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Marjani A, Alavian SM, Nassiri Toosi M, Alavian SH, Abazari MF, Khamseh A, Jazayeri SM. Hepatitis B virus infection after immunization: How serious it is? An updated review. Clin Exp Med 2025; 25:113. [PMID: 40210771 PMCID: PMC11985588 DOI: 10.1007/s10238-025-01645-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/19/2025] [Indexed: 04/12/2025]
Abstract
Infection with hepatitis B virus (HBV) is one of the significant challenges worldwide. Despite the availability of antiviral drugs against this virus, the most critical strategy to prevent HBV infection is HB vaccination. Basically, despite widespread conventional HB vaccination, due to various reasons, including waning of hepatitis B surface antibody (HBsAb) titer after vaccination, the emergence of vaccine-escape mutants, failure to respond to the vaccine due to viral and host factors, levels of response in high-risk individuals and non-responders to conventional HB vaccination remains a major, unsolved and severe concern. This review focuses on the underlying reasons for conventional hepatitis B vaccination failures. It also suggests solutions to overcome these failures by highlighting significant advances in vaccination, including hepatitis B third-generation vaccines and adjuvanted hepatitis B vaccines as efficient alternatives to second-generation vaccines. Potentially, these new strategies will compensate for the shortcomings caused by second-generation vaccines. Adherence to these denouements has a significant role in preventing the circulation of HBV among individuals and reducing the global burden of HBV-related diseases.
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Affiliation(s)
- Arezoo Marjani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohssen Nassiri Toosi
- Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Foad Abazari
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
- Division of Medical Sciences, Island Medical Program, University of British Columbia, Victoria, BC, Canada
| | - Azam Khamseh
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Science, Shiraz, Iran
| | - Seyed Mohammad Jazayeri
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran.
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Bello N, Hudu SA, Alshrari AS, Imam MU, Jimoh AO. Overview of Hepatitis B Vaccine Non-Response and Associated B Cell Amnesia: A Scoping Review. Pathogens 2024; 13:554. [PMID: 39057781 PMCID: PMC11279426 DOI: 10.3390/pathogens13070554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND The advent of the hepatitis B vaccine has achieved tremendous success in eradicating and reducing the burden of hepatitis B infection, which is the main culprit for hepatocellular carcinoma-one of the most fatal malignancies globally. Response to the vaccine is achieved in about 90-95% of healthy individuals and up to only 50% in immunocompromised patients. This review aimed to provide an overview of hepatitis B vaccine non-response, the mechanisms involved, B cell amnesia, and strategies to overcome it. METHODS Databases, including Google Scholar, PubMed, Scopus, Cochrane, and ClinicalTrials.org, were used to search and retrieve articles using keywords on hepatitis B vaccine non-response and B cell amnesia. The PRISMA guideline was followed in identifying studies, screening, selection, and reporting of findings. RESULTS A total of 133 studies on hepatitis B vaccine non-response, mechanisms, and prevention/management strategies were included in the review after screening and final selection. Factors responsible for hepatitis B vaccine non-response were found to include genetic, immunological factors, and B cell amnesia in healthy individuals. The genetic factors were sex, HLA haplotypes, and genetic polymorphisms in immune response markers (cytokines). Non-response was common in conditions of immunodeficiency, such as renal failure, haemodialysis, celiac disease, inflammatory bowel disease, hepatitis C co-infection, and latent hepatitis B infection. Others included diabetes mellitus and HIV infection. The mechanisms involved were impaired immune response by suppression of response (T helper cells) or induced suppression of response (through regulatory B and T cells). DISCUSSION A comprehensive and careful understanding of the patient factors and the nature of the vaccine contributes to developing effective preventive measures. These include revaccination or booster dose, vaccine administration through the intradermal route, and the use of adjuvants in the vaccine.
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Affiliation(s)
- Nura Bello
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840232, Nigeria;
- Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria 810107, Nigeria
| | - Shuaibu A. Hudu
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
- Department of Medical Microbiology and Parasitology, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840232, Nigeria
| | - Ahmed S. Alshrari
- Medical Laboratory Technology Department, Faculty of Applied Medical Science, Northern Border University, Arar 91431, Saudi Arabia;
| | - Mustapha U. Imam
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto 840232, Nigeria;
| | - Abdulgafar O. Jimoh
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840232, Nigeria;
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3
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Laganà A, Visalli G, Di Pietro A, Facciolà A. Vaccinomics and adversomics: key elements for a personalized vaccinology. Clin Exp Vaccine Res 2024; 13:105-120. [PMID: 38752004 PMCID: PMC11091437 DOI: 10.7774/cevr.2024.13.2.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/07/2024] [Accepted: 03/12/2024] [Indexed: 05/18/2024] Open
Abstract
Vaccines are one of the most important and effective tools in the prevention of infectious diseases and research about all the aspects of vaccinology are essential to increase the number of available vaccines more and more safe and effective. Despite the unquestionable value of vaccinations, vaccine hesitancy has spread worldwide compromising the success of vaccinations. Currently, the main purpose of vaccination campaigns is the immunization of whole populations with the same vaccine formulations and schedules for all individuals. A personalized vaccinology approach could improve modern vaccinology counteracting vaccine hesitancy and giving great benefits for human health. This ambitious purpose would be possible by facing and deepening the areas of vaccinomics and adversomics, two innovative areas of study investigating the role of a series of variables able to influence the immune response to vaccinations and the development of serious side effects, respectively. We reviewed the recent scientific knowledge about these innovative sciences focusing on genetic and non-genetic basis involved in the individual response to vaccines in terms of both immune response and side effects.
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Affiliation(s)
- Antonio Laganà
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
- Istituto Clinico Polispecialistico C.O.T., Cure Ortopediche Traumatologiche S.P.A., Messina, Italy
| | - Giuseppa Visalli
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Angela Di Pietro
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Alessio Facciolà
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
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Alamad B, Elliott K, Knight JC. Cross-population applications of genomics to understand the risk of multifactorial traits involving inflammation and immunity. CAMBRIDGE PRISMS. PRECISION MEDICINE 2024; 2:e3. [PMID: 38549844 PMCID: PMC10953767 DOI: 10.1017/pcm.2023.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/15/2023] [Accepted: 12/18/2023] [Indexed: 04/26/2024]
Abstract
The interplay between genetic and environmental factors plays a significant role in interindividual variation in immune and inflammatory responses. The availability of high-throughput low-cost genotyping and next-generation sequencing has revolutionized our ability to identify human genetic variation and understand how this varies within and between populations, and the relationship with disease. In this review, we explore the potential of genomics for patient benefit, specifically in the diagnosis, prognosis and treatment of inflammatory and immune-related diseases. We summarize the knowledge arising from genetic and functional genomic approaches, and the opportunity for personalized medicine. The review covers applications in infectious diseases, rare immunodeficiencies and autoimmune diseases, illustrating advances in diagnosis and understanding risk including use of polygenic risk scores. We further explore the application for patient stratification and drug target prioritization. The review highlights a key challenge to the field arising from the lack of sufficient representation of genetically diverse populations in genomic studies. This currently limits the clinical utility of genetic-based diagnostic and risk-based applications in non-Caucasian populations. We highlight current genome projects, initiatives and biobanks from diverse populations and how this is being used to improve healthcare globally by improving our understanding of genetic susceptibility to diseases and regional pathogens such as malaria and tuberculosis. Future directions and opportunities for personalized medicine and wider application of genomics in health care are described, for the benefit of individual patients and populations worldwide.
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Affiliation(s)
- Bana Alamad
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Kate Elliott
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Julian C. Knight
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Chinese Academy of Medical Science Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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5
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Narciso-Schiavon JL, Schiavon LDL. Hepatitis B and Celiac Disease: a cause for concern? REVISTA COLOMBIANA DE GASTROENTEROLOGÍA 2023; 38:479-485. [DOI: 10.22516/25007440.1016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Some theories suggest that the development of the immune response to clear hepatitis B triggers the intestinal tissue damage seen in celiac disease in genetically predisposed individuals. Although the role of hepatitis B virus infection in the development of autoimmune diseases has been widely discussed in the literature, it remains a controversial topic. Our objective is to review whether there is an association between hepatitis B and celiac disease and the particularities of vaccination against hepatitis B in celiac patients.
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Dudley MZ, Gerber JE, Budigan Ni H, Blunt M, Holroyd TA, Carleton BC, Poland GA, Salmon DA. Vaccinomics: A scoping review. Vaccine 2023; 41:2357-2367. [PMID: 36803903 PMCID: PMC10065969 DOI: 10.1016/j.vaccine.2023.02.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 12/24/2022] [Accepted: 02/03/2023] [Indexed: 02/21/2023]
Abstract
BACKGROUND This scoping review summarizes a key aspect of vaccinomics by collating known associations between heterogeneity in human genetics and vaccine immunogenicity and safety. METHODS We searched PubMed for articles in English using terms covering vaccines routinely recommended to the general US population, their effects, and genetics/genomics. Included studies were controlled and demonstrated statistically significant associations with vaccine immunogenicity or safety. Studies of Pandemrix®, an influenza vaccine previously used in Europe, were also included, due to its widely publicized genetically mediated association with narcolepsy. FINDINGS Of the 2,300 articles manually screened, 214 were included for data extraction. Six included articles examined genetic influences on vaccine safety; the rest examined vaccine immunogenicity. Hepatitis B vaccine immunogenicity was reported in 92 articles and associated with 277 genetic determinants across 117 genes. Thirty-three articles identified 291 genetic determinants across 118 genes associated with measles vaccine immunogenicity, 22 articles identified 311 genetic determinants across 110 genes associated with rubella vaccine immunogenicity, and 25 articles identified 48 genetic determinants across 34 genes associated with influenza vaccine immunogenicity. Other vaccines had fewer than 10 studies each identifying genetic determinants of their immunogenicity. Genetic associations were reported with 4 adverse events following influenza vaccination (narcolepsy, GBS, GCA/PMR, high temperature) and 2 adverse events following measles vaccination (fever, febrile seizure). CONCLUSION This scoping review identified numerous genetic associations with vaccine immunogenicity and several genetic associations with vaccine safety. Most associations were only reported in one study. This illustrates both the potential of and need for investment in vaccinomics. Current research in this field is focused on systems and genetic-based studies designed to identify risk signatures for serious vaccine reactions or diminished vaccine immunogenicity. Such research could bolster our ability to develop safer and more effective vaccines.
