.1% (5/159) from mothers were positive for the ORF S PCR. The predominant HBV genotype in the study population was F, subgenotype F1b; in addition, subgenotype F1a and genotype A were also characterized. Two HBV escape mutants were identified, G145R, reported worldwide, and W156*; this stop codon was identified in a child with occult HBV infection. Other mutations were found, L109R and G130E, located in critical positions of the HBsAg sequence. CONCLUSIONS This study aimed to characterize the HBV genotype F, subgenotypes F1b and F1a, and genotype A in Amerindian communities and for the first time escape mutants in Colombia. Further investigations are necessary to elucidate the frequency and the epidemiological impact of the escape mutants in the country.
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Affiliation(s)
- Carlos Mario Jaramillo
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia
| | - Fernando de La Hoz
- Grupo de Epidemiologia y Evaluación en Salud Pública, Universidad Nacional, Bogota, Colombia
| | - Alexandra Porras
- Grupo de Epidemiologia y Evaluación en Salud Pública, Universidad Nacional, Bogota, Colombia
| | - Diana di Filippo
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia
| | | | - Edra Payares
- Laboratorio Departamental de Salud Publica del Amazonas, Leticia, Colombia
| | - Neyla Montes
- Coordinacion Salud Publica, Alcaldia de Puerto Nariño, Puerto Nariño, Colombia
| | - Maria-Cristina Navas
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia
- * E-mail:
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Hsu HY, Chang MH, Ni YH, Chiang CL, Wu JF, Chen HL, Chen PJ, Chen DS. Chronologic changes in serum hepatitis B virus DNA, genotypes, surface antigen mutants and reverse transcriptase mutants during 25-year nationwide immunization in Taiwan. J Viral Hepat 2017; 24:645-653. [PMID: 28182307 DOI: 10.1111/jvh.12687] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 01/25/2017] [Indexed: 12/12/2022]
Abstract
We investigated breakthrough infection and hepatitis B virus (HBV) genetic changes in immunized subjects after 25 years of a universal infant immunization. Specifically, serum HBV DNA, genotypes, surface antigen mutants and nucleoside analog-resistant (NAr) mutants were assessed in 2853 subjects (<25 years old) surveyed in 2009, and these data were compared with the data from previous serosurveys. A comparison across different age-stratified groups using the 2009 data revealed a significant increase in the seropositive rate of anti-HBc (5.51% vs 12.38%, P=.001) and HBV DNA (1.13% vs 3.96%, P=.007) between those 17-22 and 23-24 years of age, possibly due to selective infant immunization in 1984-1986. Well-characterized NAr mutants, potential NAr mutants and surface "a" determinant mutants were detected in none, 15 (45.5%) and nine (27.3%) of 33 HBV DNA-positive subjects, respectively. Of 15 immunized, HBV DNA-positive young adults (18-24 years), three (20%) carried "a" determinant mutants. Amongst 1176 HBsAg-negative subjects evaluated for occult HBV infection, those seropositive for anti-HBc had a higher seropositive rate for HBV DNA (10/110, 9.1% vs 7/1066, 0.66%; P<.001) and "a" determinant mutants (4/110, 3.6% vs 0/1066; P<.001) than those seronegative for anti-HBc. Overall, the HBsAg-positive subjects in six serosurveys showed no significant increase in genotype C frequency in the comparison between the vaccinated and unvaccinated cohorts (25/98, 25.5% versus 14/79, 17.7%, P=.188). Over the 25-year programme, there was no increase in the prevalence of genotype C in HBsAg carriers and no increase in breakthrough HBV infection or surface mutant prevalence beyond adolescence. Nucleic acid amplification should still be considered the primary screening method for occult hepatitis B detection in high-risk recipients.
