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de Almeida Pondé RA. Detection of hepatitis B virus surface antigen, IgM and IgG antibodies to hepatitis B virus core antigen in the clinical classification and epidemiological surveillance of HBV infection. Mol Biol Rep 2025; 52:195. [PMID: 39903324 DOI: 10.1007/s11033-025-10278-9] [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: 10/15/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
Hepatitis B virus surface antigen (HBsAg), IgM and IgG antibodies to hepatitis B virus core antigen (anti-HBcIgM and anti-HBcIgG) comprise serological markers of hepatitis B virus (HBV) infection of great importance in the epidemiological surveillance of hepatitis B, since they have been routinely considered for classifying the acute and chronic clinical forms of HBV infection. This classification is established according to the expression and dynamics of these markers in the infected person's bloodstream, which serves as the basis for the differential diagnosis between the two clinical entities. However, in certain circumstances, both acute and chronic infection, the detection of these markers may not occur in the bloodstream, favoring the occurrence of atypical serological profiles of infection, and compromising the correct infection clinical classification. In addition, the complex and varied nature of hepatitis B serological profiles may compromise the health professional's ability to analyze the case and, thus, correctly classify the infection's clinical form. Since the expression of these markers in the bloodstream occurs dynamically, with consequent changes in the patient's serological profile as he progresses towards recovery or chronicity, the diagnosis of acute or chronic infection may also be compromised, if it is established based on the collection of a single sample and without knowing the patient's clinical history and their epidemiological antecedents. This manuscript addresses the sensitivity and specificity of HBsAg, anti-HBcIgM, and anti-HBcIgG serological markers detection in the clinical classification of HBV infection and in the epidemiological surveillance of hepatitis B. This review is covering the clinical and epidemiological interpretations of the markers in and of themselves, not in reference to any specific assays.
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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.
- , Rua 136 Qd F44 Lt 22/24 Ed. César Sebba- Setor Sul, Goiânia, Goiás, 74-093-250, Brazil.
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Pondé RADA, Amorim GDSP. Elimination of the hepatitis B virus: A goal, a challenge. Med Res Rev 2024; 44:2015-2034. [PMID: 38528684 DOI: 10.1002/med.22030] [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: 10/06/2023] [Revised: 01/24/2024] [Accepted: 02/05/2024] [Indexed: 03/27/2024]
Abstract
The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.
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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
- Department of Microbiology, Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil
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Cargill T, Cicconi P, Brown A, Holland L, Karanth B, Rutkowski K, Ashwin E, Mehta R, Chinnakannan S, Sebastian S, Bussey L, Sorensen H, Klenerman P, Evans T, Barnes E. HBV001: Phase I study evaluating the safety and immunogenicity of the therapeutic vaccine ChAdOx1-HBV. JHEP Rep 2023; 5:100885. [PMID: 37791379 PMCID: PMC10543776 DOI: 10.1016/j.jhepr.2023.100885] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 06/23/2023] [Accepted: 07/22/2023] [Indexed: 10/05/2023] Open
Abstract
Background & Aims Millions of people worldwide are infected chronically with HBV, which results in significant morbidity and mortality. Therapeutic vaccination is a strategy that aims to induce functional cure by restoring cellular immunity to HBV. Previously we have shown the candidate HBV immunotherapeutic vaccine ChAdOx1-HBV, encoding all major HBV antigens and a genetic adjuvant (shark invariant chain), is highly immunogenic in mice. Methods Here we report the results of HBV001, a first-in-human, phase I, non-randomised, dose-escalation trial of ChAdOx1-HBV assessed in healthy volunteers and patients with chronic HBV (CHB). Results Vaccination with a single dose of ChAdOx1-HBV was safe and well tolerated in both healthy and CHB cohorts. Vaccination induced high magnitude HBV-specific T cell responses against all major HBV antigens (core, polymerase, and surface) in healthy volunteers. Responses were detected but lower in patients with CHB. T cells generated by vaccination were cross-reactive between HBV C and D genotypes. Conclusions ChAdOx1-HBV is safe and immunogenic in healthy volunteers and patients with CHB. In further studies, ChAdOx1-HBV will be used in combination with other therapeutic strategies with an aim to overcome the attenuated immunogenicity in patients with CHB. Impact and implications Therapeutic vaccine ChAdOx1-HBV, a novel treatment for chronic hepatitis B infection (CHB), has been shown to be immunogenic in preclinical studies. In HBV001, a first-in-human phase I study, we show vaccination with ChAdOx1-HBV is safe and generates high magnitude T cell responses in healthy volunteers and lower levels of responses in patients with CHB. This is an important first step in the development of ChAdOx1-HBV as part of a wider therapeutic strategy to induce hepatitis B functional cure, and is of great interest to patients CHB and clinicians treating the condition. Clinical Trials Registration This study is registered at ClinicalTrials.gov (NCT04297917).
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Affiliation(s)
- Tamsin Cargill
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Paola Cicconi
- Jenner Vaccine Trials Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - Anthony Brown
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Louise Holland
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Jenner Vaccine Trials Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | | | | | - Emily Ashwin
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Jenner Vaccine Trials Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | | | - Senthil Chinnakannan
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | | | | | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, University of Oxford, The Joint Research Office, OUH Cowley, Oxford, UK
| | | | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, University of Oxford, The Joint Research Office, OUH Cowley, Oxford, UK
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Swadling L, Maini MK. Can T Cells Abort SARS-CoV-2 and Other Viral Infections? Int J Mol Sci 2023; 24:4371. [PMID: 36901802 PMCID: PMC10002440 DOI: 10.3390/ijms24054371] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/14/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Despite the highly infectious nature of the SARS-CoV-2 virus, it is clear that some individuals with potential exposure, or even experimental challenge with the virus, resist developing a detectable infection. While a proportion of seronegative individuals will have completely avoided exposure to the virus, a growing body of evidence suggests a subset of individuals are exposed, but mediate rapid viral clearance before the infection is detected by PCR or seroconversion. This type of "abortive" infection likely represents a dead-end in transmission and precludes the possibility for development of disease. It is, therefore, a desirable outcome on exposure and a setting in which highly effective immunity can be studied. Here, we describe how early sampling of a new pandemic virus using sensitive immunoassays and a novel transcriptomic signature can identify abortive infections. Despite the challenges in identifying abortive infections, we highlight diverse lines of evidence supporting their occurrence. In particular, expansion of virus-specific T cells in seronegative individuals suggests abortive infections occur not only after exposure to SARS-CoV-2, but for other coronaviridae, and diverse viral infections of global health importance (e.g., HIV, HCV, HBV). We discuss unanswered questions related to abortive infection, such as: 'Are we just missing antibodies? Are T cells an epiphenomenon? What is the influence of the dose of viral inoculum?' Finally, we argue for a refinement of the current paradigm that T cells are only involved in clearing established infection; instead, we emphasise the importance of considering their role in terminating early viral replication by studying abortive infections.
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Affiliation(s)
- Leo Swadling
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, Pears Building, London WC1E 6BT, UK
| | - Mala K. Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, Pears Building, London WC1E 6BT, UK
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5
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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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Di Lello FA, Martínez AP, Flichman DM. Insights into induction of the immune response by the hepatitis B vaccine. World J Gastroenterol 2022; 28:4249-4262. [PMID: 36159002 PMCID: PMC9453777 DOI: 10.3748/wjg.v28.i31.4249] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 05/21/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
After more than four decades of hepatitis B virus (HBV) vaccine implementation, its safety and efficacy in preventing HBV infection have been proven and several milestones have been achieved. Most countries have included HBV immunization schedules in their health policies and progress has been made regarding universalization of the first HBV vaccine dose at birth. All of these actions have significantly contributed to reducing both the incidence of HBV infection and its related complications. However, there are still many drawbacks to overcome. The main concerns are the deficient coverage rate of the dose at birth and the large adult population that has not been reached timely by universal immunization. Additionally, the current most widely used second-generation vaccines do not induce protective immunity in 5% to 10% of the population, particularly in people over 40-years-old, obese (body mass index > 25 kg/m2), heavy smokers, and patients undergoing dialysis or infection with human immunodeficiency virus. Recently developed and approved novel vaccine formulations using more potent adjuvants or multiple antigens have shown better performance, particularly in difficult settings. These advances re-launch the expectations of achieving the World Health Organization’s objective of completing hepatitis control by 2030.