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Affiliation(s)
- Matthew Z Dudley
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Institute for Vaccine Safety, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
| | - Jennifer E Gerber
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Survey Research Division, RTI International, Washington, DC, USA
| | - Haley Budigan Ni
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Office of Health Equity, California Department of Public Health, Richmond, CA, USA
| | - Madeleine Blunt
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Taylor A Holroyd
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; International Vaccine Access Center, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Bruce C Carleton
- Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Gregory A Poland
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA; Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN, USA
| | - Daniel A Salmon
- Department of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Institute for Vaccine Safety, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Department of Health, Behavior & Society, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
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Wang WC, Lin YS, Chang YF, Yeh CC, Su CT, Wu JS, Su FH. Association of HLA-DPA1, HLA-DPB1, and HLA-DQB1 Alleles With the Long-Term and Booster Immune Responses of Young Adults Vaccinated Against the Hepatitis B Virus as Neonates. Front Immunol 2021; 12:710414. [PMID: 34484213 PMCID: PMC8416438 DOI: 10.3389/fimmu.2021.710414] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 07/19/2021] [Indexed: 01/02/2023] Open
Abstract
The neonatal hepatitis B vaccination (HBVac) was implemented 35 years ago in Taiwan, but many vaccinees exhibit inadequate long-term vaccine-induced seroprotective hepatitis B surface antibody (anti-HBs) levels. We investigated the association of the human leukocyte antigen (HLA) alleles (DPA1, DPB1, DQA1, and DQB1) with the long-term immunological response to the neonatal HBVac and adolescent booster HBVac in a Taiwanese cohort. We divided 281 Han students (median age 22, age range 17–29 years) into the following groups: (1) Group A (n = 61): anti-HBs titer ≥ 10 mIU/mL at the beginning of the study; (2) Group B (n = 75): anti-HBs level > 1000 mIU/mL after the first booster; (3) Group C (n = 37): anti-HBs level < 10 mIU/mL after the first booster; and (4) Group D (n = 5): anti-HBs level < 10 mIU/mL after three boosters. DQA1, DQB1, DPA1, and DPB1 typing of the participants was performed using sequence-specific oligonucleotides. Associations of HLA alleles and haplotypes with effects on neonatal HBVac and booster HBVac were examined through logistic regression analysis and Fisher’s exact test. A false discovery rate-based measure of significance, the q-value, was used for multiple comparisons, and an association was considered significant if the corresponding q-value was < 0.1. DPA1 alleles were associated with the long-term immunological response to the neonatal HBVac. The estimated odds ratio (OR) of the lack of HBV protective immunity when carrying an additional DPA1*01 and DPA1*02 was 0.36 [95% confidence interval (CI) = 0.17–0.76, p = 0.0076] and 2.39 (95% CI = 1.17–4.87, p = 0.016), respectively. DPB1 and DQB1 alleles were associated with a response to the adolescent booster vaccination. The estimated ORs of being nonresponsive to the first booster when carrying an additional DPB1*05 and DQB1*02 were 2.11 (95% CI = 1.13–3.93, p = 0.019) and 3.73 (95% CI = 1.43–9.71, p = 0.0070), respectively. All DPB1*03 carriers responded to the first booster (p of Fisher’s exact test = 0.0045). In our study, we discovered that HLA-DPA1 was primarily associated with the long-term response of primary infantile HBVac, and HLA-DPB1 and HLA-DQB1 exhibited associations with the HBV booster vaccination.
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Affiliation(s)
- Wen-Chang Wang
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Shiang Lin
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan.,Department of Clinical Laboratory, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Yin-Fan Chang
- Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Ching Yeh
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.,School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan.,Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan.,Master Program in Applied Epidemiology, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Chien-Tien Su
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan.,Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Jin-Shang Wu
- Department of Family Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Family Medicine, National Cheng Kung University Hospital, Douliou Branch, College of Medicine, National Cheng Kung University, Yunlin, Taiwan.,Department of Family Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Fu-Hsiung Su
- Department of Family Medicine, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei City, Taiwan.,School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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8
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Ou G, Liu X, Jiang Y. HLA-DPB1 alleles in hepatitis B vaccine response: A meta-analysis. Medicine (Baltimore) 2021; 100:e24904. [PMID: 33832070 PMCID: PMC8036076 DOI: 10.1097/md.0000000000024904] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 01/31/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The role of the HLA-DRB1 and HLA-DQB1 genes in the antibody response to hepatitis B (HB) vaccine has been well established; however, the involvement of the HLA-DPB1 allele in the HB vaccine immune response remained to be clarified by a systematic review. METHODS A meta-analysis was performed in which databases were searched for relevant studies published in English or Chinese up until June 1, 2020. Six studies were identified and a total of 10 alleles were processed into statistical processing in this meta-analysis. RESULTS Three thousand one hundred forty four subjects (including 2477 responders and 667 non-responders) were included in this research. Alleles HLA-DPB1∗02:02, DPB1∗03:01, DPB1∗04:01, DPB1∗04:02, and DPB1∗14:01 were found to be associated with a significant increase in the antibody response to HB vaccine, and their pooled odds ratios (ORs) were 4.53, 1.57, 3.33, 4.20, and 1.79, respectively; whereas DPB1∗05:01 (OR = 0.73) showed the opposite correlation. CONCLUSIONS These findings suggested that specific HLA-DPB1 alleles are associated with the antibody response to HB vaccine.
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Affiliation(s)
- Guojin Ou
- Department of Laboratory Medicine, West China Second University Hospital, Chengdu, Sichuan
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, China
| | - Xiaojuan Liu
- Department of Laboratory Medicine, West China Second University Hospital, Chengdu, Sichuan
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, China
| | - Yongmei Jiang
- Department of Laboratory Medicine, West China Second University Hospital, Chengdu, Sichuan
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, China
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9
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Host genetics and infectious disease: new tools, insights and translational opportunities. Nat Rev Genet 2020; 22:137-153. [PMID: 33277640 PMCID: PMC7716795 DOI: 10.1038/s41576-020-00297-6] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2020] [Indexed: 12/22/2022]
Abstract
Understanding how human genetics influence infectious disease susceptibility offers the opportunity for new insights into pathogenesis, potential drug targets, risk stratification, response to therapy and vaccination. As new infectious diseases continue to emerge, together with growing levels of antimicrobial resistance and an increasing awareness of substantial differences between populations in genetic associations, the need for such work is expanding. In this Review, we illustrate how our understanding of the host–pathogen relationship is advancing through holistic approaches, describing current strategies to investigate the role of host genetic variation in established and emerging infections, including COVID-19, the need for wider application to diverse global populations mirroring the burden of disease, the impact of pathogen and vector genetic diversity and a broad array of immune and inflammation phenotypes that can be mapped as traits in health and disease. Insights from study of inborn errors of immunity and multi-omics profiling together with developments in analytical methods are further advancing our knowledge of this important area. Infectious diseases are an ever-present global threat. In this Review, Kwok, Mentzer and Knight discuss our latest understanding of how human genetics influence susceptibility to disease. Furthermore, they discuss emerging progress in the interplay between host and pathogen genetics, molecular responses to infection and vaccination, and opportunities to bring these aspects together for rapid responses to emerging diseases such as COVID-19.
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10
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Omersel J, Karas Kuželički N. Vaccinomics and Adversomics in the Era of Precision Medicine: A Review Based on HBV, MMR, HPV, and COVID-19 Vaccines. J Clin Med 2020; 9:E3561. [PMID: 33167413 PMCID: PMC7694388 DOI: 10.3390/jcm9113561] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/31/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Precision medicine approaches based on pharmacogenomics are now being successfully implemented to enable physicians to predict more efficient treatments and prevention strategies for a given disease based on the genetic background of the patient. This approach has already been proposed for vaccines, but research is lagging behind the needs of society, and precision medicine is far from being implemented here. While vaccinomics concerns the effectiveness of vaccines, adversomics concerns their side effects. This area has great potential to address public concerns about vaccine safety and to promote increased public confidence, higher vaccination rates, and fewer serious adverse events in genetically predisposed individuals. The aim here is to explore the contemporary scientific literature related to the vaccinomic and adversomic aspects of the three most-controversial vaccines: those against hepatitis B, against measles, mumps, and rubella, and against human Papilloma virus. We provide detailed information on the genes that encode human leukocyte antigen, cytokines and their receptors, and transcription factors and regulators associated with the efficacy and safety of the Hepatitis B and Measles, Mumps and Rubella virus vaccines. We also investigate the future prospects of vaccinomics and adversomics of a COVID-19 vaccine, which might represent the fastest development of a vaccine ever.
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Affiliation(s)
| | - Nataša Karas Kuželički
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia;
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11
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Kennedy RB, Ovsyannikova IG, Palese P, Poland GA. Current Challenges in Vaccinology. Front Immunol 2020; 11:1181. [PMID: 32670279 PMCID: PMC7329983 DOI: 10.3389/fimmu.2020.01181] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
The development of vaccines, which prime the immune system to respond to future infections, has led to global declines in morbidity and mortality from dreadful infectious communicable diseases. However, many pathogens of public health importance are highly complex and/or rapidly evolving, posing unique challenges to vaccine development. Several of these challenges include an incomplete understanding of how immunity develops, host and pathogen genetic variability, and an increased societal skepticism regarding vaccine safety. In particular, new high-dimensional omics technologies, aided by bioinformatics, are driving new vaccine development (vaccinomics). Informed by recent insights into pathogen biology, host genetic diversity, and immunology, the increasing use of genomic approaches is leading to new models and understanding of host immune system responses that may provide solutions in the rapid development of novel vaccine candidates.