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Affiliation(s)
- H-Y Hsu
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - M-H Chang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Y-H Ni
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - C-L Chiang
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - J-F Wu
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - H-L Chen
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Medical Education and Bioethics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - P-J Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - D-S Chen
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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Wen WH, Lai MW, Chang MH. A review of strategies to prevent mother-to-infant transmission of hepatitis B virus infection. Expert Rev Gastroenterol Hepatol 2016; 10:317-30. [PMID: 26566769 DOI: 10.1586/17474124.2016.1120667] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis B virus (HBV) infection causes long-term, life-threatening liver diseases worldwide. HBV is transmitted through either the horizontal or mother-to-infant route, which is the major route of transmission in endemic areas. Administration of hepatitis B immunoglobulin and hepatitis B vaccine to newborns of infected mothers prevents mother-to-infant transmission. Implementation of a universal hepatitis B vaccination program has proven successful in eliminating the infection and related complications. Nevertheless, efforts are still needed to improve global coverage of the hepatitis B vaccine. Infants born to highly viremic mothers are still at risk of infection despite current immunoprophylaxis. An increasing number of reports have shown promising efficacy and safety profiles with the use of nucleoside/nucleotide analogues in highly viremic pregnant women to prevent mother-to-infant transmission.
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Affiliation(s)
- Wan-Hsin Wen
- a Department of Pediatrics , Cardinal Tien Hospital , New Taipei City , Taiwan.,b School of Medicine, College of Medicine , Fu-Jen Catholic University , New Taipei City , Taiwan
| | - Ming-Wei Lai
- c Division of Pediatric Gastroenterology, Department of Pediatrics , Chang Gung Memorial Hospital , Linkou , Taiwan.,d College of Medicine , Chang Gung University , Taoyuan , Taiwan
| | - Mei-Hwei Chang
- e Department of Pediatrics , National Taiwan University Hospital, College of Medicine, National Taiwan University , Taipei , Taiwan
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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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Lai MW, Lin TY, Liang KH, Lin WR, Yeh CT. Hepatitis B viremia in completely immunized individuals negative for anti-hepatitis B core antibody. Medicine (Baltimore) 2016; 95:e5625. [PMID: 27930595 PMCID: PMC5266067 DOI: 10.1097/md.0000000000005625] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 09/07/2016] [Accepted: 11/18/2016] [Indexed: 12/16/2022] Open
Abstract
The presence of anti-hepatitis B virus (HBV) core antibody (anti-HBc) is considered a sensitive lifetime marker of HBV infection. Here, we examined this dogma by investigating the prevalence of hepatitis B viremia in anti-HBc negative complete vaccines in Taiwan.A total of 795 participants (1.7-20.0 years old) had completed HBV vaccination in infancy and were anti-HBc negative. Serum samples were available for 460 individuals with isolated anti-HBV surface antibodies (anti-HBs) (HBsAg-negative and anti-HBc negative) and for 245 individuals who tested negative for all 3 markers (triple seronegative). All samples were submitted for polymerase chain reaction (PCR) targeting both the preS/S and X/pre-C gene regions.Of the 460 participants with isolated anti-HBs, 26 (5.65%) were positive for HBV by 2-target PCR. Of the 245 triple seronegative samples, 12 (4.90%) were positive for HBV DNA. In the former group, the prevalence of viremia was significantly higher in individuals aged 6 to 10 years than in all other ages combined (11.82% vs 3.7%, P = 0.001). The anti-HBs titers were significantly lower in participants 6 to 10 years old than in all other ages combined (72.06 vs 99.64 mIU/mL, P = 0.038). In total, 7 (0.99%) subjects had quantifiable HBV DNA levels (280-18,820 IU/mL). Sequence analysis of the S gene revealed vaccine escape like mutations.Hepatitis B viremia can occur in completely vaccinated individuals who are negative for anti-HBc.