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Affiliation(s)
- Federico Alejandro Di Lello
- Microbiology, Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones en Bacteriología y Virología Molecular, Buenos Aires C1113AAD, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires C1425FQB, Argentina
| | - Alfredo Pedro Martínez
- Virology Section, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno “CEMIC”, Buenos Aires C1431FWO, Argentina
| | - Diego Martín Flichman
- Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires C1425FQB, Argentina
- Microbiology, Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y Síndrome de Inmunodeficiencia Adquirida, Buenos Aires C1121ABG, Argentina
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Zhong S, Liu Z, Zhou Y, Zhang T, Fu X, Guo L, Gu S, Tang L, Hou J, Li Y. Longitudinal mapping of hepatitis B vaccine-induced B-cell linear epitopes in healthy individuals. J Med Virol 2022; 94:4993-5006. [PMID: 35676468 DOI: 10.1002/jmv.27926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 11/08/2022]
Abstract
The elimination of hepatitis B virus (HBV) infection is partially facilitated by the prophylactic HB vaccine. As the loss of seroprotection over time remains a conundrum for long-lasting protection, a comprehensive dynamic analysis of immunogenic targets of the HB vaccine will provide novel insights into the improvement and design of potential targets. In this study, 36 healthy subjects without prior history of hepatitis B infection and negative for hepatitis B surface antibody (anti-HBs) were enrolled. Participants were given a series of three doses of HB vaccine on a 0-, 1-, and 6-month schedule and longitudinally followed up. We systematically mapped 55 overlapping 15-mer peptides covering the small S protein of hepatitis B virus (SHBs) of vaccinees' serum samples at seven time points by performing an ELISA assay. Additionally, the frequencies and function dynamics of adaptive immune response were assessed by flow cytometry. We found that the SHBs peptide coverage presented an overall upward trend along with the vaccination progress, and the individual subpartition recognition was strongly correlated with the anti-HBs titers. Moreover, we identified one dominant epitope (S29) located on "a determinant region" associated with effective vaccine response. Besides, significant correlations between the proportion of plasmablasts and proliferating B cells and levels of anti-HBs were ascertained. Taken together, our data characterized the dynamics of HB vaccine-induced neutralizing antibodies against B-cell linear epitopes on SHBs and adaptive immune response, which will be constructive to develop the next-generation vaccine.
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Affiliation(s)
- Shihong Zhong
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhipeng Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tianling Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xin Fu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ling Guo
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Peking University Shenzhen Hospital, Shenzhen, China
| | - Shuqin Gu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Libo Tang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yongyin Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Vakili ME, Faghih Z, Sarvari J, Doroudchi M, Hosseini SN, Kabelitz D, Kalantar K. Lower frequency of T stem cell memory (TSCM) cells in hepatitis B vaccine nonresponders. Immunol Res 2022; 70:469-480. [PMID: 35445310 PMCID: PMC9273562 DOI: 10.1007/s12026-022-09278-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/01/2022] [Indexed: 11/25/2022]
Abstract
Despite the availability of an effective vaccine and antiviral treatments, hepatitis B is still a global public health problem. Hepatitis B vaccination can prevent the disease. Vaccination induces long-lasting protective immune memory, and the identification of memory cell subsets can indicate the effectiveness of vaccines. Here, we compared the frequency of CD4+ memory T cell subsets between responders and nonresponders to HB vaccination. Besides, the frequency of IFN-γ+ memory T cells was compared between studied groups. Study participants were grouped according to their anti-HBsAb titer. For restimulation of CD4+ memory T cells, peripheral blood mononuclear cells (PBMCs) were cultured in the presence of HBsAg and PHA for 48 h. Besides, PMA, ionomycin, and brefeldin were added during the last 5 h of incubation to induce IFN-γ production. Flow cytometry was used for analysis. There was a statistically significant difference in the frequency of CD4+CD95+, CD4+CD95Hi, and CD4+CD95low/med T stem cell memory (TSCM) cells between responder and nonresponder groups. However, the comparison of the frequency of memory T cells producing IFN-γ showed no differences. Our results identified a possible defect of immunological CD4+ memory T cell formation in nonresponders due to their lower frequency of CD4+ TSCM cells.
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Affiliation(s)
- Mahsa Eshkevar Vakili
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Faghih
- School of Medicine, Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jamal Sarvari
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Nezamedin Hosseini
- Department of Recombinant Hepatitis B Vaccine, Production and Research Complex, Pasteur Institute of Iran, Tehran, Iran
| | - Dieter Kabelitz
- Institute of Immunology, Christian-Albrechts University of Kiel and University Hospital Schleswig, Holstein Campus Kiel, 24105, Kiel, Germany.
| | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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9
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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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10
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Humoral immunity in hepatitis B virus infection: Rehabilitating the B in HBV. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100398. [PMID: 35059620 PMCID: PMC8760517 DOI: 10.1016/j.jhepr.2021.100398] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/15/2022]
Abstract
Insights into the immunopathogenesis of chronic HBV infections are fundamental in the quest for novel treatment approaches aimed at a functional cure. While much is known about the ineffective HBV-specific T-cell responses that characterise persistent HBV replication, B cells have been left largely understudied. However, an important role for humoral immunity during the natural history of HBV infections, as well as after functional cure, has been inadvertently revealed by the occurrence of HBV flares following B cell-depleting treatments. Herein, we review our current understanding of the role of the humoral immune response in chronic HBV, both at the level of HBV-specific antibody production and at the phenotypic and broader functional level of B cells. The recent development of fluorescently labelled HBV proteins has given us unprecedented insights into the phenotype and function of HBsAg- and HBcAg-specific B cells. This should fuel novel research into the mechanisms behind dysfunctional HBsAg-specific and fluctuating, possibly pathogenic, HBcAg-specific B-cell responses in chronic HBV. Finally, novel immunomodulatory treatments that partly target B cells are currently in clinical development, but a detailed assessment of their impact on HBV-specific B-cell responses is lacking. We plead for a rehabilitation of B-cell studies related to both the natural history of HBV and treatment development programmes.
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11
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Swadling L, Diniz MO, Schmidt NM, Amin OE, Chandran A, Shaw E, Pade C, Gibbons JM, Le Bert N, Tan AT, Jeffery-Smith A, Tan CCS, Tham CYL, Kucykowicz S, Aidoo-Micah G, Rosenheim J, Davies J, Johnson M, Jensen MP, Joy G, McCoy LE, Valdes AM, Chain BM, Goldblatt D, Altmann DM, Boyton RJ, Manisty C, Treibel TA, Moon JC, van Dorp L, Balloux F, McKnight Á, Noursadeghi M, Bertoletti A, Maini MK. Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2. Nature 2022; 601:110-117. [PMID: 34758478 PMCID: PMC8732273 DOI: 10.1038/s41586-021-04186-8] [Citation(s) in RCA: 281] [Impact Index Per Article: 93.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022]
Abstract
Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4-11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication-transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.
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Affiliation(s)
- Leo Swadling
- Division of Infection and Immunity, University College London, London, UK.
| | - Mariana O Diniz
- Division of Infection and Immunity, University College London, London, UK
| | - Nathalie M Schmidt
- Division of Infection and Immunity, University College London, London, UK
| | - Oliver E Amin
- Division of Infection and Immunity, University College London, London, UK
| | - Aneesh Chandran
- Division of Infection and Immunity, University College London, London, UK
| | - Emily Shaw
- Division of Infection and Immunity, University College London, London, UK
| | - Corinna Pade
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Joseph M Gibbons
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Nina Le Bert
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore
| | - Anthony T Tan
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore
| | - Anna Jeffery-Smith
- Division of Infection and Immunity, University College London, London, UK
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Cedric C S Tan
- UCL Genetics Institute, University College London, London, UK
| | - Christine Y L Tham
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore
| | | | | | - Joshua Rosenheim
- Division of Infection and Immunity, University College London, London, UK
| | - Jessica Davies
- Division of Infection and Immunity, University College London, London, UK
| | - Marina Johnson
- Great Ormond Street Institute of Child Health NIHR Biomedical Research Centre, University College London, London, UK
| | - Melanie P Jensen
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Department of Cellular Pathology, Northwest London Pathology, Imperial College London NHS Trust, London, UK
| | - George Joy
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Institute of Cardiovascular Science, University College London, London, UK
| | - Laura E McCoy
- Division of Infection and Immunity, University College London, London, UK
| | - Ana M Valdes
- Academic Rheumatology, Clinical Sciences, Nottingham City Hospital, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Benjamin M Chain
- Division of Infection and Immunity, University College London, London, UK
| | - David Goldblatt
- Great Ormond Street Institute of Child Health NIHR Biomedical Research Centre, University College London, London, UK
| | - Daniel M Altmann
- Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Rosemary J Boyton
- Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK
- Lung Division, Royal Brompton & Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Charlotte Manisty
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Institute of Cardiovascular Science, University College London, London, UK
| | - Thomas A Treibel
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Institute of Cardiovascular Science, University College London, London, UK
| | - James C Moon
- Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
- Institute of Cardiovascular Science, University College London, London, UK
| | - Lucy van Dorp
- UCL Genetics Institute, University College London, London, UK
| | | | - Áine McKnight
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mahdad Noursadeghi
- Division of Infection and Immunity, University College London, London, UK
| | - Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore, Singapore
- Singapore Immunology Network, A*STAR, Singapore, Singapore
| | - Mala K Maini
- Division of Infection and Immunity, University College London, London, UK.