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Affiliation(s)
- Richard B Kennedy
- Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, United States
| | - Inna G Ovsyannikova
- Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, United States
| | - Peter Palese
- Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Gregory A Poland
- Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN, United States
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12
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Yao Y, Yang H, Shi L, Liu S, Li C, Chen J, Zhou Z, Sun M, Shi L. HLA Class II Genes HLA-DRB1, HLA-DPB1, and HLA-DQB1 Are Associated With the Antibody Response to Inactivated Japanese Encephalitis Vaccine. Front Immunol 2019; 10:428. [PMID: 30906300 PMCID: PMC6418001 DOI: 10.3389/fimmu.2019.00428] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 02/18/2019] [Indexed: 01/31/2023] Open
Abstract
Aim: The objective of this study was to evaluate the association of the human leukocyte antigen (HLA) class II genes HLA-DRB1, HLA-DPB1, and HLA-DQB1 with the humoral immune response elicited by inactivated Japanese encephalitis (JE) vaccine (IJEV). Methods: A total of 373 individuals aged 3–12 years in the Inner Mongolia Autonomous Region in China, who received two doses of IJEV at 0 and 7 days, were enrolled in the current study. Based on the individuals' specific JE virus (JEV)-neutralizing antibodies (NAbs), they were divided into a seropositive and a seronegative group. HLA-DRB1, HLA-DPB1, and HLA-DQB1 were genotyped using a sequencing-based typing method. Next, the association of the HLA class II genes and their haplotypes with antibody response was evaluated. Results: Based on NAbs, a total of 161 individuals were classified as seropositive and 212 as seronegative. DQB1*02:01 was significantly associated with JEV seropositivity (P < 0.001, OR = 0.364, 95% CI: 0.221–0.600), while DQB1*02:02 was significantly associated with JEV seronegativity (P = 5.03 × 10−6, OR = 7.341, 95% CI: 2.876–18.736). The haplotypes DRB1*07:01-DPB1*04:01-DQB1*02:01, DRB1*15:01-DPB1*02:01-DQB1*06:02, DRB1*07:01-DQB1*02:01, and DPB1*02:01-DQB1*06:02 were very frequent in the seropositive group, while DRB1*07:01-DPB1*17:01-DQB1*02:02, DRB1*07:01-DQB1*02:02, and DPB1*17:01-DQB1*02:02 were very frequent in the seronegative group. The presence of DRB1*01:01, DRB1*04:05, DRB1*09:01, DRB1*12:02, DRB1*13:02, and DRB1*14:01 was associated with a higher geometric mean titer (GMT) of NAbs than that of DRB1*11:01 at the DRB1 locus (P < 0.05). At the DPB1 locus, the presence of DPB1*05:01 was associated with higher GMTs than that of DPB1*02:01 and DPB1*13:01 (P < 0.05), and the presence of DPB1*04:01 and DPB1*09:01 was associated with higher GMTs than that of DPB1*13:01 (P < 0.05). Conclusions: The present study suggests that HLA class II genes may influence the antibody response to IJEV.
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Affiliation(s)
- Yufeng Yao
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Huijuan Yang
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China.,Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Disease, Kunming, China
| | - Lei Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China.,Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Disease, Kunming, China
| | - Shuyuan Liu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Chuanying Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Jun Chen
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Ziyun Zhou
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
| | - Mingbo Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China.,Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Disease, Kunming, China
| | - Li Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
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Yukimasa N, Sato S, Oboshi W, Watanabe T, Uzawa R. Influence of single nucleotide polymorphisms of cytokine genes on anti-HBs antibody production after hepatitis B vaccination in a Japanese young adult population. THE JOURNAL OF MEDICAL INVESTIGATION 2017; 63:256-61. [PMID: 27644568 DOI: 10.2152/jmi.63.256] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Hepatitis B (HB) vaccination is one of the most efficient tools to prevent the transmission of the virus. Considerable variability exists in HB vaccine responses, with 5-10% of healthy Japanese adults demonstrating no response following a standard vaccination. Recently, polymorphisms of immune-regulatory genes, such as cytokine genes, have been reported to influence the immune response to HB vaccine. The aim of this study was to investigate the underlying mechanisms of the genetic association between several cytokine gene polymorphisms and the immune response to HB vaccination in a Japanese population. One hundred and twenty three vaccinated young adults were classified according to the level of antibody-titer (anti-HBs). Single nucleotide polymorphism typing for IFN-γ (+874, 3'-UTR), IL-10 (-591, -819, -1082), and TNF-α (-308, -857), was accomplished using the PCR-RFLP or SSP-PCR method. The TNF-α (-857) CC type and the IL-10 (-1082) AG type were present more frequently in the low titer group than in the high titer group. The TNF-α (-857) CC type was found to be significantly associated with low response of serum anti-HBs. The anti-HBs antibody was not readily produced in the IL-10 (-1082) AG and TNF-α (-857) CC haplotype. Conversely, the antibody was readily produced in the IL-10 (-1082) AA and TNF-α (-857) CC haplotype, and the IL-10 (-1082) AA and TNF-α (-857) CT haplotype, suggesting a high likelihood of the IL-10 (-1082) AG type to be included in the low anti-HBs group, and high anti-HBs antibody production in those with the TNF-α (-857) CT type. These SNPs may produce ethnically-specific differences in the immune response to HB vaccine in the Japanese population. J. Med. Invest. 63: 256-261, August, 2016.
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Affiliation(s)
- Nobuyasu Yukimasa
- Graduate School of Health Sciences, Kagawa Prefectural University of Health Sciences
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Minimal association of alleles of human leukocyte antigen class II gene and long-term antibody response to hepatitis B vaccine vaccinated during infancy. Vaccine 2017; 35:2457-2462. [PMID: 28320591 DOI: 10.1016/j.vaccine.2017.03.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 02/07/2017] [Accepted: 03/08/2017] [Indexed: 12/23/2022]
Abstract
BACKGROUND The human leukocyte antigen (HLA) system plays critical roles in regulating immune responses to various vaccines. This study aimed to evaluate the association of HLA class II gene polymorphisms and the long-term duration of anti-HBs response in children vaccinated against hepatitis B during infancy. METHODS Totally 297 children 5-7years after the completion of primary vaccination against hepatitis B in infancy, without booster immunization or natural resolved infection, were enrolled. Of them, 86 children with anti-HBs <10mIU/ml were considered as long-term non- or hypo-responders, and 211 others with anti-HBs ≥10mIU/ml were defined as long-term responders. Ten alleles in HLA-DR and -DQ subregions were detected by polymerase chain reaction with sequence-specific primers. RESULTS The frequency of HLA-DQB1∗0401 was 15.1% in the long-term non- or hypo-responder group, relatively higher than 7.6% in the long-term responder group (OR=2.17, 95% CI 1.01-4.73), however, the difference had no statistical significance after Bonferroni correction (P=0.470). The frequencies of seven HLA-DRB1 alleles, including ∗01, ∗03, ∗04, ∗07, ∗08, ∗11, and ∗1301/1302, and two HLA-DQB1 alleles, including ∗0201 and ∗0501, were each similarly distributed in the long-term non- or hypo-responders and responders respectively. CONCLUSION None of the ten HLA class II gene alleles previously reported to be related with short-term antibody response to hepatitis B vaccine is associated with the long-term antibody response after vaccination during infantile.
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John M, Gaudieri S, Mallal S. Immunogenetics and Vaccination. HUMAN VACCINES 2017. [DOI: 10.1016/b978-0-12-802302-0.00005-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Sakai A, Noguchi E, Fukushima T, Tagawa M, Iwabuchi A, Kita M, Kakisaka K, Miyasaka A, Takikawa Y, Sumazaki R. Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response. Vaccine 2016; 35:703-710. [PMID: 28043736 DOI: 10.1016/j.vaccine.2016.08.068] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 07/29/2016] [Accepted: 08/23/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Genetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine. METHODS We performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies. RESULTS HLA-DRB1∗01:01, HLA-DRB1∗08:03, HLA-DQB1∗05:01, and HLA-DPB1∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84-87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses. CONCLUSION HLA-DRβ1 position 26 and HLA-DPβ1 positions 84-87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.
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Affiliation(s)
- Aiko Sakai
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
| | - Emiko Noguchi
- Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
| | - Takashi Fukushima
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
| | - Manabu Tagawa
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Atsushi Iwabuchi
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Masaki Kita
- Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Akio Miyasaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sumazaki
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
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Association of HLA-DP variants with the responsiveness to Hepatitis B virus vaccination in Korean Infants. Vaccine 2016; 34:2602-7. [PMID: 27083422 DOI: 10.1016/j.vaccine.2016.03.090] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 03/15/2016] [Accepted: 03/28/2016] [Indexed: 12/13/2022]
Abstract
Recently, HLA-DP single nucleotide polymorphisms (SNPs) have been reported to be related to responsiveness to hepatitis B virus (HBV) vaccination. The aim of this study was to investigate associations between HLA-DP SNPs and responsiveness to HBV vaccine in Korean infants. A total of 290 healthy Korean infants who were registered to Seoul Metropolitan Public Cord Blood Bank during the period of February 2007 to December 2011 were enrolled. Anti-HBs antibody level was analyzed after three doses of HBV vaccination. Genotyping of HLA-DPA1 SNPs (rs3077 and rs3830066) and HLA-DPB1 SNPs (rs7770370, rs7770501, rs3128961, and rs9277535) were performed by PCR-sequencing. HLA-A, -B, and -DRB1 genotyping was also performed by PCR-sequence-specific oligonucleotide probe kits. HLA-DPB1 SNPs (rs7770370, rs7770501, rs3128961, and rs9277535) were associated with HBV vaccine response. Allele frequencies of rs7770370 A, rs7770501 C, rs3128961 G, and rs9277535 A were significantly higher in responders than in non-responders (all p<0.01). Anti-HBs antibody levels were different according to genotypes of DPB1 rs7770370, rs7770501, rs3128961, and rs9277535 (all p<0.01). In multivariate analysis, HLA-DPB1 rs7770370 AA genotype was significantly associated with HBV vaccine response (relative risk, RR=2.5, p=0.033) and high-titer vaccine response (RR=2.7, p<0.001). In conclusion, HLA-DPB1 SNPs were significantly associated with responses to HBV vaccination in Korean infants.
