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Lei Y, Liu X, Du Q, Li Y. Bibliometric analysis of Helicobacter pylori vaccine development from 1993 to 2023. Front Microbiol 2025; 16:1479195. [PMID: 40165784 PMCID: PMC11955499 DOI: 10.3389/fmicb.2025.1479195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Background Helicobacter pylori infects half the global population and imposes a huge health burden. Developing a vaccine targeting H. pylori appears to be the most ideal preventive option. Based on Web of Science Core Collection (WoSCC) publications from 1993 to 2023, this study visually analyses the current status and trends of this field through bibliometric analysis. Methods H. pylori vaccine-related articles and reviews were retrieved from WoSCC. Microsoft Excel, CiteSpace, and VOS viewer were used to analyze the data. Results 1,199 publications from 1993 to 2023 were included in this bibliometric analysis. The results of this analysis show an overall upward trend in the number of publications and citations in this field. The United States is undoubtedly the most important contributor to this field in terms of publications, citation frequency, and national cooperation. Vaccine has the highest number of publications. Thomas F. Meyer is one of the leading scholars in the field. The most frequently cited article is "Immunization of mice with urease vaccine affords protection against H. pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses." The literature and keyword analysis show that effective treatments and multi-epitope vaccines are focus area in this field. New antigen combinations (such as UreB, outer membrane vesicles, etc.) of H. pylori vaccines are novel research directions and frontiers. Conclusion Our study is the first bibliometric analysis of H. pylori vaccine research. By summarizing the current status of H. pylori vaccine research, our study highlighted the current research direction and frontier, providing valuable data for researchers to grasp the latest advancements and accelerate H. pylori vaccine development.
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Affiliation(s)
- Yeqing Lei
- Department of Gastroenterology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Xiaochen Liu
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qin Du
- Department of Gastroenterology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yan Li
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Umar Z, Tang JW, Marshall BJ, Tay ACY, Wang L. Rapid diagnosis and precision treatment of Helicobacter pylori infection in clinical settings. Crit Rev Microbiol 2025; 51:369-398. [PMID: 38910506 DOI: 10.1080/1040841x.2024.2364194] [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: 02/28/2024] [Revised: 05/08/2024] [Accepted: 05/25/2024] [Indexed: 06/25/2024]
Abstract
Helicobacter pylori is a gram-negative bacterium that colonizes the stomach of approximately half of the worldwide population, with higher prevalence in densely populated areas like Asia, the Caribbean, Latin America, and Africa. H. pylori infections range from asymptomatic cases to potentially fatal diseases, including peptic ulcers, chronic gastritis, and stomach adenocarcinoma. The management of these conditions has become more difficult due to the rising prevalence of drug-resistant H. pylori infections, which ultimately lead to gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. In 1994, the International Agency for Research on Cancer (IARC) categorized H. pylori as a Group I carcinogen, contributing to approximately 780,000 cancer cases annually. Antibiotic resistance against drugs used to treat H. pylori infections ranges between 15% and 50% worldwide, with Asian countries having exceptionally high rates. This review systematically examines the impacts of H. pylori infection, the increasing prevalence of antibiotic resistance, and the urgent need for accurate diagnosis and precision treatment. The present status of precision treatment strategies and prospective approaches for eradicating infections caused by antibiotic-resistant H. pylori will also be evaluated.
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Affiliation(s)
- Zeeshan Umar
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jia-Wei Tang
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
| | - Barry J Marshall
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
- Marshall International Digestive Diseases Hospital, Zhengzhou University, Zhengzhou, Henan Province, China
- Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Alfred Chin Yen Tay
- Marshall Laboratory of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- The Marshall Centre for Infectious Diseases Research and Training, The University of Western Australia, Crawley, Western Australia, China
- Marshall International Digestive Diseases Hospital, Zhengzhou University, Zhengzhou, Henan Province, China
- Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Liang Wang
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
- Division of Microbiology and Immunology, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, China
- Center for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, China
- School of Agriculture and Food Sustainability, University of Queensland, Brisbane, Queensland, Australia
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Nahian M, Khan MR, Rahman F, Reza HM, Bayil I, Nodee TA, Basher T, Sany MR, Munmun RN, Habib SMA, Mazumder L, Acharjee M. Immunoinformatic strategy for developing multi-epitope subunit vaccine against Helicobacter pylori. PLoS One 2025; 20:e0318750. [PMID: 39919064 PMCID: PMC11805379 DOI: 10.1371/journal.pone.0318750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 01/20/2025] [Indexed: 02/09/2025] Open
Abstract
Helicobacter pylori is a gram-negative bacterium that persistently infects the human stomach, leading to peptic ulcers, gastritis, and an increased risk of gastric cancer. The extremophilic characteristics of this bacterium make it resistant to current drug treatments, and there are no licensed vaccines available against H. pylori. Computational approaches offer a viable alternative for designing antigenic, stable, and safe vaccines to control infections caused by this pathogen. In this study, we employed an immunoinformatic strategy to design a set of candidate multi-epitope subunit vaccines by combining the most potent B and T cell epitopes from three targeted antigenic proteins (BabA, CagA, and VacA). Out of the 12 hypothetical vaccines generated, two (HP_VaX_V1 and HP_VaX_V2) were found to be strongly immunogenic, non-allergenic, and structurally stable. The proposed vaccine candidates were evaluated based on population coverage, molecular docking, immune simulations, codon adaptation, secondary mRNA structure, and in silico cloning. The vaccine candidates exhibited antigenic scores of 1.19 and 1.01, with 93.5% and 90.4% of the most rama-favored regions, respectively. HP_VaX_V1 and HP_VaX_V2 exhibited the strongest binding affinity towards TLR-7 and TLR-8, as determined by molecular docking simulations (ΔG = -20.3 and -20.9, respectively). Afterward, multi-scale normal mode analysis simulation revealed the structural flexibility and stability of vaccine candidates. Additionally, immune simulations showed elevated levels of cell-mediated immunity, while repeated exposure simulations indicated rapid antigen clearance. Finally, in silico cloning was performed using the expression vector pET28a (+) with optimized restriction sites to develop a viable strategy for large-scale production of the chosen vaccine constructs. These analyses suggest that the proposed vaccines may elicit potent immune responses against H. pylori, but laboratory validation is needed to verify their safety and immunogenicity.