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12
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Hui BB, Padeniya TN, Rebuli N, Gray RT, Wood JG, Donovan B, Duan Q, Guy R, Hocking JS, Lahra MM, Lewis DA, Whiley DM, Regan DG, Seib KL. A gonococcal vaccine has the potential to rapidly reduce the incidence of Neisseria gonorrhoeae infection among urban men who have sex with men. J Infect Dis 2021; 225:983-993. [PMID: 34894134 PMCID: PMC8922007 DOI: 10.1093/infdis/jiab581] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Background A gonococcal vaccine is urgently needed due to increasing gonorrhea incidence and emerging multidrug-resistant gonococcal strains worldwide. Men who have sex with men (MSM) have among the highest incidences of gonorrhea and may be a key target population for vaccination when available. Methods An individual-based, anatomical site-specific mathematical model was used to simulate Neisseria gonorrhoeae transmission in a population of 10 000 MSM. The impact of vaccination on gonorrhea prevalence was assessed. Results With a gonococcal vaccine of 100% or 50% protective efficacy, gonorrhea prevalence could be reduced by 94% or 62%, respectively, within 2 years if 30% of MSM are vaccinated on presentation for sexually transmitted infection (STI) testing. Elimination of gonorrhea is possible within 8 years with vaccines of ≥ 50% efficacy lasting 2 years, providing a booster vaccination is available every 3 years on average. A vaccine’s impact may be reduced if it is not effective at all anatomical sites. Conclusions Our study indicates that with a vaccine of modest efficacy and an immunization strategy that targets MSM presenting for STI screening, the prevalence of gonorrhea in this population could be rapidly and substantially reduced.
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Affiliation(s)
- Ben B Hui
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | | | - Nic Rebuli
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Richard T Gray
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - James G Wood
- School of Population Health, UNSW Sydney, Sydney, NSW, Australia
| | - Basil Donovan
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Qibin Duan
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.,School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Rebecca Guy
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Jane S Hocking
- Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
| | - Monica M Lahra
- Microbiology Department, New South Wales Health Pathology, The Prince of Wales Hospital, Randwick, NSW, Australia.,School of Medical Sciences, UNSW Sydney, NSW, Australia
| | - David A Lewis
- Western Sydney Sexual Health Centre, Western Sydney Local Health District, Parramatta, NSW, Australia.,Westmead Clinical School, Faculty of Health and Medicine & Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Westmead, NSW, Australia.,Division of Medical Virology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - David M Whiley
- Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia
| | - David G Regan
- The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Kate L Seib
- Institute for Glycomics, Griffith University, QLD Australia
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13
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Pappas SC. Hepatitis B and Health Care Workers. Clin Liver Dis 2021; 25:859-874. [PMID: 34593158 DOI: 10.1016/j.cld.2021.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Owing to standard precautions and initiatives for universal hepatitis B virus (HBV) vaccination in the general population and health care workers, risk of transmission of HBV infection from the patient to a health care worker (and vice versa) is very low. The need for mandatory HBV screening and vaccination in health care workers is less clear than in the past. Health care workers with chronic HBV infection neither require restrictions on professional practice nor disclosure of infection status to a patient. Further study is required to develop effective revaccination strategies to manage health care workers who are vaccine nonresponders.
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Affiliation(s)
- Stephen C Pappas
- Ben Taub General Hospital, 5th Fl, 5-PO 71 002b, 1504 Ben Taub Loop, Houston, TX 77030, USA.
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14
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Cornberg M, Sandmann L, Protzer U, Niederau C, Tacke F, Berg T, Glebe D, Jilg W, Wedemeyer H, Wirth S, Höner Zu Siederdissen C, Lynen-Jansen P, van Leeuwen P, Petersen J. S3-Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) zur Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion – (AWMF-Register-Nr. 021-11). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:691-776. [PMID: 34255317 DOI: 10.1055/a-1498-2512] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Markus Cornberg
- Deutsches Zentrum für Infektionsforschung (DZIF), Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover; Centre for individualised infection Medicine (CiiM), Hannover.,Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Ulrike Protzer
- Institut für Virologie, Technische Universität München/Helmholtz Zentrum München, München
| | | | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin
| | - Thomas Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig
| | - Dieter Glebe
- Institut für Medizinische Virologie, Nationales Referenzzentrum für Hepatitis-B-Viren und Hepatitis-D-Viren, Justus-Liebig-Universität Gießen, Gießen
| | - Wolfgang Jilg
- Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensberg, Regensburg
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
| | - Stefan Wirth
- Zentrum für Kinder- und Jugendmedizin, Helios Universitätsklinikum Wuppertal, Wuppertal
| | | | - Petra Lynen-Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Pia van Leeuwen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin
| | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St. Georg, Hamburg
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15
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Santoro JD, Saucier LE, Tanna R, Wiegand SE, Pagarkar D, Tempchin AF, Khoshnood M, Ahsan N, Van Haren K. Inadequate Vaccine Responses in Children With Multiple Sclerosis. Front Pediatr 2021; 9:790159. [PMID: 34926358 PMCID: PMC8678906 DOI: 10.3389/fped.2021.790159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/10/2021] [Indexed: 01/05/2023] Open
Abstract
Objective: Immunizations against Hepatitis B virus (HBV) and Varicella Zoster virus (VZV), are recommended for patients with pediatric onset multiple sclerosis (POMS) and may be required prior to initiation of some disease modifying therapies. However, the efficacy of routine vaccine administration in POMS has never been studied. We sought to assess the humoral mediated vaccine response to HBV and VZV in children with POMS. Methods: A multi-center retrospective chart-based review of 62 patients with POMS was performed. Clinical data and antibody titers against HBV and VZV were collected prior to initiation of disease modifying therapy or steroids and compared to institutional control data, using t-test and chi squared analysis. Results: There were low rates of immunity against both HBV and VZV (33 and 25% respectively) among individuals with POMS. Fifteen individuals (24%) were non-immune to both. Compared to institutional control data, individuals with POMS were significantly less likely to be immune to and HBV (p = 0.003, 95% CI: 0.22-0.75) and VZV (p < 0.001, 95% CI: 0.09-0.39). Interpretation: Individuals with POMS have low rates of antibody-mediated immunity against HBV and VZV, despite receiving the appropriate vaccinations. This suggests an association between POMS and systemic immune dysregulation although further study is needed.
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Affiliation(s)
- Jonathan D Santoro
- Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Laura E Saucier
- Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
| | - Runi Tanna
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Sarah E Wiegand
- Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Dania Pagarkar
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Adam F Tempchin
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Mellad Khoshnood
- Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Nusrat Ahsan
- Division of Neurology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, United States.,Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Keith Van Haren
- Department of Neurology, Stanford University School of Medicine, Stanford, CA, United States
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16
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SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 2020; 584:457-462. [PMID: 32668444 DOI: 10.1038/s41586-020-2550-z] [Citation(s) in RCA: 1450] [Impact Index Per Article: 290.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/07/2020] [Indexed: 12/11/2022]
Abstract
Memory T cells induced by previous pathogens can shape susceptibility to, and the clinical severity of, subsequent infections1. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to 'common cold' human-associated coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.
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17
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Komatsu H, Klenerman P, Thimme R. Discordance of hepatitis B vaccination policies for healthcare workers between the USA, the UK, and Germany. Hepatol Res 2020; 50:272-282. [PMID: 31845478 DOI: 10.1111/hepr.13470] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/04/2019] [Accepted: 12/08/2019] [Indexed: 02/08/2023]
Abstract
The hepatitis B (HB) vaccine is effective for the prevention of HB virus infection. It has been widely accepted that an anti-HB surface antibody (HBs) level ≥10 mIU/mL is protective against HB virus infection. Although transient infection can occur in individuals who attain a peak level of anti-HBs ≥10 mIU/mL after primary vaccination, long-term follow-up studies show that successful primary vaccination can prevent individuals from acute clinical hepatitis and chronic infection. Healthcare workers (HCWs) are at-risk individuals. Based on the accumulated data, the USA considers an anti-HBs level ≥10 mIU/mL to constitute successful vaccination for HCWs. In contrast, because some anti-HBs assays cannot accurately measure in the low anti-HBs range, including 10 mIU/mL, the UK and Germany consider an anti-HBs level ≥100 mIU/mL to constitute successful vaccination for HCWs. In the USA and UK, a booster dose is unnecessary for HCWs after successful vaccination. In Germany, anti-HBs testing is recommended for HCWs who are at particularly high individual exposure risk 10 years after successful primary immunization, and a booster dose is offered if the anti-HBs level has declined to ˂100 mIU/mL. The differences in the goal of HB vaccination, reliability of anti-HBs assays, and use of booster vaccination cause discordance in HB vaccination policies for HCWs.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Chiba, Japan
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Robert Thimme
- Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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18
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De Schryver A, Lambaerts T, Lammertyn N, François G, Bulterys S, Godderis L. European survey of hepatitis B vaccination policies for healthcare workers: An updated overview. Vaccine 2020; 38:2466-2472. [PMID: 32057571 DOI: 10.1016/j.vaccine.2020.02.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 01/30/2020] [Accepted: 02/02/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND The risk of transmission of bloodborne pathogens, including hepatitis B virus (HBV) to healthcare workers (HCWs) is well known. In 2005 we performed a survey on HBV prevention in HCWs in the European Union (EU). An update of the 2005 survey deemed necessary as an EU Council Directive (2010/32/EU) on sharps injuries was to be implemented into national legislation by 11 May 2013 and more countries were starting universal HBV vaccination. METHODS We performed an electronic survey in 2016, among national representatives from the Occupational Medicine section of the European Union of Medical Specialists (UEMS), to find out how policies have been put into practice in the European Union countries (plus Norway and Switzerland). The data were updated in 2019. RESULTS Answers were received from 21 countries (among them 19 EU Member States), representing 78% of the population and 60% of HCWs in the EU-28. HBV vaccination was mandatory for medical and nursing staff in 10 countries; for other paramedical staff, medical and nursing students in 9 countries; for paramedical students in 8 countries; for cleaning staff in 7 countries; and for technical staff in 5 countries; it was recommended in all but one of other countries. Serotesting before vaccination was done in 7 countries. The vaccination schedule most often used was 0, 1, 6 months (18countries), monovalent HBV vaccine was used in 14 countries, and combined (HAV + HBV) vaccine in 11 countries. Serotesting after vaccination was done in 18 countries and boosters were recommended in 14 countries. A non-responder policy was present in 18 countries. HBV vaccination coverage (5 countries) was 70-95%. Sharps injuries were reported in 13 countries, nationwide in 7 of them; European-wide reporting was not mentioned by respondents. DISCUSSION These results show the variation in the implementation of EU legislation in the participating countries. More consultation between actors at EU level, including enhancing medical surveillance in occupational medicine could help to optimise policies in European countries in order to further reduce HBV transmission to HCWs.