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Affiliation(s)
- Ming-Wei Lai
- Division of Pediatric Gastroenterology
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch
- Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - Tzou-Yien Lin
- Division of Pediatric Infectious Diseases, Department of Pediatrics
- Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch
- Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Department of Gastroenterology and Hepatology
- Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch
- Molecular Medicine Research Center, Chang Gung University
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48
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Study of Genotype, Subtype and Mutation in the S Gene in Hepatitis B Patients Co-infected with HIV in Iran. Jundishapur J Microbiol 2016. [DOI: 10.5812/jjm.34009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Komatsu H, Inui A, Umetsu S, Tsunoda T, Sogo T, Konishi Y, Fujisawa T. Evaluation of the G145R Mutant of the Hepatitis B Virus as a Minor Strain in Mother-to-Child Transmission. PLoS One 2016; 11:e0165674. [PMID: 27812178 PMCID: PMC5094722 DOI: 10.1371/journal.pone.0165674] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 10/14/2016] [Indexed: 02/06/2023] Open
Abstract
The role of the hepatitis B virus (HBV) mutant G145R, with a single change in amino acid 145 of the surface protein, as a minor population remains unknown in mother-to-child transmission. The minor strain as well as the major strain of the G145R mutant were evaluated in three cohorts using a locked nucleic acid probe-based real-time PCR. The breakthrough cohort consisted of children who were born to HBV carrier mothers and became HBV carriers despite immnoprophylaxis (n = 25). The control cohort consisted of HBV carriers who had no history of receiving the hepatitis B vaccine, hepatitis B immunoglobulin or antiviral treatment (n = 126). The pregnant cohort comprised pregnant women with chronic HBV infection (n = 31). In the breakthrough cohort, 6 showed positive PCR results (major, 2; minor, 4). In the control cohort, 13 showed positive PCR results (major, 0; minor, 13). HBeAg-positive patients were prone to have the G145R mutant as a minor population. Deep sequencing was performed in a total of 32 children (PCR positive, n = 13; negative, n = 19). In the breakthrough cohort, the frequency of the G145R mutant ranged from 0.54% to 6.58%. In the control cohort, the frequency of the G145R mutant ranged from 0.42% to 4.1%. Of the 31 pregnant women, 4 showed positive PCR results (major, n = 0; minor, n = 4). All of the pregnant women were positive for HBeAg and showed a high viral load. Three babies born to 3 pregnant women with the G145R mutant were evaluated. After the completion of immunoprophylaxis, 2 infants became negative for HBsAg. The remaining infant became negative for HBsAg after the first dose of HB vaccine. G145R was detected in one-fourth of the children with immunoprophylaxis failure. However, the pre-existence of the G145R mutant as a minor population in pregnant women does not always cause breakthrough infection in infants.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Chiba, Japan
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Shuichiro Umetsu
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Tomoyuki Tsunoda
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Tsuyoshi Sogo
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Yasuhiro Konishi
- Department of Obstetrics & Gynecology, Eastern Yokohama Hospital, Kanagawa, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Eastern Yokohama Hospital, Kanagawa, Japan
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Aghakhani A, Mohraz M, Aghasadeghi MR, Banifazl M, Vahabpour R, Karami A, Foroughi M, Ramezani A. Occult hepatitis B virus infection and S gene escape mutants in HIV-infected patients after hepatitis B virus vaccination. Int J STD AIDS 2016; 27:967-972. [DOI: 10.1177/0956462415602419] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Hepatitis B virus (HBV) vaccination is recommended for HIV patients. Despite the relative success of HBV vaccination, breakthrough infections can occur infrequently in patients, and it can be due to occult HBV infection, vaccine unresponsiveness and/or emergence of escape mutants. This study assessed the presence of occult HBV infection and S gene escape mutants in HIV-positive patients after HBV vaccination. Ninety-two HIV-positive patients were enrolled in this study, including 52 responders to HBV vaccine and 40 non-responders. All of the cases received HBV vaccine according to routine HBV vaccination protocols. The presence of HBV-DNA was determined by real-time polymerase chain reaction (PCR). In HBV-DNA positive samples, the most conserved regions of S gene sequences were amplified by nested PCR and PCR products were sequenced. Occult HBV infection was detected in two cases. Glycine to arginine mutation at residue 145 (G145R) within the ‘a’ region of the S gene was detected in one of the occult HBV infection cases who was in the non-responder group. This study showed that the prevalence of occult HBV infection and vaccine escape mutants was low in our HBV-vaccinated HIV-positive patients in both responder and non-responder groups, so there was no alarming evidence indicating breakthrough HBV infection in our vaccinated HIV-positive cases.
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Affiliation(s)
- Arezoo Aghakhani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
| | - Minoo Mohraz
- Iranian Research Center for HIV/AIDS, Tehran, Iran
| | | | - Mohammad Banifazl
- Iranian Society for Support of Patients with Infectious Diseases, Tehran, Iran
| | | | | | | | - Amitis Ramezani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, Iran
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