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Affiliation(s)
- Md. Nahian
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Md. Rasel Khan
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Fabiha Rahman
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Hossain Mohammed Reza
- Faculty of Life and Health Sciences, School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, Northern Ireland
| | - Imren Bayil
- Department of Bioinformatics and Computational Biology, Gaziantep University, Gaziantep, Turkey
| | | | - Tabassum Basher
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | | | | | | | - Lincon Mazumder
- Department of Microbiology, Jagannath University, Dhaka, Bangladesh
| | - Mrityunjoy Acharjee
- Department of Microbiology, Stamford University Bangladesh, Dhaka, Bangladesh
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Elbehiry A, Marzouk E, Abalkhail A, Sindi W, Alzahrani Y, Alhifani S, Alshehri T, Anajirih NA, ALMutairi T, Alsaedi A, Alzaben F, Alqrni A, Draz A, Almuzaini AM, Aljarallah SN, Almujaidel A, Abu-Okail A. Pivotal role of Helicobacter pylori virulence genes in pathogenicity and vaccine development. Front Med (Lausanne) 2025; 11:1523991. [PMID: 39850097 PMCID: PMC11756510 DOI: 10.3389/fmed.2024.1523991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/13/2024] [Indexed: 01/25/2025] Open
Abstract
One of the most prevalent human infections is Helicobacter pylori (H. pylori), which affects more than half of the global population. Although H. pylori infections are widespread, only a minority of individuals develop severe gastroduodenal disorders. The global resistance of H. pylori to antibiotics has reached concerning levels, significantly impacting the effectiveness of treatment. Consequently, the development of vaccines targeting virulence factors may present a viable alternative for the treatment and prevention of H. pylori infections. This review aims to provide a comprehensive overview of the current understanding of H. pylori infection, with a particular focus on its virulence factors, pathophysiology, and vaccination strategies. This review discusses various virulence factors associated with H. pylori, such as cytotoxin-associated gene A (cagA), vacuolating cytotoxin gene (vacA), outer membrane proteins (OMPs), neutrophil-activated protein (NAP), urease (ure), and catalase. The development of vaccines based on these virulence characteristics is essential for controlling infection and ensuring long-lasting protection. Various vaccination strategies and formulations have been tested in animal models; however, their effectiveness and reproducibility in humans remain uncertain. Different types of vaccines, including vector-based vaccines, inactivated whole cells, genetically modified protein-based subunits, and multiepitope nucleic acid (DNA) vaccines, have been explored. While some vaccines have demonstrated promising results in murine models, only a limited number have been successfully tested in humans. This article provides a thorough evaluation of recent research on H. pylori virulence genes and vaccination methods, offering valuable insights for future strategies to address this global health challenge.