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Affiliation(s)
- Antoon De Schryver
- Department of Epidemiology and Social Medicine, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium; IDEWE Occupational Services, Interleuvenlaan 58, BE 3001 Leuven, Belgium.
| | - Tom Lambaerts
- IDEWE Occupational Services, Interleuvenlaan 58, BE 3001 Leuven, Belgium
| | - Nathalie Lammertyn
- IDEWE Occupational Services, Interleuvenlaan 58, BE 3001 Leuven, Belgium
| | - Guido François
- Department of Epidemiology and Social Medicine, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium
| | - Simon Bulterys
- IDEWE Occupational Services, Interleuvenlaan 58, BE 3001 Leuven, Belgium
| | - Lode Godderis
- IDEWE Occupational Services, Interleuvenlaan 58, BE 3001 Leuven, Belgium; Department of Public Health and Primary Care, KU Leuven, Kapucijnenvoer 35 blok d, bus 7001, BE 3000 Leuven, Belgium
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19
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Van Damme P, Dionne M, Leroux‐Roels G, Van Der Meeren O, Di Paolo E, Salaun B, Surya Kiran P, Folschweiller N. Persistence of HBsAg-specific antibodies and immune memory two to three decades after hepatitis B vaccination in adults. J Viral Hepat 2019; 26:1066-1075. [PMID: 31087382 PMCID: PMC6852111 DOI: 10.1111/jvh.13125] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 04/11/2019] [Accepted: 04/23/2019] [Indexed: 12/18/2022]
Abstract
The duration of protection after hepatitis B vaccination is not exactly known. This phase IV study evaluated antibody persistence and immune memory 20-30 years after adult immunization with recombinant hepatitis B vaccine (HBsAg vaccine, Engerix-B) in routine clinical practice. Men and women 40-60 years old, with documented evidence of vaccination with three or four HBsAg vaccine doses 20-30 years earlier and without subsequent booster, were enrolled and received HBsAg vaccine as challenge dose. HBsAg-specific antibodies (anti-HBs) and frequencies of HBsAg-specific circulating memory B cells and CD4+ T cells expressing combinations of activation markers (CD40L, IL2, IFNγ, TNFα) were measured prechallenge, 7 and 30 days postchallenge. Of 101 participants in the according-to-protocol cohort for immunogenicity, 90.1% had anti-HBs concentrations ≥ 10 mIU/mL prechallenge administration; 84.2% and 100% mounted an anamnestic response 7 and 30 days postchallenge, respectively. HBsAg-specific memory B and CD4+ T cells expressing at least two activation markers were low prechallenge and increased markedly postchallenge. These results suggest sustained immune memory and long-term protection 20-30 years after a complete primary HBsAg vaccination course during adulthood, in line with current recommendations that a booster is not needed in fully vaccinated immunocompetent adults.
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Affiliation(s)
- Pierre Van Damme
- Centre for the Evaluation of Vaccination (CEV)Vaccine & Infectious Disease Institute (VAXINFECTIO)University of AntwerpWilrijkBelgium
| | - Marc Dionne
- Centre Hospitalier Universitaire de Québec‐Université LavalQuebec CityQuebecCanada
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20
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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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21
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Cheng Y, Zhu YO, Becht E, Aw P, Chen J, Poidinger M, de Sessions PF, Hibberd ML, Bertoletti A, Lim SG, Newell EW. Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection. Sci Immunol 2019; 4:4/32/eaau6905. [DOI: 10.1126/sciimmunol.aau6905] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022]
Abstract
Associations between chronic antigen stimulation, T cell dysfunction, and the expression of various inhibitory receptors are well characterized in several mouse and human systems. During chronic hepatitis B virus (HBV) infection (CHB), T cell responses are blunted with low frequencies of virus-specific T cells observed, making these parameters difficult to study. Here, using mass cytometry and a highly multiplexed combinatorial peptide–major histocompatibility complex (pMHC) tetramer strategy that allows for the detection of rare antigen-specific T cells, we simultaneously probed 484 unique HLA-A*1101–restricted epitopes spanning the entire HBV genome on T cells from patients at various stages of CHB. Numerous HBV-specific T cell populations were detected, validated, and profiled. T cells specific for two epitopes (HBVpol387and HBVcore169) displayed differing and complex heterogeneities that were associated with the disease progression, and the expression of inhibitory receptors on these cells was not linearly related with their extent of T cell dysfunction. For HBVcore169-specific CD8+T cells, we found cellular markers associated with long-term memory, polyfunctionality, and the presence of several previously unidentified public TCR clones that correlated with viral control. Using high-dimensional trajectory analysis of these cellular phenotypes, a pseudo-time metric was constructed that fit with the status of viral infection in corresponding patients. This was validated in a longitudinal cohort of patients undergoing antiviral therapy. Our study uncovers complex relationships of inhibitory receptors between the profiles of antigen-specific T cells and the status of CHB with implications for new strategies of therapeutic intervention.
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Osiowy C. From infancy and beyond… ensuring a lifetime of hepatitis B virus (HBV) vaccine-induced immunity. Hum Vaccin Immunother 2018; 14:2093-2097. [PMID: 29641290 PMCID: PMC6150009 DOI: 10.1080/21645515.2018.1462428] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Despite the long-term efficacy and immune persistence observed following HBV vaccination of infants, the need for a booster dose following infant immunization continues to be deliberated. Evidence from HBV booster dose response studies and long-term immunization program reviews are the basis for the recommendation that a vaccine booster is not necessary. However, further studies continue to emerge and highlight the need for standardization among observational studies in order to appropriately compare outcomes. There is an assumption that neonatal and infant (within 12 months of age) vaccine immune responses are equivalent; however, evidence exists for distinct vaccine responses within the first year of life. HBV vaccine programs have evolved over time, particularly regarding the type and dosage of vaccine used. Several universal neonatal immunization programs initially incorporated a 2.5 μg dosage (Recombivax-HB, Merck). This dosage has been shown in multiple long-term studies and meta-analyses to be associated with a lower primary response, decreased antibody persistence over time, and a reduced booster response 10 to 20 years following immunization. Ongoing surveillance of this and other HBV neonatally-vaccinated populations, particularly in low endemic regions, is necessary to understand the impact on long-term protection in order to ensure lifelong protection against hepatitis B infection.
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Affiliation(s)
- Carla Osiowy
- a National Microbiology Laboratory , Public Health Agency of Canada , Winnipeg , Manitoba , Canada
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23
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Corti D, Benigni F, Shouval D. Viral envelope-specific antibodies in chronic hepatitis B virus infection. Curr Opin Virol 2018; 30:48-57. [PMID: 29738926 DOI: 10.1016/j.coviro.2018.04.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/26/2018] [Accepted: 04/02/2018] [Indexed: 12/20/2022]
Abstract
While the cellular immune response associated with acute and chronic HBV infection has been thoroughly studied, the B cell response in chronic hepatitis B and the role of antibodies raised against the HBV envelope antigens in controlling and prevention of infection requires further investigation. The detection of anti-HBs antibodies is considered as one of the biomarkers for functional cure of chronic hepatitis B virus infection, as well as for protective immunity. Indeed, vaccine-induced neutralizing anti-HBs antibodies have been shown to protect against HBV challenge. Yet, the therapeutic potential of viral envelope-specific antibodies and the mechanism involved in protection and prevention of cell-to-cell transmission warrants additional investigative efforts. In this review, we will provide a critical overview of the available preclinical and clinical literature supporting the putative role of active and passive vaccination and neutralizing envelope-specific antibodies for therapeutic intervention in combination regimens intended to cure persistent HBV infection.
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Affiliation(s)
- Davide Corti
- Humabs BioMed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.
| | - Fabio Benigni
- Humabs BioMed SA, A Subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
| | - Daniel Shouval
- Liver Unit, Institute for Gastroenterology and Hepatology, Hadassah-Hebrew University Hospital, P.O. Box 12000, 91120 Jerusalem, Israel.