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Deltex1 Polymorphisms Are Associated with Hepatitis B Vaccination Non-Response in Southwest China. PLoS One 2016; 11:e0149199. [PMID: 26894927 PMCID: PMC4760674 DOI: 10.1371/journal.pone.0149199] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 01/28/2016] [Indexed: 12/15/2022] Open
Abstract
Background Hepatitis B vaccination is the most important tool available for preventing hepatitis B virus (HBV) infection and reducing the prevalence of infection. However, epidemiological studies have demonstrated that morethan 5% of patients exhibit a non- or hypo-response to the HBV vaccine. Genetic variations associated with T cell immunity contribute to the immune response to HBV vaccination. The deltex 1 (DTX1) gene is involved in T cell anergy, which may also be associated with the immune response to the HBV vaccination. Methods We detected 10 single nucleotide polymorphisms (SNPs) in or around the DTX1 gene in 601 infants out of a population from Southwest China, including 299 high responders(HRs; HBsAb > 100 mIU/mL) and 302 non-responders (NRs; HBsAb < 10 mIU/mL). An additional validation study was performed, comprising 230 adult patients(135 HRs and 95 NRs) from Southwest China. Results This study found that the minor allele ‘G’ of rs2384077 (adjusted p = 2.63E-04,) and the minor allele ‘C’ of rs10744794 (adjusted p = 3.69E-04) in the first intron of the DTX1 gene were remarkably associated with the immune response to HBV vaccination in both infant and adult populations. Moreover, a subsequent analysis indicated that haplotypes (A-T, G-C) of the two SNPs were significantly associated with the immune response to HBV vaccination. Conclusions Two SNPs (rs2384077 and rs10744794) in an intron of DTX1 and the linkage disequilibrium (LD) block are significantly associated with the immune response to HBV vaccination. The functional element annotation of the LD block between the two SNPs contains four transcriptional regulatory elements. The results suggest that these two SNPs may be involved in the immune response to HBV vaccination.
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Mentzer AJ, O'Connor D, Pollard AJ, Hill AVS. Searching for the human genetic factors standing in the way of universally effective vaccines. Philos Trans R Soc Lond B Biol Sci 2016; 370:rstb.2014.0341. [PMID: 25964463 DOI: 10.1098/rstb.2014.0341] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Vaccines have revolutionized modern public health. The effectiveness of some vaccines is limited by the variation in response observed between individuals and across populations. There is compelling evidence that a significant proportion of this variability can be attributed to human genetic variation, especially for those vaccines administered in early life. Identifying and understanding the determinants of this variation could have a far-reaching influence upon future methods of vaccine design and deployment. In this review, we summarize the genetic studies that have been undertaken attempting to identify the genetic determinants of response heterogeneity for the vaccines against hepatitis B, measles and rubella. We offer a critical appraisal of these studies and make a series of suggestions about how modern genetic techniques, including genome-wide association studies, could be used to characterize the genetic architecture of vaccine response heterogeneity. We conclude by suggesting how the findings from such studies could be translated to improve vaccine effectiveness and target vaccination in a more cost-effective manner.
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Affiliation(s)
- Alexander J Mentzer
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Daniel O'Connor
- Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK Oxford Biomedical Research Centre, Oxford OX3 7LE, UK
| | - Andrew J Pollard
- Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK Oxford Biomedical Research Centre, Oxford OX3 7LE, UK
| | - Adrian V S Hill
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK Oxford Biomedical Research Centre, Oxford OX3 7LE, UK
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Tao J, Su K, Yu C, Liu X, Wu W, Xu W, Jiang B, Luo R, Yao J, Zhou J, Zhan Y, Ye C, Yuan W, Jiang X, Cui W, Li MD, Li L. Fine mapping analysis of HLA-DP/DQ gene clusters on chromosome 6 reveals multiple susceptibility loci for HBV infection. Amino Acids 2015. [PMID: 26197724 DOI: 10.1007/s00726-015-2054-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Recent genome-wide association studies have revealed the HLA region on chromosome 6p21 as a susceptibility locus for hepatitis B virus (HBV) infection, a finding subsequently replicated in independent samples. However, only limited single nucleotide polymorphisms (SNPs) were analyzed in most of these studies, and it remains to be determined which SNPs contribute to the detected association. After genotyping 140 SNPs within this genomic region in a total of 1657 HBV-positive patients and 1456 HBV-negative controls, we conducted a series of genetic epidemiological and bioinformatics analysis, including individual SNP-based association analysis, haplotype-based association analysis, and conditional analysis. We identified 76 SNPs and 5 LD blocks in HLA-DP/DQ clusters that are significantly associated with HBV infection, with the smallest P value being 3.88 × 10(-18) for rs9277535 in HLA-DPB1. With conditional analysis, we further revealed that the genes contributing to the effects of variants in HLA-DP/DQ on infection are independent of each other, and the LD block 5 in the 3'-UTR region of HLA-DPB1 had a predominant effect in the association of HLA-DP with HBV infection. We also found that the SNPs in the 3'-UTR region of HLA-DPB1 were significant between the subgroups of inactive HBV carrier, chronic hepatitis B, or hepatic cirrhosis from the case group and the spontaneous HBV-clearance subgroup from the control group. Finally, we did further association analysis of SNPs in this region with different subgroups from the case group, which revealed no association of these SNPs with the progression of HBV-related diseases. In sum, we showed, for the first time, that the HLA-DP/DQ clusters contribute independently to HBV infection, and the 3'-UTR region of HLA-DPB1 represents an important functional region involved in HBV infection.
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Affiliation(s)
- Jingjing Tao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Kunkai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Chengbo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Xiaoli Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wei Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wei Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Bingxun Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Rui Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Jian Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Jiawei Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Yan Zhan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Chao Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wenji Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Xianzhong Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Wenyan Cui
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China
| | - Ming D Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China. .,Department of Psychiatry and Neurobehavioral Science, University of Virginia, 450 Ray C Hunt Drive, Charlottesville, VA, 22903, USA.
| | - Lianjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou, 310003, Zhejiang, China.
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Wu TW, Chen CF, Lai SK, Lin HH, Chu CC, Wang LY. SNP rs7770370 in HLA-DPB1 loci as a major genetic determinant of response to booster hepatitis B vaccination: results of a genome-wide association study. J Gastroenterol Hepatol 2015; 30:891-9. [PMID: 25389088 DOI: 10.1111/jgh.12845] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/04/2014] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Hepatitis B (HB) vaccination is highly effective in reducing the risk of hepatitis B virus infection. However, breakthrough and chronic hepatitis B virus infections in vaccinated subjects raised concern about its long-term efficacy. The specific aim of the study was to explore the host genetic determinants of long-term immunological memory against HB vaccination. METHODS We conducted a case-control study nested in a cohort of HB booster recipients who had received primary HB vaccination during infancy but failed to reside an anti-HBs titers ≥ 10 mIU/mL at the age of 15-18 years. We used a genome-wide single nucleotide polymorphism (SNP) array plate to scan autosomal chromosomes and assayed the human leukocyte antigen (HLA)-DPB1 genotype by sequence-based techniques. RESULTS We found that 10 of the 112 candidate SNPs (P-value < 5.0 × 10(-5) ) clustered within a 47-Kb region of the HLA-DP loci. All the minor alleles of these HLA-DP candidate SNPs were correlated with lower likelihoods of nonresponse to HB vaccine. There was a significant linkage disequilibrium between these HLA-DP candidate SNPs and HLA-DPB1 protective alleles. Multivariate analyses showed that rs7770370 was the most significant genetic factor. As compared with rs7770370 GG homozygotes, adjusted odds ratios were 0.524 (95% confidence interval, 0.276-0.993) and 0.095 (95% confidence interval, 0.030-0.307) for AG heterozygotes and AA homozygotes, respectively. CONCLUSION Our results showed that rs7770370 was the most significant genetic factor of response to HB booster. The rs7770370 and nearby SNPs may also contribute to the long-term immunological memory against HB vaccination.
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Affiliation(s)
- Tzu-Wei Wu
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
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Garman L, Vineyard AJ, Crowe SR, Harley JB, Spooner CE, Collins LC, Nelson MR, Engler RJM, James JA. Humoral responses to independent vaccinations are correlated in healthy boosted adults. Vaccine 2014; 32:5624-31. [PMID: 25140930 PMCID: PMC4323156 DOI: 10.1016/j.vaccine.2014.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 07/11/2014] [Accepted: 08/06/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Roughly half of U.S. adults do not receive recommended booster vaccinations, but protective antibody levels are rarely measured in adults. Demographic factors, vaccination history, and responses to other vaccinations could help identify at-risk individuals. We sought to characterize rates of seroconversion and determine associations of humoral responses to multiple vaccinations in healthy adults. METHODS Humoral responses toward measles, mumps, tetanus toxoid, pertussis, hepatitis B surface antigen, and anthrax protective antigen were measured by ELISA in post-immunization samples from 1465 healthy U.S. military members. We examined the effects of demographic and clinical factors on immunization responses, as well as assessed correlations between vaccination responses. RESULTS Subsets of boosted adults did not have seroprotective levels of antibodies toward measles (10.4%), mumps (9.4%), pertussis (4.7%), hepatitis B (8.6%) or protective antigen (14.4%) detected. Half-lives of antibody responses were generally long (>30 years). Measles and mumps antibody levels were correlated (r=0.31, p<0.001), but not associated with select demographic features or vaccination history. Measles and mumps antibody levels also correlated with tetanus antibody response (r=0.11, p<0.001). CONCLUSIONS Vaccination responses are predominantly robust and vaccine specific. However, a small but significant portion of the vaccinated adult population may not have quantitative seroprotective antibody to common vaccine-preventable infections.
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Affiliation(s)
- Lori Garman
- Oklahoma Medical Research Foundation, Department of Arthritis and Clinical Immunology, Oklahoma City, OK 73104, USA; Oklahoma University Health Science Center, Department of Microbiology and Immunology, Oklahoma City, OK 73104, USA
| | - Amanda J Vineyard
- Oklahoma Medical Research Foundation, Department of Arthritis and Clinical Immunology, Oklahoma City, OK 73104, USA
| | - Sherry R Crowe
- Oklahoma Medical Research Foundation, Department of Arthritis and Clinical Immunology, Oklahoma City, OK 73104, USA
| | - John B Harley
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA
| | | | - Limone C Collins
- Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
| | - Michael R Nelson
- Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
| | - Renata J M Engler
- Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
| | - Judith A James
- Oklahoma Medical Research Foundation, Department of Arthritis and Clinical Immunology, Oklahoma City, OK 73104, USA; Oklahoma University Health Science Center, Department of Microbiology and Immunology, Oklahoma City, OK 73104, USA; Oklahoma University Health Science Center, Departments of Medicine and Pathology, Oklahoma City, OK 73104, USA.