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Affiliation(s)
- Ayman Elbehiry
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Eman Marzouk
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Adil Abalkhail
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Wael Sindi
- Department of Population, Public and Environmental Health, General Administration of Health Services, Ministry of Defense, Riyadh, Saudi Arabia
| | - Yasir Alzahrani
- Department of Psychiatry, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Salem Alhifani
- Department of Psychiatry, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Turki Alshehri
- Department of Dental, Alhada Armed Forces Hospital, Taif, Saudi Arabia
| | - Nuha Abdulaziz Anajirih
- Department of Medical Emergency Services, Faculty of Health Sciences, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia
| | - Turki ALMutairi
- Department of Education and Training, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia
| | - Ahmad Alsaedi
- Department of Education and Training, Prince Sultan Military College of Health Sciences, Dammam, Saudi Arabia
| | - Feras Alzaben
- Department of Food Service, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Abdullah Alqrni
- Department of Preventive Medicine, King Fahad Armed Hospital, Jeddah, Saudi Arabia
| | - Abdelmaged Draz
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Abdulaziz M. Almuzaini
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Sahar N. Aljarallah
- Department of Pharmacy Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Abdulrahman Almujaidel
- Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Akram Abu-Okail
- Department of Veterinary Preventive Medicine, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
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Zhang H, Liu Z, Li Y, Tao Z, Shen L, Shang Y, Huang X, Liu Q. Adjuvants for Helicobacter pylori vaccines: Outer membrane vesicles provide an alternative strategy. Virulence 2024; 15:2425773. [PMID: 39501551 PMCID: PMC11583678 DOI: 10.1080/21505594.2024.2425773] [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: 01/29/2024] [Revised: 09/19/2024] [Accepted: 10/31/2024] [Indexed: 11/12/2024] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that colonizes the human stomach, leading to various gastric diseases. The efficacy of traditional treatments, such as bismuth-based triple and quadruple therapies, has been reduced due to increasing antibiotic resistance and drug toxicity. As a result, the development of effective vaccines was proposed to control H. pylori-induced infections; however, one of the primary challenges is the lack of potent adjuvants. Although various adjuvants, both toxic (e.g. cholera toxin and Escherichia coli heat-labile toxin) and non-toxic (e.g. aluminum and propolis), have been tested for vaccine development, no clinically favorable adjuvants have been identified due to high toxicity, weak immunostimulatory effects, inability to elicit specific immune responses, or latent side effects. Outer membrane vesicles (OMVs), mainly secreted by gram-negative bacteria, have emerged as promising candidates for H. pylori vaccine adjuvants due to their potential applications. OMVs enhance mucosal immunity and Th1 and Th17 cell responses, which have been recognized to have protective effects and guarantee safety and efficacy. The development of an effective vaccine against H. pylori infection is ongoing, with clinical trials expected in the future.
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Affiliation(s)
- Hanchi Zhang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- The Second Clinical Medical College, Nanchang University, Nanchang, China
| | - Zhili Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yi Li
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- The First Clinical Medical College, Nanchang University, Nanchang, China
| | - Ziwei Tao
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Lu Shen
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yinpan Shang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xiaotian Huang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Qiong Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
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Hossain MK, Davidson M, Feehan J, Matsoukas JM, Nurgali K, Apostolopoulos V. A methamphetamine vaccine using short monoamine and diamine peptide linkers and poly-mannose. Bioorg Med Chem 2024; 113:117930. [PMID: 39306972 DOI: 10.1016/j.bmc.2024.117930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 08/20/2024] [Accepted: 09/16/2024] [Indexed: 10/13/2024]
Abstract
Methamphetamine (METH) substance use disorder is a long-standing and ever-growing public health concern. Efforts to develop successful immunotherapies are ongoing with vaccines that generate strong antibody responses are an area of significant research interest. Herein, we describe the development of a METH Hapten conjugate vaccine comprised of either two short-length peptides as linkers and mannan as an immunogenic delivery carrier. Initially, Hapten 1 (with a monoamine linker) and Hapten 2 (with a diamine linker) were synthesised. Each step of the Hapten synthesis were characterized by LC-MS and purified by Flash Chromatography and the identity of the purified Haptens were confirmed by 1H NMR. Haptens were conjugated with mannan (a polymannose), and conjugation efficiency was confirmed by LC-MS, TLC, 1H NMR, and 2,4 DNPH tests. The immunogenic potential of the two conjugated vaccines were assessed in mice with a 3-dose regimen. Concentrations of anti-METH antibodies were measured by enzyme-linked immunosorbent assay. All the analytical techniques confirmed the identity of Hapten 1 and 2 during the synthetic phase. Similarly, all the analytical approaches confirmed the conjugation between the Haptens and mannan. Mouse immunogenicity studies confirmed that both vaccine candidates were immunogenic and the vaccine with the monoamine linker plus adjuvants induced the highest antibody response after the second booster.