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24
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Souza FDO, de Araújo TM. Occupational exposure and hepatitis B vaccination among health care workers. Rev Bras Med Trab 2018; 16:36-43. [PMID: 32270072 PMCID: PMC7104817 DOI: 10.5327/z1679443520180091] [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: 09/14/2017] [Accepted: 01/31/2018] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Through its vaccination schedules, the National Immunization Program ensures immunization against hepatitis B gratis to health care professionals at high risk for infection at the workplace. OBJECTIVE To analyze the association between variables related to occupational exposure and complete hepatitis B vaccination schedule. METHOD Cross-sectional study with 3,084 primary care and medium complexity health care workers from five municipalities in the state of Bahia, Brazil. RESULTS The factors associated with complete hepatitis B vaccination schedule on bivariate analysis were: contact with biological materials, preparation of medications, use of personal protective equipment (PPE), search for orientation after a work accident and skill demands. CONCLUSIONS Workers in the health sector resist adhering to some preventive measures. Strategies to encourage vaccination might be enhanced by creating room for discussion at work on the burden to which employees are exposed. Plans and policies for workers' health should be formulated in the light of governmental policies set for the overall population.
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Affiliation(s)
- Fernanda de Oliveira Souza
- Health Department, Health, Education and Work Unit, Federal University of Recôncavo da Bahia (Universidade Federal do Recôncavo da Bahia - UFRB) - Santo Antônio de Jesus (BA), Brazil.
| | - Tânia Maria de Araújo
- Health Department, Epidemiology Unit, Graduate Program in Collective Health, State University of Feira de Santana (Universidade Estadual de Feira de Santana - UEFS)- Feira de Santana (BA), Brazil.
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25
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Block TM, Locarnini S, McMahon BJ, Rehermann B, Peters MG. Use of Current and New Endpoints in the Evaluation of Experimental Hepatitis B Therapeutics. Clin Infect Dis 2018; 64:1283-1288. [PMID: 28200098 DOI: 10.1093/cid/cix129] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 02/10/2017] [Indexed: 12/15/2022] Open
Abstract
New hepatitis B virus (HBV) therapies are expected to have breakthrough benefit for patients. HBV functional cure is sustained hepatitis B surface antigen loss and anti-HBs gain, with normalization of serum aminotransferases off therapy. Virologic or complete cure additionally includes loss of HBV covalently closed circular DNA. Currently available endpoints of therapy are inadequate to evaluate the efficacy of many of the new therapeutics. Therefore, either new ways of using the existing virologic endpoints and laboratory values or entirely new biomarkers are needed. In this review, we discuss the currently used endpoints, potential new endpoints, as well as what new markers are needed to assess the ability of HBV therapeutics to achieve functional and virologic cure in various phases of HBV infection. In addition, we discuss how patient selection from differing phases of HBV impacts the choice of HBV drug(s) needed to achieve cure.
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Affiliation(s)
- Timothy M Block
- Hepatitis B Foundation and Baruch S. Blumberg Institute, Doylestown, Pennsylvania, USA
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, Australia
| | | | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Marion G Peters
- Department of Medicine, University of California, San Francisco, USA
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26
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27
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Hepatitis C cross-genotype immunity and implications for vaccine development. Sci Rep 2017; 7:12326. [PMID: 28951612 PMCID: PMC5615075 DOI: 10.1038/s41598-017-10190-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/02/2017] [Indexed: 01/03/2023] Open
Abstract
While about a quarter of individuals clear their primary hepatitis C (HCV) infections spontaneously, clearance (spontaneous or treatment-induced) does not confer sterilizing immunity against a future infection. Since successful treatment does not prevent future infections either, an effective vaccine is highly desirable in preventing HCV (re)infection. However, development of an effective vaccine has been complicated by the diversity of HCV genotypes, and complexities in HCV immunological responses. Smaller studies on humans and chimpanzees reported seemingly opposing results regarding cross-neutralizing antibodies. We report a lack of cross-genotype immunity in the largest cohort of people to date. In the adjusted Cox proportional hazards model, reinfection with a heterologous HCV genotype (adjusted Hazard Ratio [aHR]: 0.45, 95% CI: 0.25–0.84) was associated with a 55% lower likelihood of re-clearance. Among those who cleared their first infection spontaneously, the likelihood of re-clearance was 49% lower (aHR: 0.51, 95% CI: 0.27–0.94) when reinfected with a heterologous HCV genotype. These findings indicate that immunity against a particular HCV genotype does not offer expanded immunity to protect against subsequent infections with a different HCV genotype. A prophylactic HCV vaccine boosted with multiple HCV genotype may offer a broader and more effective protection.
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28
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HBV/HCV dual infection impacts viral load, antibody response, and cytokine expression differently from HBV or HCV single infection. Sci Rep 2016; 6:39409. [PMID: 28009018 PMCID: PMC5180099 DOI: 10.1038/srep39409] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 11/23/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus/hepatitis C virus (HBV/HCV) dual infection is common among high-risk individuals. To characterize the virological and immunological features of patients with HBV/HCV dual infection, we enrolled 1,049 individuals who have been identified as injection drug users. Patients were divided into single and dual infection groups according to the serological markers. We found the average HCV RNA level was significantly lower; however, HBV viral load was significantly higher in HBV/HCV dual-infected patients (n = 42) comparing HCV single infection (n = 340) or HBV single infection (n = 136). The level of anti-HBs in patients who experienced spontaneous HBV clearance was higher than that in HCV single-infected patients with HBV spontaneous clearance. The level of anti-HCV E2 in HBV/HCV dual infection was lower than that detected in HCV single infection. Serum levels of IL-6, IL-8, and TNF-α were significantly lower in HBV/HCV dual-infected patients than in patients infected with HBV or HCV alone. Taken together, two viral replications are imbalanced in dual infected patients. The anti-HBs and anti-HCV E2 antibody production were impaired and proinflammatory IL-6, IL-8, and TNF-α also downregulated due to dual infection. These findings will help further understanding the pathogenesis of HBV/HCV dual infection.
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29
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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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30
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Abstract
Hepatitis B virus is a worldwide leading cause of acute and chronic liver disease including cirrhosis and hepatocellular carcinoma. Effective vaccines have been available since the early '80s. Vaccination against hepatitis B virus infection has proved highly successful in reducing the disease burden, the development of the carrier state and the hepatitis B-related morbidity and mortality in the countries where vaccination has been implemented. Despite success and efficacy of preventive vaccines, a huge number of chronically infected patients still remain. Therapeutic vaccination may prove to be useful coupled with current antivirals and other immunomodulatory approaches to treat these patients. This review summarizes current unresolved issues and future perspectives on vaccination required for global cure of hepatitis B virus infection.
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Affiliation(s)
- Marie-Louise Michel
- Laboratoire PVHB, Bâtiment Lwoff, Inserm U994, Institut Pasteur, 28, rue du Docteur Roux, 75015 Paris, France
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31
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Simons BC, Spradling PR, Bruden DJT, Zanis C, Case S, Choromanski TL, Apodaca M, Brogdon HD, Dwyer G, Snowball M, Negus S, Bruce MG, Morishima C, Knall C, McMahon BJ. A Longitudinal Hepatitis B Vaccine Cohort Demonstrates Long-lasting Hepatitis B Virus (HBV) Cellular Immunity Despite Loss of Antibody Against HBV Surface Antigen. J Infect Dis 2016; 214:273-80. [PMID: 27056956 DOI: 10.1093/infdis/jiw142] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 04/01/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Long-lasting protection resulting from hepatitis B vaccine, despite loss of antibody against hepatitis B virus (HBV) surface antigen (anti-HBs), is undetermined. METHODS We recruited persons from a cohort vaccinated with plasma-derived hepatitis B vaccine in 1981 who have been followed periodically since. We performed serological testing for anti-HBs and microRNA-155 and assessed HBV-specific T-cell responses by enzyme-linked immunospot and cytometric bead array. Study subgroups were defined 32 years after vaccination as having an anti-HBs level of either ≥10 mIU/mL (group 1; n = 13) or <10 mIU/mL (group 2; n = 31). RESULTS All 44 participants, regardless of anti-HBs level, tested positive for tumor necrosis factor α, interleukin 10, or interleukin 6 production by HBV surface antigen-specific T cells. The frequency of natural killer T cells correlated with the level of anti-HBs (P = .008). The proportion of participants who demonstrated T-cell responses to HBV core antigen varied among the cytokines measured, suggesting some natural exposure to HBV in the study group. No participant had evidence of breakthrough HBV infection. CONCLUSIONS Evidence of long-lasting cellular immunity, regardless of anti-HBs level, suggests that protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 32 years.