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Doganay L, Fejzullahu A, Katrinli S, Enc FY, Ozturk O, Colak Y, Ulasoglu C, Tuncer I, Doganay GD. Association of human leukocyte antigen DQB1 and DRB1 alleles with chronic hepatitis B. World J Gastroenterol 2014; 20:8179-8186. [PMID: 25009391 PMCID: PMC4081690 DOI: 10.3748/wjg.v20.i25.8179] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 02/17/2014] [Accepted: 04/01/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of human leukocyte antigen (HLA) DRB1 and DQB1 alleles on the inactive and advanced stages of chronic hepatitis B. METHODS Patient records at a single institution's hepatology clinic were reviewed. Demographic data, laboratory results, endoscopy results, virological parameters, biopsy scores and treatment statuses were recorded. In total, 355 patients were eligible for the study, of whom 226 (63.7%) were male. Overall, 82 (23.1%) were hepatitis B early antigen (HBeAg) positive, 87 (24.5%) had cirrhosis, and 66 (18.6%) had inactive disease. The presence of DQB1 and DRB1 alleles was determined by polymerase chain reaction with sequence-specific primers. The distribution of the genotyped alleles among patients with cirrhosis and patients with chronic active hepatitis was analyzed. RESULTS The most frequent HLA DQB1 allele was DQB1*03:01 (48.2%), and the most frequent HLA DRB1 allele was DRB1*13/14 (51.8%). DQB1*05:01 was more frequent in patients with active disease than in inactive patients (27% vs 9.1%; P = 0.002, Pc = 0.026). DRB1*07 was rare in patients with cirrhosis compared with non-cirrhotics (3.4% vs 16%; P = 0.002, Pc = 0.022). Older age (P < 0.001) and male gender (P = 0.008) were the other factors that affected the presence of cirrhosis. In a multivariate logistic regression analysis, DRB1*07 remained a significant negative predictor of cirrhosis (P = 0.015). A bioinformatics analysis revealed that a polymorphic amino acid sequence in DRB1*07 may alter interaction with the T-cell recognition site. CONCLUSION This study demonstrates that HLA alleles may influence cirrhosis development and disease activity in Turkish chronic hepatitis B patients.
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Ovsyannikova IG, Pankratz VS, Larrabee BR, Jacobson RM, Poland GA. HLA genotypes and rubella vaccine immune response: additional evidence. Vaccine 2014; 32:4206-13. [PMID: 24837503 DOI: 10.1016/j.vaccine.2014.04.091] [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: 11/18/2013] [Revised: 03/26/2014] [Accepted: 04/28/2014] [Indexed: 10/25/2022]
Abstract
Recent population-based studies have demonstrated the genetic heritability of rubella vaccine response and assessed that the HLA system may explain about 20% of the inter-individual variance in humoral immune response to this vaccine. Our earlier studies compared HLA allelic associations with rubella vaccine-specific antibodies between two smaller cohorts of healthy Rochester, MN, children (346 and 396 subjects) after two doses of rubella-containing vaccine. This study found that specific HLA alleles were consistently associated with rubella-specific antibody titers (B*27:05, DPA1*02:01, and DPB1*04:01 alleles). The current study examined HLA associations in an independent larger cohort of 1012 healthy San Diego, CA, subjects (age 19-40 years) after rubella vaccine in order to replicate our previous findings in the Rochester subjects. Two HLA associations of comparable magnitudes were consistently observed between B*27:05 (median NT50 Rochester cohort 48.9, p=0.067; San Diego cohort 54.8, p=0.047) and DPB1*04:01 (median NT50 Rochester cohort 61.6, p<0.001; San Diego cohort 70.8, p=0.084) alleles and rubella virus-neutralizing antibody titers. Additional HLA alleles resulted in consistent effects on IL-6 production in both cohorts, but did not meet criteria for statistical significance. Our data suggest these HLA alleles play a role in rubella vaccine-induced immunity and provide the basis for future studies that may explain the mechanism(s) by which these HLA polymorphisms affect immune responses to rubella vaccine.
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Affiliation(s)
- Inna G Ovsyannikova
- Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA; Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905, USA
| | - V Shane Pankratz
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Beth R Larrabee
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Robert M Jacobson
- Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Gregory A Poland
- Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA; Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905, USA.
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Kennedy RB, Ovsyannikova IG, Lambert ND, Haralambieva IH, Poland GA. The personal touch: strategies toward personalized vaccines and predicting immune responses to them. Expert Rev Vaccines 2014; 13:657-69. [PMID: 24702429 DOI: 10.1586/14760584.2014.905744] [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]
Abstract
The impact of vaccines on public health and wellbeing has been profound. Smallpox has been eradicated, polio is nearing eradication, and multiple diseases have been eliminated from certain areas of the world. Unfortunately, we now face diseases such as hepatitis C, malaria or tuberculosis, as well as new and re-emerging pathogens for which we lack effective vaccines. Empirical approaches to vaccine development have been successful in the past, but may not be up to the current infectious disease challenges facing us. New, directed approaches to vaccine design, development, and testing need to be developed. Ideally these approaches will capitalize on cutting-edge technologies, advanced analytical and modeling strategies, and up-to-date knowledge of both pathogen and host. These approaches will pay particular attention to the causes of inter-individual variation in vaccine response in order to develop new vaccines tailored to the unique needs of individuals and communities within the population.
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HLA-DPB1 and anti-HBs titer kinetics in hepatitis B booster recipients who completed primary hepatitis B vaccination during infancy. Genes Immun 2013; 15:47-53. [DOI: 10.1038/gene.2013.62] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 10/21/2013] [Accepted: 10/24/2013] [Indexed: 12/23/2022]
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Reber A, Katz J. Immunological assessment of influenza vaccines and immune correlates of protection. Expert Rev Vaccines 2013; 12:519-36. [PMID: 23659300 DOI: 10.1586/erv.13.35] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Influenza vaccines remain the primary public health tool in reducing the ever-present burden of influenza and its complications. In seeking more immunogenic, more effective and more broadly cross-protective influenza vaccines, the landscape of influenza vaccines is rapidly expanding, both in near-term advances and next-generation vaccine design. Although the first influenza vaccines were licensed over 60 years ago, the hemagglutination-inhibition antibody titer is currently the only universally accepted immune correlate of protection against influenza. However, hemagglutination-inhibition titers appear to be less effective at predicting protection in populations at high risk for severe influenza disease; older adults, young children and those with certain medical conditions. The lack of knowledge and validated methods to measure alternate immune markers of protection against influenza remain a substantial barrier to the development of more immunogenic, broadly cross-reactive and effective influenza vaccines. Here, the authors review the knowledge of immune effectors of protection against influenza and discuss assessment methods for a broader range of immunological parameters that could be considered in the evaluation of traditional or new-generation influenza vaccines.
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Affiliation(s)
- Adrian Reber
- Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road Atlanta, GA 30333, USA
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Genetic variants within the MHC region are associated with immune responsiveness to childhood vaccinations. Vaccine 2013; 31:5381-91. [PMID: 24075919 DOI: 10.1016/j.vaccine.2013.09.026] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 07/29/2013] [Accepted: 09/13/2013] [Indexed: 12/19/2022]
Abstract
The influence of genetic variability within the major histocompatibility complex (MHC) region on variations in immune responses to childhood vaccination was investigated. The study group consisted of 135 healthy infants who had been immunized with hepatitis B (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using Illumina Goldengate MHC panels (Mapping and Exon Centric). At the 1 year post vaccination check-up total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. A number of single nucleotide polymorphisms (SNPs) within MHC Class I and II genes were found to be associated with variations in the vaccine specific antibody responses and serum levels of immunoglobulins (IgG, IgM) and IgG isotypes (IgG1, IgG4) (all at p<0.001). Linkage disequilibrium patterns and functional annotations showed that significant SNPs were strongly correlated with other functional regulatory SNPs. These SNPs were found to regulate the expression of a group of genes involved in antigen processing and presentation including HLA-A, HLA-C, HLA-G, HLA-H, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DOB, and TAP-2. The results suggest that genetic variations within particular MHC genes can influence immune response to common childhood vaccinations, which in turn may influence vaccine efficacy.
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Doganay L, Tuncer I, Katrinli S, Enc FY, Ozturk O, Colak Y, Ulasoglu C, Dinler G. The effect of HLA-DQB1 alleles on virologic breakthroughs during chronic hepatitis B treatment with genetically low barrier drugs. Clin Res Hepatol Gastroenterol 2013; 37:359-364. [PMID: 23273495 DOI: 10.1016/j.clinre.2012.10.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 08/21/2012] [Accepted: 10/08/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Chronic hepatitis B treatment with oral antiviral drugs is a long course. During this course, antiviral resistance is a serious issue, particularly, if genetically low barrier drugs are in use. Host immunity is accepted to have an effect on antiviral resistance development. The earliest clinical sign of drug resistance is virologic breakthrough. In this study, we aimed to investigate the relation between HLA-DQB1 alleles and virologic breakthrough events. SUBJECTS AND METHODS The patient records at single institution hepatology clinic were reviewed. Local institution ethics committee approval was taken. The patients' demographic data, virologic parameters, treatment statues were noted. Patients who had received lamivudine or adefovir were recruited and grouped into two according to virologic breakthrough occurrence. Patients who were not compliant to the given treatment were excluded. Blood samples were taken for DNA extraction. HLA-DQB1 alleles were determined at high level by sequence-specific primers-polymerase chain reaction. The distribution of DQB1 alleles among groups was analyzed. RESULTS One hundred ninety-eight patients were eligible for the study. Ninety-six of them had virologic breakthrough where 102 did not have. DQB1 0503 allele was more frequent in patients without breakthrough (28.4% vs. 12.4%, P=0.006). In univariate analysis, HBeAg seropositivity (P<0.001), absence of cirrhosis (P=0.007), younger age (P=0.002) and higher pretreatment logDNA (P<0.001) were related to breakthrough events. However, in multivariate analysis only logDNA (P<0.001) and DQB1*0503 (P=0.02) allele revealed statistically significant relation with breakthrough events. CONCLUSION Host immunity may have an effect on outcome during treatment with oral antiviral drugs. A patient with better immunologic profile may suppress the viral replication better and this may cause less resistance occurrence during treatment with genetically low barrier drugs.