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Affiliation(s)
- Md Kamal Hossain
- Institute for Health and Sport, Victoria University, Immunology and Translational Research Group, Werribee, VIC 3030, Australia; Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, United States
| | - Majid Davidson
- Institute for Health and Sport, Victoria University, Immunology and Translational Research Group, Werribee, VIC 3030, Australia
| | - Jack Feehan
- Immunology Program, Australian Institute for Musculoskeletal Sciences (AIMSS), Melbourne, VIC 3021, Australia; School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia
| | - John M Matsoukas
- Institute for Health and Sport, Victoria University, Immunology and Translational Research Group, Werribee, VIC 3030, Australia; NewDrug PC, Patras Science Park, Patras 26504, Greece; Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta T2N4N1, Canada; Department of Chemistry, University of Patras, Patras 26500, Greece
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Immunology and Translational Research Group, Werribee, VIC 3030, Australia; Regenerative Medicine and Stem Cell Program, Australian Institute for Musculoskeletal Sciences, Melbourne, VIC 3021, Australia; Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
| | - Vasso Apostolopoulos
- Immunology Program, Australian Institute for Musculoskeletal Sciences (AIMSS), Melbourne, VIC 3021, Australia; School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
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Zhang Z, Cui M, Ji X, Su G, Zhang YX, Du L. Candidate Antigens and the Development of Helicobacter pylori Vaccines. Helicobacter 2024; 29:e13128. [PMID: 39177204 DOI: 10.1111/hel.13128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND Infection with Helicobacter pylori (Hp) mostly occurs during childhood, and persistent infection may lead to severe gastric diseases and even gastric cancer. Currently, the primary method for eradicating Hp is through antibiotic treatment. However, the increasing multidrug resistance in Hp strains has diminished the effectiveness of antibiotic treatments. Vaccination could potentially serve as an effective intervention to resolve this issue. AIMS Through extensive research and analysis of the vital protein characteristics involved in Hp infection, we aim to provide references for subsequent vaccine antigen selection. Additionally, we summarize the current research and development of Hp vaccines in order to provide assistance for future research. MATERIALS AND METHODS Utilizing the databases PubMed and the Web of Science, a comprehensive search was conducted to compile articles pertaining to Hp antigens and vaccines. The salient aspects of these articles were then summarized to provide a detailed overview of the current research landscape in this field. RESULTS Several potential antigens have been identified and introduced through a thorough understanding of the infection process and pathogenic mechanisms of Hp. The conserved and widely distributed candidate antigens in Hp, such as UreB, HpaA, GGT, and NAP, are discussed. Proteins such as CagA and VacA, which have significant virulence effects but relatively poor conservatism, require further evaluation. Emerging antigens like HtrA and dupA have significant research value. In addition, vaccines based on these candidate antigens have been compiled and summarized. CONCLUSIONS Vaccines are a promising method for preventing and treating Hp. While some Hp vaccines have achieved promising results, mature products are not yet available on the market. Great efforts have been directed toward developing various types of vaccines, underscoring the need for developers to select appropriate antigens and vaccine formulations to improve success rates.
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Affiliation(s)
- Zhanhua Zhang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Research and Development Centre, Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd., Beijing, China
- Beijing Bacterial Vaccine Engineering Research Centre, Beijing, China
| | - Man Cui
- Research and Development Centre, Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd., Beijing, China
- Beijing Bacterial Vaccine Engineering Research Centre, Beijing, China
| | - Xiaohui Ji
- Research and Development Centre, Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd., Beijing, China
- Beijing Bacterial Vaccine Engineering Research Centre, Beijing, China
| | - Guimin Su
- Research and Development Centre, Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd., Beijing, China
- Beijing Bacterial Vaccine Engineering Research Centre, Beijing, China
| | - Yi-Xuan Zhang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Lin Du
- Research and Development Centre, Beijing Zhifei Lvzhu Biopharmaceutical Co., Ltd., Beijing, China
- Beijing Bacterial Vaccine Engineering Research Centre, Beijing, China
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Dayhimi V, Ziadlou F, Nafian S, Nafian F. An Immunoinformatic Approach to Designing a Multi-epitope Vaccine against Helicobacter pylori with the VacA Toxin and BabA Adhesion. CURR PROTEOMICS 2024; 21:97-112. [DOI: 10.2174/0115701646302487240524103934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 03/27/2024] [Accepted: 04/27/2024] [Indexed: 01/03/2025]
Abstract
Objective:
Helicobacter pylori, as a carcinogen, has been related to the development of
gastric cancer, particularly in developing countries. The main challenge with therapy is the recurrence
of antibiotic-resistant bacteria, and vaccination is still a problem. Therefore, the objective of
the current study was to rationally design a multi-epitope vaccine using two immunogenic proteins
found in H. pylori.
Methods:
Promising epitopes for the Leb-binding adhesin A (BabA) and vacuolating cytotoxin
(VacA) proteins were characterized through an immunoinformatics approach. Epitope-rich fragments
were selected based on high-binding affinities with HLA classes I and II to be specifically
presented to B and T lymphocytes and to selectively elicit both humoral and cellular immune responses.
Results:
Six constructs were planned by fusing these fragments in different arrangements with the
help of GPGPG linkers. The most stable three-dimensional structure was found in Construct 6 during
molecular dynamics. To improve immunogenicity and stability, an adjuvant called human β-
defensin 2 (hBD-2) was joined to the N-terminus of Construct 6. Following molecular docking,
the final vaccine reacted appropriately with each toll-like receptor 2 (TLR-2), TLR3, and TLR-4.
The final DNA sequence was optimized for expression in E. coli K12 and in silico cloned into a
pET-28a(+) plasmid. As a result of the vaccination in silico, substantial responses were developed
against H. pylori.