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Affiliation(s)
- Brenna C Simons
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC) WWAMI School of Medical Education, College of Health, University of Alaska Anchorage
| | - Philip R Spradling
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC, Atlanta, Georgia
| | - Dana J T Bruden
- Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC)
| | - Carolyn Zanis
- Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC)
| | - Samantha Case
- Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC)
| | | | - Minjun Apodaca
- Department of Laboratory Medicine, University of Washington, Seattle
| | - Hazel D Brogdon
- WWAMI School of Medical Education, College of Health, University of Alaska Anchorage
| | - Gaelen Dwyer
- WWAMI School of Medical Education, College of Health, University of Alaska Anchorage
| | - Mary Snowball
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium
| | - Susan Negus
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium
| | - Michael G Bruce
- Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC)
| | - Chihiro Morishima
- Department of Laboratory Medicine, University of Washington, Seattle
| | - Cindy Knall
- WWAMI School of Medical Education, College of Health, University of Alaska Anchorage
| | - Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium Arctic Investigations Program, Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC)
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32
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Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol 2016; 64:S71-S83. [PMID: 27084039 DOI: 10.1016/j.jhep.2016.01.026] [Citation(s) in RCA: 352] [Impact Index Per Article: 39.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 01/12/2016] [Accepted: 01/25/2016] [Indexed: 02/06/2023]
Abstract
During hepatitis B virus (HBV) infection, the presence of HBV-specific antibody producing B cells and functional HBV-specific T cells (with helper or cytotoxic effects) ultimately determines HBV infection outcome. In this review, in addition to summarizing the present state of knowledge of HBV-adaptive immunity, we will highlight controversies and uncertainties concerning the HBV-specific B and T lymphocyte response, and propose future directions for research aimed at the generation of more efficient immunotherapeutic strategies.
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Affiliation(s)
- Antonio Bertoletti
- Emerging Infectious Diseases (EID) Program, Duke-NUS Medical School, Singapore; Viral Hepatitis Laboratory, Singapore Institute for Clinical Sciences, Agency of Science Technology and Research (A*STAR), Singapore.
| | - Carlo Ferrari
- Divisione Malattie Infettive, Ospdale Maggiore Parma, Parma, Italy
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33
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Brunskole Hummel I, Zitzmann A, Erl M, Wenzel JJ, Jilg W. Characteristics of immune memory 10-15 years after primary hepatitis B vaccination. Vaccine 2015; 34:636-642. [PMID: 26718687 DOI: 10.1016/j.vaccine.2015.12.033] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/08/2015] [Accepted: 12/11/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND AIMS The definition of immune memory after hepatitis B vaccination is still under debate. Therefore, we analysed hepatitis B surface antigen (HBsAg)-specific memory in more detail by investigating the kinetics of humoral and cellular responses after hepatitis B booster vaccination. METHODS The anti-HBs kinetics of 23 individuals with anti-HBs titres below 10 IU/l, who had been vaccinated 10-15 years ago, was monitored at day 0, 3, 7, 14 and 28 after booster vaccination. HBsAg-specific IFNγ- and IL5-secreting cells in enriched CD4(+) fraction were measured at day 0, 7 and 28 post-booster by enzyme-linked immunospot assay (ELISpot). RESULTS 22 of 23 subjects showed similar anti-HBs kinetic curves, including 3 of 4 subjects who did not reach anti-HBs titres of 10 IU/l. The steep anti-HBs increase started between day 3 and 7 and peaked around day 14. A plateau or only minimal changes were visible between day 14 and 28. 17.4% of subjects showed pre-booster cellular responses, and this rate had increased to 47.8% and 56.5% after 7 and 28 days, respectively. The kinetic patterns of T cell responses differed considerably among subjects. A dominance of Th2 responses (IL5 secretion) over Th1 responses (IFNγ secretion) could be observed. CONCLUSIONS The presence of B cell memory could be shown by a typical anamnestic anti-HBs response curve after a booster dose in all but one individual. In contrast, T cell responses to booster vaccination, which occurred in approximately 50% of participants, were rather heterogeneous.
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Affiliation(s)
- Irena Brunskole Hummel
- Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany.
| | - Anita Zitzmann
- Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany.
| | - Monika Erl
- Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany.
| | - Jürgen J Wenzel
- Institute of Clinical Microbiology and Hygiene, University Medical Centre Regensburg, 93053 Regensburg, Germany.
| | - Wolfgang Jilg
- Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany.
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34
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Friedrich P, Sattler A, Müller K, Nienen M, Reinke P, Babel N. Comparing Humoral and Cellular Immune Response Against HBV Vaccine in Kidney Transplant Patients. Am J Transplant 2015; 15:3157-65. [PMID: 26137874 DOI: 10.1111/ajt.13380] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 04/20/2015] [Accepted: 05/09/2015] [Indexed: 01/25/2023]
Abstract
Host protection upon vaccination usually results from the complex interplay of humoral and cellular components of the immune system. Exploring hepatitis B surface antigen (HBsAg)-specific T cell responses and their correlation with humoral responses under immunosuppression, we analyzed 51 renal transplant recipients, differing in HBV vaccine-specific antibody titers (non [NRs]-, low [LRs]-, and high responders [HRs]) and in 22 healthy controls (HCs) in a cross-sectional study. HBsAg-specific T cells were analyzed by flow cytometry according to expression of activation markers CD40L and/or CD69, and the cytokines IFNγ, IL-2, TNFα, and IL-17. No significant differences in responder rate and magnitude of HBsAg-specific T cell responses were found between HCs and HRs. Interestingly, HBsAg-specific Th-cells were also observed in 50% of humoral NRs. Frequencies of HBsAg-specific CD40L+ Th-cells were significantly higher in HRs compared to LRs (p = 0.009) and in LRs in comparison to NRs (p = 0.043). All but NRs showed a predominance of multi-potent HBsAg-specific TNFα+IL-2+ Th-cells. As expected, HBsAg-specific CD8(+) T cells were rarely found. In conclusion, mounting of hepatitis B vaccine-specific T cell responses is possible in kidney transplant recipients despite immunosuppression. Detection of HBV-specific Th-cells in a significant proportion of humoral NRs contributes to the current discussion on conferring immune protection by cellular memory in such patients.
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Affiliation(s)
- P Friedrich
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Berlin, Germany
| | - A Sattler
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Berlin, Germany
| | - K Müller
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Berlin, Germany
| | - M Nienen
- Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, Bochum, Germany
| | - P Reinke
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Berlin, Germany.,Department of Nephrology, Charité University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany
| | - N Babel
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Berlin, Germany.,Medical Clinic I, Marien Hospital Herne, Ruhr University Bochum, Bochum, Germany
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35
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Wang Q, Sachse P, Semmo M, Lokhande M, Montani M, Dufour JF, Zoulim F, Klenerman P, Semmo N. T- and B-cell responses and previous exposure to hepatitis B virus in 'anti-HBc alone' patients. J Viral Hepat 2015; 22:1068-78. [PMID: 26075501 DOI: 10.1111/jvh.12428] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 04/30/2015] [Indexed: 12/18/2022]
Abstract
A serologic response to hepatitis B virus (HBV) defined as 'anti-HBc alone' is commonly observed, but its significance remains unclear. This study aimed to define the relationship between 'anti-HBc alone' serostatus and HBV infection, including HBV-specific T- and B-cell memory responses. We enrolled 31 'anti-HBc alone' patients. Total HBV DNA and cccDNA were tested by nested polymerase chain reaction (PCR) analysis in liver samples from 22 'anti-HBc alone' patients vs controls (chronic or resolved HBV infection), followed by HBsAg/HBcAg immunohistochemical (IHC) staining. IFN-γ secretion by HBV-specific T cells was compared in individuals who were 'anti-HBc alone' (n = 27), resolved HBV (n = 21), chronic HBV (n = 24) and 12 healthy controls using enzyme-linked immunospot (ELISpot) assays. An HBsAg-IgG B-cell ELISpot assay was performed in 'anti-HBc alone' patients before and after one dose of recombinant HBsAg vaccine. The majority (23/31, 74.2%) of the 'anti-HBc alone' individuals were co-infected with HCV. Infrequent intrahepatic total HBV DNA (2/22, 9.1%) and cccDNA (1/22, 4.5%) were detected in biopsies; HBsAg and HBcAg IHC staining was negative. HBV-specific T-cell responses were similar between 'anti-HBc alone' individuals and HBV resolvers. Circulating HBV-memory B-cell responses were detected in all 'anti-HBc alone' individuals, consistent with an HBsAg-specific memory pool. After one HBV vaccine dose, increased anti-HBs antibody levels were observed, accompanied by an expansion of HBsAg-specific memory B cells (P = 0.0226). 'Anti-HBc alone' individuals showed HBV-specific T-cell and memory B-cell responses typical of previous viral exposure and protective memory, suggesting a resolved infection.