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Affiliation(s)
- Levent Doganay
- Department of Gastroenterology, Goztepe Teaching and Research Hospital, Medeniyet University, Istanbul, Turkey.
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Moss AJ, Gaughran FP, Karasu A, Gilbert AS, Mann AJ, Gelder CM, Oxford JS, Stephens HA, Lambkin-Williams R. Correlation between human leukocyte antigen class II alleles and HAI titers detected post-influenza vaccination. PLoS One 2013; 8:e71376. [PMID: 23951151 PMCID: PMC3739771 DOI: 10.1371/journal.pone.0071376] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 07/02/2013] [Indexed: 01/19/2023] Open
Abstract
Influenza is a major cause of morbidity and mortality. Despite vaccination, many elderly recipients do not develop a protective antibody response. To determine whether Human Leukocyte Antigen (HLA) alleles modulate seroprotection to influenza, a cohort of HLA class II-typed high-risk vaccine recipients was investigated. Haemagglutinin inhibition (HAI) titres were measured 14–40 days post-subunit vaccination. Seroprotection was defined as HAI titres reaching 40 or greater for all three vaccine strains. HLA-DRB1*04∶01 and HLA-DPB1*04∶01 alleles were detected at higher frequencies in seroprotected compared with non-seroprotected individuals. Thus, the presence of certain HLA class II alleles may determine the magnitude of antibody responses to influenza vaccination.
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Affiliation(s)
- Alastair J Moss
- Southampton General Hospital, Southampton, Hampshire, United Kingdom.
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31
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Wu TW, Chu CC, Ho TY, Chang Liao HW, Lin SK, Lin M, Lin HH, Wang LY. Responses to booster hepatitis B vaccination are significantly correlated with genotypes of human leukocyte antigen (HLA)-DPB1 in neonatally vaccinated adolescents. Hum Genet 2013; 132:1131-9. [DOI: 10.1007/s00439-013-1320-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Accepted: 05/26/2013] [Indexed: 12/18/2022]
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Falola MI, Wiener HW, Wineinger NE, Cutter GR, Kimberly RP, Edberg JC, Arnett DK, Kaslow RA, Tang J, Shrestha S. Genomic copy number variants: evidence for association with antibody response to anthrax vaccine adsorbed. PLoS One 2013; 8:e64813. [PMID: 23741398 PMCID: PMC3669407 DOI: 10.1371/journal.pone.0064813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Accepted: 04/09/2013] [Indexed: 01/09/2023] Open
Abstract
Background Anthrax and its etiologic agent remain a biological threat. Anthrax vaccine is highly effective, but vaccine-induced IgG antibody responses vary widely following required doses of vaccinations. Such variation can be related to genetic factors, especially genomic copy number variants (CNVs) that are known to be enriched among genes with immunologic function. We have tested this hypothesis in two study populations from a clinical trial of anthrax vaccination. Methods We performed CNV-based genome-wide association analyses separately on 794 European Americans and 200 African-Americans. Antibodies to protective antigen were measured at week 8 (early response) and week 30 (peak response) using an enzyme-linked immunosorbent assay. We used DNA microarray data (Affymetrix 6.0) and two CNV detection algorithms, hidden markov model (PennCNV) and circular binary segmentation (GeneSpring) to determine CNVs in all individuals. Multivariable regression analyses were used to identify CNV-specific associations after adjusting for relevant non-genetic covariates. Results Within the 22 autosomal chromosomes, 2,943 non-overlapping CNV regions were detected by both algorithms. Genomic insertions containing HLA-DRB5, DRB1 and DQA1/DRA genes in the major histocompatibility complex (MHC) region (chromosome 6p21.3) were moderately associated with elevated early antibody response (β = 0.14, p = 1.78×10−3) among European Americans, and the strongest association was observed between peak antibody response and a segmental insertion on chromosome 1, containing NBPF4, NBPF5, STXMP3, CLCC1, and GPSM2 genes (β = 1.66, p = 6.06×10−5). For African-Americans, segmental deletions spanning PRR20, PCDH17 and PCH68 genes on chromosome 13 were associated with elevated early antibody production (β = 0.18, p = 4.47×10−5). Population-specific findings aside, one genomic insertion on chromosome 17 (containing NSF, ARL17 and LRRC37A genes) was associated with elevated peak antibody response in both populations. Conclusion Multiple CNV regions, including the one consisting of MHC genes that is consistent with earlier research, can be important to humoral immune responses to anthrax vaccine adsorbed.
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Affiliation(s)
- Michael I. Falola
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Howard W. Wiener
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Nathan E. Wineinger
- Scripps Translational Science Institute, La Jolla, California, United States of America
| | - Gary R. Cutter
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Robert P. Kimberly
- Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jeffrey C. Edberg
- Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Donna K. Arnett
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Richard A. Kaslow
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Jianming Tang
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Sadeep Shrestha
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- * E-mail:
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Halperin SA, Ward BJ, Dionne MS, Langley JM, McNeil SA, Smith B, MacKinnon-Cameron D, Heyward WL, Martin JT. Immunogenicity of an investigational hepatitis B vaccine (hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide) in nonresponders to licensed hepatitis B vaccine. Hum Vaccin Immunother 2013; 9:1438-44. [DOI: 10.4161/hv.24256] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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The role of human leukocyte antigen tissue groups in hepatitis B virus vaccination in Turkey. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2013; 47:9-14. [PMID: 23523043 DOI: 10.1016/j.jmii.2013.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Revised: 01/09/2013] [Accepted: 01/18/2013] [Indexed: 12/28/2022]
Abstract
BACKGROUND/PURPOSE Between 5% and 10% of the vaccinated population responds less well to standard vaccination schedules irrespective of hepatitis B virus (HBV) vaccination. This manuscript aims at describing possible correlation of different major histocompatibility complex (MHC) Class-I and MHC Class-II haplotype to anti-HBV humoral responsiveness following HBV vaccination. MATERIALS AND METHODS The study was conducted on 944 vaccinated hospital staff members and concentrated on the 38 nonresponders as defined by enzyme-linked immunosorbent assay (ELISA) results. In order to define significance of the different haplotypes from the nonresponders, their frequency was compared to the frequency of the same haplotype in 18 randomly selected responders. Human leukocyte antigen (HLA)-A and HLA-B antigens were typed among total mononuclear cells using a standard two-stage microlymphocytotoxicity test. The typing method of HLA Class-II is based on a technique that involves amplification of the second exon of different HLA Class-II genes by PCR. RESULTS Positive correlations were found between four HLA-DR (HLA-DRB1*04X, DRB1*0401X, DRB1*11/13, and DRB1*0401X0201) haplotypes and nonresponders but there was a negative correlation with one Class-I (HLA-B13). CONCLUSION This study suggested that certain HLA types are associated with nonresponsiveness to vaccination. The different HLA of ethnic groups should also be kept in mind when evaluating the response to hepatitis vaccination. The different HLA gene frequencies of ethnic groups should be examined in further large-scale population-based studies.
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Karimi M, Raee A, Baghianimoghadam B, Fallahzadeh MH. Vaccine-Induced Anti-HBs Level in 5-6 Year-Old Malnourished Children. HEPATITIS MONTHLY 2013; 13:e7048. [PMID: 23658590 PMCID: PMC3644421 DOI: 10.5812/hepatmon.7048] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 09/13/2012] [Accepted: 12/28/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Malnutrition is the most common cause of immune deficiency. It results in reduced secretion of T-cells and B-cell-stimulating factors leading to declining of special immunoglobulins. On the other hand, hepatitis B, as a major world health problem, can be prevented effectively by vaccination. Three doses of hepatitis B virus (HBV) vaccine induce protective levels of anti-hepatitis B surface (anti-HBs) in 95% of healthy children. This level decreases gradually over time. OBJECTIVES The goal of this study was to assess anti-HBs in malnourished children, who confronted to some degrees of immune deficiency. PATIENTS AND METHODS This is a cross-sectional study conducted during May to August 2010 in therapeutic clinics of Yazd, Iran. Samples were selected simply and consecutively among 5-6 year-old children with a history of three doses of HBV vaccine in infancy. On the basis of World Health Organization's definition on malnutrition, which considers anthropometric measurements, malnourished children entered the study. Totally 83 cases (37 boys and 46 girls) were gathered and classified into three groups of mild, moderate, and severe malnutrition. One milliliter of venous blood was taken and anti-HBs were tested by enzyme linked immunosorbant assay (ELISA). RESULTS Overall, seroprotection rate and geometric mean titer (GMT) of anti-HBs were 60.2% and 15.47 ± 10.92 mIU/mL, respectively. Seroprotection rate was 71.4%, 55.2%, and 72.7% in mild, moderate, and severe malnourished children, respectively. GMT was 30.78 mIU/mL, 12.15 mIU/mL, and 22.95 mIU/mL in these groups, respectively. None of these two indices were significant in these groups (P = 0.471, P = 0.364). Seroprotection rate and GMT were 54.1% and 13.26 ± 11.59 mIU/mL in boys, and 65.2% and 17.5 ± 10.59 mIU/mL in girls, respectively, showing no significant relationship with gender (P = 0.302, P = 0.602). Lowest seroprotection rate was in stunted cases (47.1%) and highest in wasted children (77.8%). This difference also was not significant (P = 0.43). CONCLUSIONS The seroprotection rate and GMT of anti-HBs observed in this study do not show a high level of immunity. These two indices were not related to severity of malnutrition. We conclude that severity of malnutrition does not affect vaccine-induced antibody level and seroprotection rate; however small sample size in each group of study hinders decisive conclusion. Moreover, GMT and seroprotection rate showed no relationship with type of abnormal anthropometric index, including weight for height, weight for age, and height for age.