Conclusion:
According to the immune response simulation, activated B and T lymphocytes and
memory cell production increased. Macrophages and dendritic cells proliferated continuously, and
IFN-γ and Cytokines, such as IL-2 were raised.
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Affiliation(s)
- Viana Dayhimi
- Department of Biochemistry, University of Windsor, Ontario, Canada
| | - Fatemeh Ziadlou
- Department of Medical Biotechnology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Simin Nafian
- Department of Stem Cell and Regenerative Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering & Biotechnology (NIGEB), Tehran, Iran
| | - Fatemeh Nafian
- Department of Medical Laboratory Sciences, Faculty of Paramedical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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9
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Muñoz-Alía MÁ, Nace RA, Balakrishnan B, Zhang L, Packiriswamy N, Singh G, Warang P, Mena I, Narjari R, Vandergaast R, Peng KW, García-Sastre A, Schotsaert M, Russell SJ. Surface-modified measles vaccines encoding oligomeric, prefusion-stabilized SARS-CoV-2 spike glycoproteins boost neutralizing antibody responses to Omicron and historical variants, independent of measles seropositivity. mBio 2024; 15:e0292823. [PMID: 38193729 PMCID: PMC10865805 DOI: 10.1128/mbio.02928-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
Serum titers of SARS-CoV-2-neutralizing antibodies (nAbs) correlate well with protection from symptomatic COVID-19 but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are lifelong after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We, therefore, sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain, and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive in vivo mouse testing demonstrated the potent induction of high titer nAbs in measles-immune mice and confirmed the significant contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin display of the SARS-CoV-2 spike glycoprotein. In animals primed and boosted with a measles virus (MeV) vaccine encoding the ancestral SARS-CoV-2 spike, high-titer nAb responses against ancestral virus strains were only weakly cross-reactive with the Omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the Omicron BA.1 spike, antibody titers to both ancestral and Omicron strains were robustly elevated, and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that by engineering the antigen, we can develop potent measles-based vaccine candidates against SARS-CoV-2.IMPORTANCEAlthough the live-attenuated measles virus (MeV) is one of the safest and most efficacious human vaccines, a measles-vectored COVID-19 vaccine candidate expressing the SARS-CoV-2 spike failed to elicit neutralizing antibody (nAb) responses in a phase-1 clinical trial, especially in measles-immune individuals. Here, we constructed a comprehensive panel of MeV-based COVID-19 vaccine candidates using a MeV with extensive modifications on the envelope glycoproteins (MeV-MR). We show that artificial trimerization of the spike is critical for the induction of nAbs and that their magnitude can be significantly augmented when the spike protein is synchronously fused to a dodecahedral scaffold. Furthermore, preexisting measles immunity did not abolish heterologous immunity elicited by our vector. Our results highlight the importance of antigen optimization in the development of spike-based COVID-19 vaccines and therapies.
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Affiliation(s)
- Miguel Á. Muñoz-Alía
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Vyriad Inc, Rochester, Minnesota, USA
| | - Rebecca A. Nace
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Lianwen Zhang
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Gagandeep Singh
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Prajakta Warang
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ignacio Mena
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | | | - Kah-Whye Peng
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Vyriad Inc, Rochester, Minnesota, USA
- Imanis Life Sciences, Rochester, Minnesota, USA
| | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Stephen J. Russell
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Vyriad Inc, Rochester, Minnesota, USA
- Imanis Life Sciences, Rochester, Minnesota, USA
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
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10
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Ji Q, Ma J, Wang S, Liu Q. Embedding of exogenous B cell epitopes on the surface of UreB structure generates a broadly reactive antibody response against Helicobacter pylori. Immunology 2024; 171:212-223. [PMID: 37899627 DOI: 10.1111/imm.13703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/28/2023] [Indexed: 10/31/2023] Open
Abstract
Since Helicobacter pylori (H. pylori) resistance to antibiotic regimens has increased, vaccination is becoming an increasingly important alternative therapy to control H. pylori infection. UreB, FlaA, AlpB, SabA, and HpaA proteins of H. pylori were previously proved to be used as candidate vaccine antigens. Here, we developed an engineered antigen based on a recombinant chimeric protein containing a structural scaffold from UreB and B cell epitopes from FlaA, AlpB, SabA, and HpaA. The multi-epitope chimeric antigen, named MECU, could generate a broadly reactive antibody response including antigen-specific antibodies and neutralising antibodies against H. pylori urease and adhesins. Moreover, therapeutic immunisation with MECU could reduce H. pylori colonisation in the stomach and protect the stomach in BALB/c mice. This study not only provides promising immunotherapy to control H. pylori infection but also offers a reference for antigen engineering against other pathogens.