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Affiliation(s)
- Q Wang
- Hepatology, Department of Clinical Research, Inselspital, University of Bern, Bern, Switzerland.,State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - P Sachse
- Hepatology, Department of Clinical Research, Inselspital, University of Bern, Bern, Switzerland
| | - M Semmo
- Department of Nephrology, Inselspital, University of Bern, Bern, Switzerland
| | - M Lokhande
- Hepatology, Department of Clinical Research, Inselspital, University of Bern, Bern, Switzerland.,Department of Hepatology, Inselspital, University Clinic of Visceral Surgery and Medicine, Bern, Switzerland
| | - M Montani
- Institute of Pathology, Inselspital, University of Bern, Bern, Switzerland
| | - J-F Dufour
- Hepatology, Department of Clinical Research, Inselspital, University of Bern, Bern, Switzerland.,Department of Hepatology, Inselspital, University Clinic of Visceral Surgery and Medicine, Bern, Switzerland
| | - F Zoulim
- Inserm, U1052, UMR CNRS 5268, Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | - P Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - N Semmo
- Hepatology, Department of Clinical Research, Inselspital, University of Bern, Bern, Switzerland.,Department of Hepatology, Inselspital, University Clinic of Visceral Surgery and Medicine, Bern, Switzerland
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36
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Rybczynska J, Campbell K, Kamili S, Locarnini S, Krawczynski K, Walker CM. CD4+ T Cells Are Not Required for Suppression of Hepatitis B Virus Replication in the Liver of Vaccinated Chimpanzees. J Infect Dis 2015; 213:49-56. [PMID: 26324781 DOI: 10.1093/infdis/jiv348] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 06/12/2015] [Indexed: 01/12/2023] Open
Abstract
Humans vaccinated with hepatitis B virus (HBV) surface antigen (HBsAg) sometimes develop humoral and cellular immunity to HBV proteins such as core and polymerase that are not vaccine components, providing indirect evidence that vaccine-induced immunity is not sterilizing. We previously described CD4(+) T-cell immunity against HBsAg and polymerase in chimpanzees after vaccination and HBV challenge. Here, vaccinated chimpanzees with protective levels of anti-HBsAg antibodies were rechallenged with HBV after antibody-mediated CD4(+) T-cell depletion. HBV DNA was detected in liver for at least 3 months after rechallenge, but virus replication was suppressed, as revealed by the absence of HBV DNA and HBsAg in serum. These observations provide direct virological evidence for nonsterilizing immunity in individuals with anti-HBsAg antibodies and are consistent with translation of HBV proteins to prime immune responses. They also indicate that CD4(+) T cells were not required for suppression of HBV replication in previously vaccinated individuals.
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Affiliation(s)
- Jolanta Rybczynska
- Department of Pathology, Medical University of Warsaw, Poland Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | | | - Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Stephen Locarnini
- Victorian Infectious Disease Reference Laboratory, North Melbourne, Australia
| | - Krzysztof Krawczynski
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Christopher M Walker
- Center for Vaccines and Immunity, Nationwide Children's Hospital Department of Pediatrics, College of Medicine, The Ohio State University, Columbus
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Vanwolleghem T, Hou J, van Oord G, Andeweg AC, Osterhaus ADME, Pas SD, Janssen HLA, Boonstra A. Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells. Hepatology 2015; 62:87-100. [PMID: 25808668 DOI: 10.1002/hep.27805] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 03/20/2015] [Indexed: 12/11/2022]
Abstract
UNLABELLED To identify immunological mechanisms that govern distinct clinical phases of a chronic hepatitis B virus (HBV) infection-immune tolerant (IT), immune active (IA), inactive carrier (IC), and hepatitis B e antigen (HBeAg)-negative (ENEG) hepatitis phases-we performed a systems biology study. Serum samples from untreated chronic HBV patients (n = 71) were used for multiplex cytokine measurements, quantitative hepatitis B surface antigen (HBsAg), HBeAg levels, HBV genotype, and mutant analysis. Leukocytes were phenotyped using multicolor flow cytometry, and whole-blood transcriptome profiles were generated. The latter were compared with liver biopsy transcriptomes from IA (n = 16) and IT (n = 3) patients. HBV viral load as well as HBeAg and HBsAg levels (P < 0.001), but not leukocyte composition, differed significantly between distinct phases. Serum macrophage chemotactic protein 1, interleukin-12p40, interferon (IFN)-gamma-inducible protein 10, and macrophage inflammatory protein 1 beta levels were different between two or more clinical phases (P < 0.05). Comparison of blood transcriptomes identified 64 differentially expressed genes. The gene signature distinguishing IA from IT and IC patients was predominantly composed of highly up-regulated immunoglobulin-encoding genes. Modular repertoire analysis using gene sets clustered according to similar expression patterns corroborated the abundant expression of B-cell function-related genes in IA patients and pointed toward increased (ISG) transcript levels in IT patients, compared to subsequent phases. Natural killer cell activities were clustered in clinical phases with biochemical liver damage (IA and ENEG phases), whereas T-cell activities were higher in all phases, compared to IT patients. B-cell-related transcripts proved to be higher in biopsies from IA versus IT patients. CONCLUSION HBV clinical phases are characterized by distinct blood gene signatures. Innate IFN and B-cell responses are highly active during the IT and IA phases, respectively. This suggests that the presumed immune tolerance in chronic HBV infections needs to be redefined.
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Affiliation(s)
- Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Jun Hou
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Gertine van Oord
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Arno C Andeweg
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - A D M E Osterhaus
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Suzan D Pas
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.,Liver Clinic, University Health Network, Toronto, Ontario, Canada
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
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38
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Said ZNA, Abdelwahab KS. Induced immunity against hepatitis B virus. World J Hepatol 2015; 7:1660-1670. [PMID: 26140085 PMCID: PMC4483547 DOI: 10.4254/wjh.v7.i12.1660] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 01/15/2015] [Accepted: 05/27/2015] [Indexed: 02/06/2023] Open
Abstract
Prevention of hepatitis B virus (HBV) infection with its consequent development of HBV chronic liver disease and hepatocellular carcinoma is a global mandatory goal. Fortunately, safe and effective HBV vaccines are currently available. Universal hepatitis B surface antigen HBV vaccination coverage is almost done. Growing knowledge based upon monitoring and surveillance of HBV vaccination programs has accumulated and the policy of booster vaccination has been evaluated. This review article provides an overview of the natural history of HBV infection, immune responses and the future of HBV infection. It also summarizes the updated sources, types and uses of HBV vaccines, whether in the preclinical phase or in the post-field vaccination.
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Affiliation(s)
- Zeinab Nabil Ahmed Said
- Zeinab Nabil Ahmed Said, Kouka Saadeldin Abdelwahab, Department of Microbiology and Immunology, Faculty of Medicine (for girls), Al-Azhar University, Cairo 11754, Egypt
| | - Kouka Saadeldin Abdelwahab
- Zeinab Nabil Ahmed Said, Kouka Saadeldin Abdelwahab, Department of Microbiology and Immunology, Faculty of Medicine (for girls), Al-Azhar University, Cairo 11754, Egypt
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39
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Prophylactic vaccination against hepatitis B: achievements, challenges and perspectives. Med Microbiol Immunol 2014; 204:39-55. [PMID: 25523195 DOI: 10.1007/s00430-014-0373-y] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 10/01/2014] [Indexed: 02/06/2023]
Abstract
Large-scale vaccination against hepatitis B virus (HBV) infection started in 1984 with first-generation vaccines made from plasma of chronic carriers containing HBV surface antigen (HBsAg). Thereafter, it was replaced in most countries by second-generation vaccines manufactured in yeast cells transformed with gene S encoding HBsAg. Both generations of vaccines have been applied for universal neonate and early childhood vaccination worldwide and have led to a 70-90 % decrease in chronic HBV carrier rates. However, 10-30% of newborns from HBsAg/HBeAg-positive mothers cannot be protected by passive/active vaccination alone and become chronic HBV carriers themselves. Asymptomatic occult HBV infections are frequent even in those who have protective levels of anti-HBs. Suboptimal protection may be due to heterologous HBsAg subtypes that are present in 99% of HBV carriers worldwide. Second-generation vaccines contain partially misfolded HBsAg and lack preS1 antigen that carries the major HBV attachment site and neutralizing epitopes. Third-generation vaccines produced in mammalian cells contain correctly folded HBsAg and neutralizing epitopes of the preS antigens, induce more rapid protection, overcome nonresponse to second-generation vaccines and, most importantly, may provide better protection for newborns of HBV-positive mothers. PreS/S vaccines expressed in mammalian cells are more expensive to manufacture, but introduction of more potent HBV vaccines should be considered in regions with a high rate of vertical transmission pending assessment of health economics and healthcare priorities. With optimal vaccines and vaccination coverage, eradication of HBV would be possible.
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40
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Mosaad M, Al Nozha OM, Yamany H, Amer S. A survey of hepatitis B immune status of Taibah University medical students. J Taibah Univ Med Sci 2014. [DOI: 10.1016/j.jtumed.2014.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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41
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Gara N, Abdalla A, Rivera E, Zhao X, Werner JM, Liang TJ, Hoofnagle JH, Rehermann B, Ghany MG. Durability of antibody response against hepatitis B virus in healthcare workers vaccinated as adults. Clin Infect Dis 2014; 60:505-13. [PMID: 25389254 DOI: 10.1093/cid/ciu867] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Follow-up studies of recipients of hepatitis B vaccine from endemic areas have reported loss of antibody to hepatitis B surface antigen (anti-HBs) in a high proportion of persons vaccinated at birth. In contrast, the long-term durability of antibody in persons vaccinated as adults in nonendemic areas is not well defined. We aimed to assess the durability of anti-HBs among healthcare workers (HCWs) vaccinated as adults and response to a booster among those without protective levels of antibody. METHODS Adult HCWs aged 18-60 at the time of initial vaccination were recruited. All were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and anti-HBs level. HCWs with anti-HBs <12 mIU/mL were offered a booster and levels were measured 1, 7, and 21 days afterward. RESULTS Anti-HBs levels were <12 mIU/mL in 9 of 50 (18%), 13 of 50 (26%), and 14 of 59 (24%) HCWs 10-15, 16-20, and >20 years postvaccination, respectively, (P = ns). Four HCWs were anti-HBc positive; none had HBsAg. By logistic regression, older age at vaccination was the only predictor of inadequate anti-HBs level (P = .0005). Thirty-four of 36 subjects with inadequate anti-HBs levels received a booster and 32 (94%) developed levels >12 mIU/mL within 3 weeks. CONCLUSIONS Anti-HBs levels decrease after 10-31 years and fall below a level considered protective in approximately 25% of cases. The rapid and robust response to a booster vaccine suggests a long-lasting amnestic response. Hepatitis B vaccination provides long-term protection against hepatitis B and booster vaccination does not appear to be necessary in HCWs. Clinical Trials Registration. NCT01182311.