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Affiliation(s)
- Mehran Karimi
- Children Growth Disorders Research Center, Shahid Sadoughi University of Medical Science, Yazd, IR Iran
| | - Ali Raee
- Department of Pediatrics, Shahid Sadoughi University of Medical Science, Yazd, IR Iran
| | - Behnam Baghianimoghadam
- Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Science, Yazd, IR Iran
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T cell epitope mapping of JC polyoma virus-encoded proteome reveals reduced T cell responses in HLA-DRB1*04:01+ donors. J Virol 2013; 87:3393-408. [PMID: 23302880 DOI: 10.1128/jvi.02803-12] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
JC polyomavirus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. It is only during immunocompromise and especially impaired CD4(+) T cell function in the brain, as seen in AIDS patients or natalizumab-treated multiple sclerosis patients, that JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4(+) T cells likely play an important role in controlling JCV infection, we here describe the T cell response to JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. We identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. We observed positive JCV-specific T cell responses in 28.6% to 77.6%, humoral immune response in 42.6% to 89.4%, and urinary viral shedding in 36.4% to 45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01(+), DRB1*07(+), DRB1*11(+), DRB1*13(+), DRB1*15(+), and DRB1*03(+) individuals. We show for the first time that JCV-specific T cell responses may be directed not only against JCV VP1 and large T antigen but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01(+) individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV.
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Pan L, Zhang W, Liang Z, Wu X, Zhu X, Li J, Li T, Wang L, Li H, Liu Y. Association between polymorphisms of the cytokine and cytokine receptor genes and immune response to hepatitis B vaccination in a Chinese Han population. J Med Virol 2011; 84:26-33. [PMID: 22052597 DOI: 10.1002/jmv.22251] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2011] [Indexed: 01/02/2023]
Abstract
The immune response to hepatitis B vaccination varies among individuals. It has been reported that polymorphisms in cytokine and cytokine receptor genes are associated with these individual differences. The aim of the current study was to investigate the association between polymorphisms of the Th1/Th2 cytokine and cytokine receptor genes and the response to hepatitis B vaccination in a Chinese Han population. A total of 10 single nucleotide polymorphisms distributed in 6 genes (TNFRSF1A, IL12A, IL12B, IFNG, IL4, and IL10) were genotyped in 214 high-responders [hepatitis B surface antibody (anti-HBs) ≥1,000 mIU/ml] and 107 low-responders (anti-HBs: 10-99 mIU/ml). The minor CTCTAA allele of rs17860508 in the IL12B gene was associated with a low response to hepatitis B vaccination (P = 0.039, odds ratio = 1.41, 95% confidence interval = 1.00-1.99). In addition, a significant gene-gene interaction was found: the frequency of the combined genotypes IL12A rs2243115 TT and IL12B rs17860508 CTCTAA/CTCTAA was significantly higher in the low-response group than in the high-response group (P = 0.008, odds ratio = 2.19, 95% confidence interval = 1.23-3.93). These findings suggest that polymorphisms in the IL12A and IL12B genes might play an important role jointly in determining the response to hepatitis B vaccination.
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Affiliation(s)
- Liping Pan
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
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Transmission of HLA-DP variants from parents to children with B-cell precursor acute lymphoblastic leukemia: log-linear analysis using the case-parent design. Hum Immunol 2011; 72:897-903. [PMID: 21645570 DOI: 10.1016/j.humimm.2011.05.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Revised: 04/27/2011] [Accepted: 05/13/2011] [Indexed: 01/10/2023]
Abstract
Childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL) is usually initiated in utero and is thought to progress to overt leukemia under the influence of delayed exposure to a common infection. Based on the hypothesis that polymorphic HLA-DP variants can restrict T-cell responses to infection, we previously compared DP supertype frequencies in BCP ALL patients with that of unrelated newborn controls. We reported that the DP2 supertype was associated with susceptibility, whereas DP1 was associated with protection. However, the association of genetic variants in children with early-onset diseases such as ALL may be a proxy for parental effects. Here we examine whether maternal DP1 and DP2 are associated with BCP ALL by fitting log-linear models in a combined series of family triads (both parents and case child) and dyads (1 parent and case child; n = 571) in comparison with similar models in non-BCP leukemia (n = 198). We report no evidence of maternal DP1 or DP2 associations with BCP ALL, but we did identify suggestive evidence of maternal undertransmission of the infrequent supertypes DP11 and DP15. Although these results require confirmation, they suggest that DP11 and DP15 may be protective or that there is transmission ratio distortion of these supertypes in BCP ALL.
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Association of HLA and TNF polymorphisms with the outcome of HBV infection in the South Indian population. Genes Immun 2011; 12:552-8. [PMID: 21593777 DOI: 10.1038/gene.2011.32] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The role of host genetic factors in the pathogenesis and outcome of hepatitis B virus (HBV) infection is not well known. We assessed the association of HLA and TNF (rs361525, rs1800629, rs1799724, rs1800630 and rs1799964) polymorphisms with HBV outcome in the South Indian population. Association of HLA polymorphism was analyzed in 90 individuals from each group, that is, spontaneous recovery (SR) and chronic-HBV (C-HBV) infection. The role of TNF polymorphisms was evaluated in 150 subjects with SR and 137 patients with C-HBV infection. After adjusting for age and sex, HLA-DRB1*07:01 was strongly associated with chronicity (corrected P-value (pc) <0.005, odds ratio (OR) 3.76, 95% confidence interval (CI) 1.84-7.68). The rs1800630 genotype was associated with HBV outcome in codominant (pc<0.01, OR=1.99, 95% CI 1.30-3.05) and dominant (pc<0.01, OR=2.28, 95% CI 1.35-3.84) analyzing models after adjusting for age and sex. Similarly, the rs1799964 genotype was associated with HBV outcome in codominant (pc=0.01, OR=1.57, 95% CI 1.09-2.27) and dominant (pc<0.01, OR=2.21, 95% CI 1.27-3.83) analyzing models. Haplotype analysis (rs1799964/rs1800630/rs1799724/rs1800629/rs361525) revealed that the CACGG haplotype was strongly associated with C-HBV infection (P=0.0004). Our study suggests that inheritance of HLA and TNF polymorphisms might explain the outcome of HBV infection in the South Indian population.
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Abstract
The clinical course of hepatitis B virus (HBV) infection varies from spontaneous recovery to chronic persistent infection leading to severe liver injury. Mounting evidence has recently highlighted the influence of host genotype in the complex interplay between viral and host factors. Studies in adults have suggested the existence of a genetic predisposition to HBV infection secondary to certain defects in the host response. These defects include opsonic deficiency, compromised antigen processing and presentation by human leucocyte antigen variations, attenuated T- and B-cell response, impaired cytokine and chemokine release, and production of receptors for several pertinent factors such as vitamin D and estrogen. By contrast, little is known about the genetic factors involved in the susceptibility to HBV transmission in early childhood. Herein, we review the literature regarding the association between host genetics and susceptibility to primary HBV infection, and we discuss the prospects of investigation in this field. A better understanding of HBV infection immunopathogenesis in the critical period of infancy may allow the development of optimal and innovative prevention and treatment.
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Chou HY, Lin XZ, Pan WY, Wu PY, Chang CM, Lin TY, Shen HH, Tao MH. Hydrogel-Delivered GM-CSF Overcomes Nonresponsiveness to Hepatitis B Vaccine through the Recruitment and Activation of Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2010; 185:5468-75. [DOI: 10.4049/jimmunol.1001875] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Davila S, Froeling FEM, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M. New genetic associations detected in a host response study to hepatitis B vaccine. Genes Immun 2010; 11:232-8. [PMID: 20237496 DOI: 10.1038/gene.2010.1] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The immune response to hepatitis B vaccination differs greatly among individuals, with 5-10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 x 10(-10); OR (95%CI)=0.61 (0.52-0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3' downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 x 10(-6); OR (95%CI)=1.38 (1.2-1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.
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Affiliation(s)
- S Davila
- Genome Institute of Singapore, Singapore
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Abstract
Vaccines are one of the most cost effective methods to control infectious diseases and at the same time one of the most complex products of the pharmaceutical industry. In contrast to other drugs, vaccines are used mainly in healthy individuals, often in children. For this reason, very high standards are set for their production. Subunit vaccines, especially peptide vaccines, can provide a safe and cost-effective alternative to vaccines produced from attenuated or inactivated pathogen preparations. Biochemical and structural studies of class II MHC-peptide complexes are beginning to provide a conceptual foundation for the rational design of subunit and peptide vaccines. In this review, we show how analysis of peptide-class II MHC complexes together with developing understanding of antigen processing pathways has opened the door to understanding the major rules that govern selection of T cell epitopes. We review progress towards computational prediction of such epitopes, and efforts to evaluate algorithms that incorporate various structural and/or biochemical aspects of the MHC-peptide interaction. Finally, using malaria as a model, we describe the development of a minimal subunit vaccine for the human malaria parasite Plasmodium falciparum.
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Affiliation(s)
- Lawrence J Stern
- Department of Pathology, Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
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Abstract
The field of pharmacogenomics and pharmacogenetics provides a promising science base for vaccine research and development. A broad range of phenotype/genotype data combined with high-throughput genetic sequencing and bioinformatics are increasingly being integrated into this emerging field of vaccinomics. This paper discusses the hypothesis of the 'immune response gene network' and genetic (and bioinformatic) strategies to study associations between immune response gene polymorphisms and variations in humoral and cellular immune responses to prophylactic viral vaccines, such as measles-mumps-rubella, influenza, HIV, hepatitis B and smallpox. Immunogenetic studies reveal promising new vaccine targets by providing a better understanding of the mechanisms by which gene polymorphisms may influence innate and adaptive immune responses to vaccines, including vaccine failure and vaccine-associated adverse events. Additional benefits from vaccinomic studies include the development of personalized vaccines, the development of novel vaccines and the development of novel vaccine adjuvants.
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Affiliation(s)
- Gregory A Poland
- Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN 55905, USA.