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Affiliation(s)
- Qianyu Ji
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Junfei Ma
- College of Agriculture and Forestry, Linyi University, Linyi, China
| | - Shuying Wang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Qing Liu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
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11
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Hasanuzzaman M, Bang CS, Gong EJ. Antibiotic Resistance of Helicobacter pylori: Mechanisms and Clinical Implications. J Korean Med Sci 2024; 39:e44. [PMID: 38288543 PMCID: PMC10825452 DOI: 10.3346/jkms.2024.39.e44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/29/2023] [Indexed: 02/01/2024] Open
Abstract
Helicobacter pylori is a pathogenic bacterium associated with various gastrointestinal diseases, including chronic gastritis, peptic ulcers, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. The increasing rates of H. pylori antibiotic resistance and the emergence of multidrug-resistant strains pose significant challenges to its treatment. This comprehensive review explores the mechanisms underlying the resistance of H. pylori to commonly used antibiotics and the clinical implications of antibiotic resistance. Additionally, potential strategies for overcoming antibiotic resistance are discussed. These approaches aim to improve the treatment outcomes of H. pylori infections while minimizing the development of antibiotic resistance. The continuous evolution of treatment perspectives and ongoing research in this field are crucial for effectively combating this challenging infection.
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Affiliation(s)
- Md Hasanuzzaman
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Eun Jeong Gong
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea.
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12
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Graham DY. Helicobacter pylori. Curr Top Microbiol Immunol 2024; 445:127-154. [PMID: 34224014 DOI: 10.1007/82_2021_235] [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] [Indexed: 10/19/2022]
Abstract
Helicobacter pylori (H. pylori) is an important human pathogen etiologically associated with peptic ulcers and gastric cancer. The infection is present in approximately one-half of the world's population. Population-based H. pylori eradiation has confirmed that cure or prevention of the infection produces a marked reduction in gastric cancer and peptic ulcer disease. Antimicrobial therapy has become increasingly ineffective, and complexity and costs of antimicrobial therapy for infected individuals residing in and, immigrating from, the developing world combined with the cost of treatment for cancer make vaccine development a cost-effective alternative. Challenge studies allowed making a "go-no go" decision regarding vaccine effectiveness. We provide detailed protocols regarding challenge strain selection and administration as well as guidance regarding the clinical and laboratory tests used to confirm and monitor experimental infection. Experience shows that reliance of noninvasive methods led to the erroneous conclusion that some subjects were not infected. The current data suggests that histologic assessment of gastric mucosal biopsies may be one of the most sensitive and specific means of assessment of the presence of experimental infection as well as of successful H. pylori eradication. We recommend detailed recommendations for acquiring, processing, embedding, sectioning, and examining the gastric biopsies.
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Affiliation(s)
- David Y Graham
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, RM 3A-390A (111D), 2002 Holcombe Boulevard, Houston, TX, 77030, USA.
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13
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Keshri AK, Kaur R, Rawat SS, Arora N, Pandey RK, Kumbhar BV, Mishra A, Tripathi S, Prasad A. Designing and development of multi-epitope chimeric vaccine against Helicobacter pylori by exploring its entire immunogenic epitopes: an immunoinformatic approach. BMC Bioinformatics 2023; 24:358. [PMID: 37740175 PMCID: PMC10517479 DOI: 10.1186/s12859-023-05454-2] [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: 03/16/2023] [Accepted: 08/25/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Helicobacter pylori is a prominent causative agent of gastric ulceration, gastric adenocarcinoma and gastric lymphoma and have been categorised as a group 1 carcinogen by WHO. The treatment of H. pylori with proton pump inhibitors and antibiotics is effective but also leads to increased antibiotic resistance, patient dissatisfaction, and chances of reinfection. Therefore, an effective vaccine remains the most suitable prophylactic option for mass administration against this infection. RESULTS We modelled a multi-chimera subunit vaccine candidate against H. pylori by screening its secretory/outer membrane proteins. We identified B-cell, MHC-II and IFN-γ-inducing epitopes within these proteins. The population coverage, antigenicity, physiochemical properties and secondary structure were evaluated using different in-silico tools, which showed it can be a good and effective vaccine candidate. The 3-D construct was predicted, refined, validated and docked with TLRs. Finally, we performed the molecular docking/simulation and immune simulation studies to validate the stability of interaction and in-silico cloned the epitope sequences into a pET28b(+) plasmid vector. CONCLUSION The multiepitope-constructed vaccine contains T- cells, B-cells along with IFN-γ inducing epitopes that have the property to generate good cell-mediated immunity and humoral response. This vaccine can protect most of the world's population. The docking study and immune simulation revealed a good binding with TLRs and cell-mediated and humoral immune responses, respectively. Overall, we attempted to design a multiepitope vaccine and expect this vaccine will show an encouraging result against H. pylori infection in in-vivo use.
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Affiliation(s)
- Anand K Keshri
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, Mandi, 175005, India
| | - Rimanpreet Kaur
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, Mandi, 175005, India
| | - Suraj S Rawat
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, Mandi, 175005, India
| | - Naina Arora
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, Mandi, 175005, India
| | - Rajan K Pandey
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177, Stockholm, Sweden
| | | | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, 342011, India
| | - Shweta Tripathi
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, Mandi, 175005, India.
| | - Amit Prasad
- School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, Mandi, 175005, India.