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Affiliation(s)
| | | | | | | | | | | | - Jay H Hoofnagle
- Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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42
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Zaffina S, Marcellini V, Santoro AP, Scarsella M, Camisa V, Vinci MR, Musolino AM, Nicolosi L, Rosado MM, Carsetti R. Repeated vaccinations do not improve specific immune defenses against Hepatitis B in non-responder health care workers. Vaccine 2014; 32:6902-6910. [PMID: 25444815 DOI: 10.1016/j.vaccine.2014.10.066] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 09/22/2014] [Accepted: 10/27/2014] [Indexed: 01/28/2023]
Abstract
Hepatitis B is a major infectious occupational hazard for health care workers and can be prevented with a safe and effective vaccine. The serum titer of anti-HBsAg antibodies is the most commonly used correlate of protection and post-vaccination anti-HBsAg concentrations of ≥ 10 mIU/ml are considered protective. Subjects with post-vaccination anti-HBsAg titers of <10 mIU/ml 1-6 months post-vaccination, who tested negative for HBsAg and anti-HBc, are defined as non-responders. The question of whether non-responders should be repeatedly vaccinated is still open. The aim of the study was to (i) evaluate the distribution of lymphocyte subpopulations and the percentage of HBsAg-specific memory B cells in responders and non-responders (ii) assess whether non-responders can be induced to produce antibodies after administration of a booster dose of vaccine (iii) determine whether booster vaccination increases the number of specific memory B cells in non-responders. Combining flow-cytometry, ELISPOT and serology we tested the integrity and function of the immune system in 24 health care workers, confirmed to be non-responders after at least three vaccine injections. We compared the results with those obtained in 21 responders working in the same institution. We found that the great majority of the non-responders had a functional immune system and a preserved ability to respond to other conventional antigens. Our most important findings are that the frequency of HBsAg-specific memory B cells is comparable in non-responders and controls and that booster immunization does not lead either to antibody production or memory B cell increase in non-responders.
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Affiliation(s)
- Salvatore Zaffina
- Health Technology Assessment & Safety Research Unit and Occupational Medicine Service, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - Valentina Marcellini
- Immunology Unit, Immunology and Pharmacotherapy Research Area, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - Anna Paola Santoro
- Health Technology Assessment & Safety Research Unit and Occupational Medicine Service, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - Marco Scarsella
- Immunology Unit, Immunology and Pharmacotherapy Research Area, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - Vincenzo Camisa
- Health Technology Assessment & Safety Research Unit and Occupational Medicine Service, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - Maria Rosaria Vinci
- Health Technology Assessment & Safety Research Unit and Occupational Medicine Service, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - Anna Maria Musolino
- Paediatric Emergency Department, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - Luciana Nicolosi
- Department of Pediatrics, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy
| | - M Manuela Rosado
- Immunology Unit, Immunology and Pharmacotherapy Research Area, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy.
| | - Rita Carsetti
- Immunology Unit, Immunology and Pharmacotherapy Research Area, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy; Diagnostic Immunology Unit, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCSS, Piazza S. Onofrio 4, 00165 Roma, Italy.
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43
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Loras C, Gisbert JP, Saro MC, Piqueras M, Sánchez-Montes C, Barrio J, Ordás I, Montserrat A, Ferreiro R, Zabana Y, Chaparro M, Fernández-Bañares F, Esteve M. Impact of surveillance of hepatitis b and hepatitis c in patients with inflammatory bowel disease under anti-TNF therapies: multicenter prospective observational study (REPENTINA 3). J Crohns Colitis 2014; 8:1529-38. [PMID: 25052345 DOI: 10.1016/j.crohns.2014.06.009] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 06/11/2014] [Accepted: 06/27/2014] [Indexed: 02/08/2023]
Abstract
AIMS Assess IBD patients starting anti-TNF for the impact of preventive measures in HBV and/or HCV, and the predictive response factors to HBV vaccination. METHODS Multicenter prospective study including 389 IBD patients. Four interventions were established: I-1) anti-HBs <100IU/L: HBV vaccination with double doses at 0-1-2months, and revaccination if titres <100IU/L (seroprotection defined as anti-HBs10-100IU/L and effective vaccination anti-HBs >100IU/L); I-2) anti-HBs >100IU/L (previous effective vaccination): monitoring levels; I-3) anti-HBc and/or HCV+: analysis every two months; I-4) HBsAg+: start anti-virals. RESULTS I-1 and I-2) For first vaccination, effective vaccination and seroprotection were obtained in 26.4% and 43.5%, and for revaccination 31.3% and 44.4%, respectively. Predictive factors of effective vaccination were age ≤30years (OR=2.2) and being vaccinated simultaneously with anti-TNF (OR=5.2) instead of late vaccination, whereas age ≤30years (OR=2.6) and anti-TNF monotherapy (OR=2.4) were predictive for seroprotection. 80.8% of patients previously vaccinated maintained titres at 29months follow-up. The only factor related to maintaining titres was previous vaccination versus achieving effective vaccination during anti-TNF (HR=2.49); I-3 and I-4) HBV-DNA + without reactivation was detected in 7% of 29 anti-HBc. No reactivation was found in the remaining HCV (n=5) or HBsAg (n=4) patients. CONCLUSIONS 1) Response to vaccination/revaccination is low in patients with anti-TNF. Young patients vaccinated at the beginning of anti-TNF and receiving it as a monotheraphy showed better response. 2) Long-lasting effective vaccination is greatest in patients previously vaccinated. 3) Following-up the established surveillance and/or preventive anti-viral therapy seems to be safe in HBV and HCV patients.
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Affiliation(s)
- C Loras
- Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, Fundació per la Recerca Mútua de Terrassa, Terrassa, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - J P Gisbert
- Department of Gastroenterology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - M C Saro
- Department of Gastroenterology, Hospital de Cabueñes, Gijón, Asturias, Spain
| | - M Piqueras
- Department of Gastroenterology, Consorci Sanitari de Terrassa, Catalonia, Spain
| | - C Sánchez-Montes
- Department of Gastroenterology, Hospital Universitari la Fe, Valencia, Spain
| | - J Barrio
- Department of Gastroenterology, Hospital Universitario Río Hortega, Valladolid, Spain
| | - I Ordás
- Department of Gastroenterology, Hospital Clínic, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - A Montserrat
- Department of Gastroenterology, Hospital de Sabadell, Corporació Sanitària i Universitària Parc Taulí de Sabadell, Catalonia, Spain
| | - R Ferreiro
- Department of Gastroenterology, Hospital Santiago de Compostela, Santiago de Compostela, Galicia, Spain
| | - Y Zabana
- Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, Fundació per la Recerca Mútua de Terrassa, Terrassa, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - M Chaparro
- Department of Gastroenterology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - F Fernández-Bañares
- Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, Fundació per la Recerca Mútua de Terrassa, Terrassa, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - M Esteve
- Department of Gastroenterology, Hospital Universitari Mútua de Terrassa, Fundació per la Recerca Mútua de Terrassa, Terrassa, Catalonia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
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Glebe D, König A. Molecular virology of hepatitis B virus and targets for antiviral intervention. Intervirology 2014; 57:134-40. [PMID: 25034480 DOI: 10.1159/000360946] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The members of the viral family Hepadnaviridae comprise one of the smallest enveloped DNA viruses and cause acute and chronic infections in mammals and birds, leading to large virus and antigen loads in the blood. They have a restricted host range and depend on differentiated hepatocytes for replication. Hepatitis B virus (HBV) is the prototype of the Hepadnaviridae. HBV can persist in infected hepatocytes and has evolved elaborate strategies to evade the immune system. HBV replicates like HIV (family of Retroviridae) via reverse transcription. Drugs licensed for inhibition of HIV reverse transcriptase lower the viral load of chronic HBV patients, but they do not cure the infection. HBV genomes are archived in the nucleus of hepatocytes as episomal DNA before reverse transcription. In contrast, the RNA genome of HIV first needs reverse transcription before proviral integration within the host genome. Wild-type HBV remains relatively stable in chronic HBV patients during the immunotolerant state, but is able to evolve mutants rapidly upon selective pressure due to therapy or immune reactions. Current therapies for chronic hepatitis B are far from optimal. To extend therapeutic options, further studies on HBV and its interaction with the host are urgently needed.
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Affiliation(s)
- Dieter Glebe
- Institute of Medical Virology, Justus Liebig University Giessen, National Reference Center for Hepatitis B and D Viruses, German Center for Infection Research (DZIF), Biomedical Research Center Seltersberg, Giessen, Germany
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