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Abstract
The next 'golden age' in vaccinology will be ushered in by the new science of vaccinomics. In turn, this will inform and allow the development of personalized vaccines, based on our increasing understanding of immune response phenotype: genotype information. Rapid advances in developing such data are already occurring for hepatitis B, influenza, measles, mumps, rubella, anthrax and smallpox vaccines. In addition, newly available data suggest that some vaccine-related adverse events may also be genetically determined and, therefore, predictable. This paper reviews the basis and logic of personalized vaccines, and describes recent advances in the field.
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Affiliation(s)
- Gregory A Poland
- Mayo Clinic College of Medicine, Mayo Vaccine Research Group, Program in TranslationalImmunovirology and Biodefense, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Velu V, Saravanan S, Nandakumar S, Shankar EM, Vengatesan A, Jadhav SS, Kulkarni PS, Thyagarajan SP. Relationship between T-lymphocyte cytokine levels and sero-response to hepatitis B vaccines. World J Gastroenterol 2008; 14:3534-40. [PMID: 18567083 PMCID: PMC2716617 DOI: 10.3748/wjg.14.3534] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the cellular defects by analyzing the (Th1/Th2) cytokine levels in vaccine responders and non-responders.
METHODS: Peripheral blood mononuclear cell (PBMC) from responders and non-responders were stimulated with or with out recombinant HBsAg or PHA. Broad spectrum of cytokines viz (Th1) IFN-γ, IL-2, TNF-α, IL-12 and (Th2) IL-10, IL-4 were measured after in vitro stimulation with recombinant HBsAg and were compared with respective antibody titers.
RESULTS: A significant decrease (P = 0.001) in Th1 and Th2 cytokines namely, IL-2, INF-γ, TNF-α and IL-10 in non-responders was observed. The level of IL-4 was not significant between the three groups. Furthermore, despite a strong Th1 and Th2 cytokine response, the level of IL-12 was elevated in high-responders compared to other groups (P = 0.001) and demonstrated a positive correlation with anti-HBs titers and Th1 cytokine response.
CONCLUSION: Our findings suggest that unresponsiveness to recombinant hepatitis B vaccines (rHB) is multifactorial, including specific failure of antigen presentation or the lack of both T helper Th1 and Th2 response.
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Nemes E, Lefler E, Szegedi L, Kapitány A, Kovács JB, Balogh M, Szabados K, Tumpek J, Sipka S, Korponay-Szabó IR. Gluten intake interferes with the humoral immune response to recombinant hepatitis B vaccine in patients with celiac disease. Pediatrics 2008; 121:e1570-6. [PMID: 18519462 DOI: 10.1542/peds.2007-2446] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Patients with celiac disease, who often carry human leukocyte antigen-DR3;DQ2, are prone to inadequate response to hepatitis B immunization. We evaluated vaccine response in relation to disease activity and whether previous treatment with a gluten-free diet influences the achievement of protective antibody titers. PATIENTS AND METHODS We studied 128 children and adolescents with celiac disease and 113 age-matched control subjects. Twenty-two patients with celiac disease were prospectively immunized after diagnosis during dietary treatment (group 1). A total of 106 (group 2) and the control subjects received vaccination by mass immunization in schools at 14 years of age regardless of diet status and when celiac disease was still undiagnosed in 27 of these children. Diet compliance and celiac disease activity were monitored by measurement of antibodies against transglutaminase and endomysium. Vaccine response was determined by measuring antihepatitis B antibodies from serum. RESULTS The seroconversion after hepatitis B vaccination was 95.5% in group 1. All of these patients carried human leukocyte antigen DQ2. The response rate in group 2 was 50.9% and correlated with gluten intake (untreated patients: 25.9%, non-strict diet: 44.4%, strict diet: 61.4%). Treated and compliant patients did not significantly differ from control subjects (75.2%). Thirty-seven antihepatitis B-negative patients with celiac disease received a booster during a controlled gluten-free diet, and 36 (97.3%) seroconverted, irrespective of the presence of human leukocyte antigen DQ2. CONCLUSIONS Nonresponse to recombinant hepatitis B surface antigen may be a sign of undiagnosed celiac disease. However, there is a good vaccine response in adequately treated patients. Human leukocyte antigen DQ alleles do not seem to have a primary role. Revaccination is recommended during a controlled gluten-free diet.
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Affiliation(s)
- Eva Nemes
- Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Nagyerdei krt 98, H-4032 Debrecen, Hungary.
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Lin HH, Liao HWC, Lin SK, Wang LY. HLA and response to booster hepatitis B vaccination in anti-HBs-seronegative adolescents who had received primary infantile vaccination. Vaccine 2008; 26:3414-20. [PMID: 18501999 DOI: 10.1016/j.vaccine.2008.04.038] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Revised: 03/11/2008] [Accepted: 04/15/2008] [Indexed: 12/18/2022]
Abstract
To explore contemporarily genetic and non-genetic determinants of long-term immunological memory to hepatitis B (HB) vaccination, we conducted a case-control study nested in an adolescent cohort of booster recipients who had received primary infantile HB vaccination but with residual anti-HBs titers <10 mIU/mL at 15-18 years of age. High-resolution phenotypes of human leukocyte antigen (HLA)-A, -B, and -DRB1 loci were determined by sequence-specific oligonucleotide probe hybridization. After controlling for pre-booster anti-HBs levels, the absences of HLA-A*02 and -DRB1*08, simply expressed as A*02(-) and -DRB1*08(-), and the presence of B*15 were significantly associated with elevated risks of non-response (post-booster anti-HBs titers<10 mIU/mL) to booster vaccination. The adjusted odds ratios (ORs) were 3.85 (CI, 1.82-8.33), 4.55 (CI, 1.23-16.67), 3.59 (CI, 1.40-9.17), respectively. There was multiplicative synergism between A*02 and B*15 on the risk of non-response to booster vaccination. The multivariate-adjusted ORs for A*02(-)/B*15, A*02(-)/B*15(-), A*02/B*15, and A*02/B*15(-) haplotypes were 20.39 (p=0.0003), 3.29 (p=0.007), 1.32 (p>0.05), and 1.0, respectively. Recent cigarette smoking and/or betel-quid chewing was associated with a 12-fold risk of non-response to booster vaccination. Further comparisons between responders and adolescents who had undetectable post-booster anti-HBs titers (<0.1 mIU/mL) demonstrated similar results. Our results indicated that response to booster HB vaccination as well as long-term immunological responses to HB vaccination are closely related with host genetic factors, and probably modified by recent substance use.
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Weihrauch MR, Bergwelt-Baildon MV, Kandic M, Weskott M, Klamp W, Rösler J, Schultze JL. T cell responses to hepatitis B surface antigen are detectable in non-vaccinated individuals. World J Gastroenterol 2008; 14:2529-33. [PMID: 18442200 PMCID: PMC2708364 DOI: 10.3748/wjg.14.2529] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate, whether humoral hepatitis-B-vaccine non-responders also fail to mount a T cell response and to compare these results to normal vaccines.
METHODS: Fourty-seven health care employees were enrolled in this study including all available non-responders (n = 13) with an anti-HBsAg titer < 10 kU/L and all available low-responders (n = 12) with an anti-HBsAg titer < 100 kU/L. Also, 12 consecutive anti-HBsAg negative pre-vaccination subjects were enrolled as well as 10 subjects (+7 from the vaccinated group) with titers > 1000 kU/L as controls. PBMC from all subjects were analyzed by IFN-γ and IL-4 ELISPOT assays for the presence of hepatitis B surface antigen (HBsAg) reactive T cells.
RESULTS: Non-responders and low-responders had no or only very limited T cell responses, respectively. Individuals responding to vaccination with the induction of a high anti-HBsAg titer showed a strong T cell response after the third vaccination. Surprisingly, these individuals showed response even before the first vaccination. T cell response to control antigens and mitogens was similar in all groups.
CONCLUSION: Our data suggest that there is no general immune deficiency in non-/low-responders. Thus, we hypothesize that the induction of anti-HBsAg responses by vaccination is significantly dependent on the pre-existing T cell repertoire against the specific antigen rather than the presence of a general T cell defect.
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Wörns MA, Teufel A, Kanzler S, Shrestha A, Victor A, Otto G, Lohse AW, Galle PR, Höhler T. Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases. Am J Gastroenterol 2008; 103:138-46. [PMID: 17970833 DOI: 10.1111/j.1572-0241.2007.01609.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Hepatitis A virus (HAV) or hepatitis B virus (HBV) superinfection is associated with an increased mortality in patients with chronic liver diseases (CLD). Despite official recommendations, it was reported that the vaccination rate against HAV is low in patients with chronic hepatitis C infection. To evaluate the situation in patients with autoimmune liver diseases, we conducted a retrospective cohort study. METHODS Susceptibility to HAV and HBV infections, course of HAV and HBV infections, vaccination rates against HAV and HBV, and efficacy of hepatitis A/B vaccines were evaluated by antibody testing in 225 patients with autoimmune liver diseases during 1,677 person-years. RESULTS Susceptibility to HAV/HBV infection was 51/86%. Incidence of HAV/HBV infection was 1.3/1.4 per 1,000 person-years. One HAV infection occurred, but the patient recovered spontaneously. Two patients were HBV-infected after receiving an anti-HBc-positive (antibody to hepatitis B core antigen) donor graft during orthotopic liver transplantation, and one of them developed chronic HBV infection. Vaccination rates were 11% (HBV) and 13% (HAV), respectively. Seventy-six percent of the vaccinated patients (HBV vaccine) developed anti-HBs (antibody to hepatitis surface antigen) >or=10 UI/L. Ten out of 13 vaccinated patients, showing a low or nonresponse to hepatitis B vaccine, had concomitant immunosuppressive therapy. Anti-HAV was detectable in all patients after administration of HAV vaccine. CONCLUSIONS Patients with autoimmune liver diseases have a high susceptibility to HAV and HBV infections. Vaccination rates are low in this patient cohort and efficacy of hepatitis B vaccine is reduced due to immunosuppressive therapy. Improving adherence to vaccine recommendations is essential to prevent HAV and HBV infections in patients with autoimmune liver diseases.
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Affiliation(s)
- Marcus A Wörns
- Department of Internal Medicine I, Johannes Gutenberg-University, Mainz, Germany
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