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14
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Li S, Zhao W, Xia L, Kong L, Yang L. How Long Will It Take to Launch an Effective Helicobacter pylori Vaccine for Humans? Infect Drug Resist 2023; 16:3787-3805. [PMID: 37342435 PMCID: PMC10278649 DOI: 10.2147/idr.s412361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/02/2023] [Indexed: 06/22/2023] Open
Abstract
Helicobacter pylori infection often occurs in early childhood, and can last a lifetime if not treated with medication. H. pylori infection can also cause a variety of stomach diseases, which can only be treated with a combination of antibiotics. Combinations of antibiotics can cure H. pylori infection, but it is easy to relapse and develop drug resistance. Therefore, a vaccine is a promising strategy for prevention and therapy for the infection of H. pylori. After decades of research and development, there has been no appearance of any H. pylori vaccine reaching the market, unfortunately. This review summarizes the aspects of candidate antigens, immunoadjuvants, and delivery systems in the long journey of H. pylori vaccine research, and also introduces some clinical trials that have displayed encouraging or depressing results. Possible reasons for the inability of an H. pylori vaccine to be available over the counter are cautiously discussed and some propositions for the future of H. pylori vaccines are outlined.
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Affiliation(s)
- Songhui Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
| | - Wenfeng Zhao
- Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
| | - Lei Xia
- Bloomage Biotechnology Corporation Limited, Jinan, People’s Republic of China
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
| | - Lei Yang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009People’s Republic of China
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15
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Luo Q, Liu N, Pu S, Zhuang Z, Gong H, Zhang D. A review on the research progress on non-pharmacological therapy of Helicobacter pylori. Front Microbiol 2023; 14:1134254. [PMID: 37007498 PMCID: PMC10063898 DOI: 10.3389/fmicb.2023.1134254] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/03/2023] [Indexed: 03/19/2023] Open
Abstract
Helicobacter pylori is a pathogenic microorganism that mainly resides in the human stomach and is the major cause of chronic gastritis, peptic ulcer and gastric cancer. Up to now, the treatment of Helicobacter pylori has been predominantly based on a combination of antibiotics and proton pump inhibitors. However, the increasing antibiotic resistance greatly limits the efficacy of anti-Helicobacter pylori treatment. Turning to non-antibiotic or non-pharmacological treatment is expected to solve this problem and may become a new strategy for treating Helicobacter pylori. In this review, we outline Helicobacter pylori's colonization and virulence mechanisms. Moreover, a series of non-pharmacological treatment methods for Helicobacter pylori and their mechanisms are carefully summarized, including probiotics, oxygen-rich environment or hyperbaric oxygen therapy, antibacterial photodynamic therapy, nanomaterials, antimicrobial peptide therapy, phage therapy and modified lysins. Finally, we provide a comprehensive overview of the challenges and perspectives in developing new medical technologies for treating Helicobacter pylori without drugs.
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Affiliation(s)
- Qian Luo
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Na Liu
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Sugui Pu
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Ze Zhuang
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Hang Gong
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Dekui Zhang
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
- Key Laboratory of Digestive Diseases, LanZhou University Second Hospital, Lanzhou, China
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16
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Castagnini LA, Gilger MA. Helicobacter pylori. PRINCIPLES AND PRACTICE OF PEDIATRIC INFECTIOUS DISEASES 2023:954-959.e5. [DOI: 10.1016/b978-0-323-75608-2.00174-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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17
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Fu HW, Lai YC. The Role of Helicobacter pylori Neutrophil-Activating Protein in the Pathogenesis of H. pylori and Beyond: From a Virulence Factor to Therapeutic Targets and Therapeutic Agents. Int J Mol Sci 2022; 24:ijms24010091. [PMID: 36613542 PMCID: PMC9820732 DOI: 10.3390/ijms24010091] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Helicobacter pylori neutrophil-activating protein (HP-NAP), a major virulence factor of H. pylori, plays a role in bacterial protection and host inflammation. HP-NAP activates a variety of innate immune cells, including neutrophils, monocytes, and mast cells, to induce their pro-oxidant and pro-inflammatory activities. This protein also induces T-helper type 1 (Th1) immune response and cytotoxic T lymphocyte (CTL) activity, supporting that HP-NAP is able to promote gastric inflammation by activation of adaptive immune responses. Thus, HP-NAP is a potential therapeutic target for the treatment of H. pylori-induced gastric inflammation. The inflammatory responses triggered by HP-NAP are mediated by a PTX-sensitive G protein-coupled receptor and Toll-like receptor 2. Drugs designed to block the interactions between HP-NAP and its receptors could alleviate the inflammation in gastric mucosa caused by H. pylori infection. In addition, HP-NAP acts as a promising therapeutic agent for vaccine development, allergy treatment, and cancer immunotherapy. The high antigenicity of HP-NAP makes this protein a component of vaccines against H. pylori infection. Due to its immunomodulatory activity to stimulate the Th1-inducing ability of dendritic cells, enhance Th1 immune response and CTL activity, and suppress Th2-mediated allergic responses, HP-NAP could also act as an adjuvant in vaccines, a drug candidate against allergic diseases, and an immunotherapeutic agent for cancer. This review highlights the role of HP-NAP in the pathogenesis of H. pylori and the potential for this protein to be a therapeutic target in the treatment of H. pylori infection and therapeutic agents against H. pylori-associated diseases, allergies, and cancer.
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Affiliation(s)
- Hua-Wen Fu
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
- Department of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan
- Correspondence: ; Tel.: +886-3-574-2485
| | - Yu-Chang Lai
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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18
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Muñoz-Alía MÁ, Nace RA, Balakrishnan B, Zhang L, Packiriswamy N, Singh G, Warang P, Mena I, Narjari R, Vandergaast R, García-Sastre A, Schotsaert M, Russell SJ. Surface-modified measles vaccines encoding oligomeric, fusion-stabilized SARS-CoV-2 spike glycoproteins bypass measles seropositivity, boosting neutralizing antibody responses to omicron and historical variants. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2022:2022.12.16.520799. [PMID: 36561187 PMCID: PMC9774211 DOI: 10.1101/2022.12.16.520799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/11/2023]
Abstract
Serum titers of SARS-CoV-2 neutralizing antibodies (nAb) correlate well with protection from symptomatic COVID-19, but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are life-long after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We therefore sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive in vivo mouse testing demonstrated potent induction of high titer nAb in measles-immune mice and confirmed the significant incremental contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin-display of the SARS-CoV-2 spike glycoprotein, and vaccine resurfacing. In animals primed and boosted with a MeV vaccine encoding the ancestral SARS-CoV-2 spike, high titer nAb responses against ancestral virus strains were only weakly cross-reactive with the omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the omicron BA.1 spike, antibody titers to both ancestral and omicron strains were robustly elevated and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that antigen engineering can enable the development of potent measles-based SARS-CoV-2 vaccine candidates.
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Affiliation(s)
- Miguel Á. Muñoz-Alía
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
- Vyriad Inc, Rochester, MN, USA
| | - Rebecca A. Nace
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Lianwen Zhang
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | | | - Gagandeep Singh
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Prajakta Warang
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ignacio Mena
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen J. Russell
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
- Vyriad Inc, Rochester, MN, USA
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Imanis Life Sciences, Rochester, MN, USA
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
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19
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Zhang X, Sang S, Guan Q, Tao H, Wang Y, Liu C. Oral Administration of a Shigella 2aT32-Based Vaccine Expressing UreB-HspA Fusion Antigen With and Without Parenteral rUreB-HspA Boost Confers Protection Against Helicobacter pylori in Mice Model. Front Immunol 2022; 13:894206. [PMID: 35769459 PMCID: PMC9234132 DOI: 10.3389/fimmu.2022.894206] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative pathogen classified as a class I carcinogen. The H. pylori urease B subunit (UreB) and heat shock protein A (HspA) are two important vaccine candidate antigens. In this study, we evaluated the immunogenicity and immunoprotective effect of the attenuated Shigella vector vaccine SH02 expressing the UreB-HspA fusion protein of H. pylori in a mouse model. Oral SH02 with or without subcutaneous injection of rUreB-HspA induced antigen-specific serum IgG, mucosal sIgA, and T cells immune response. Subcutaneous injection of the candidate antigen rUreB-HspA enhanced the level of serum antigen-specific IgG antibodies (p < 0.0001) and the levels of IgG1/IgG2a/IgG2b subtypes. In addition, injection boost also increased the proportion of spleen antigen-specific CD4+CD154+ T cells (p < 0.001), and the proportion of CD4+CD154+ T cells that secrete IFN-γ and IL-17A. Following the H. pylori challenge, the levels of H. pylori colonization in the two experimental groups (Groups A and B) significantly reduced compared with the control group (p < 0.001), indicating that the candidate vaccine yielded a preventive effect of anti-H.pylori infection. Compared with the non-subcutaneous booster injection group (Group A), the subcutaneous booster injection group (Group B) exhibited less gastric inflammation, but there was no significant difference in the level of colonization (p > 0.05). These results lay a foundation for the development of a vaccine against H. pylori and the optimization of immunization methods and procedures to prevent H. pylori infection.
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Affiliation(s)
- Xin Zhang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
- Department of Pharmacy, Medical Supplies Center, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Shuli Sang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Qing Guan
- State Key Laboratory of Pathogen and Biosecurity, Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Haoxia Tao
- State Key Laboratory of Pathogen and Biosecurity, Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Yanchun Wang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
- *Correspondence: Chunjie Liu, ; Yanchun Wang,
| | - Chunjie Liu
- State Key Laboratory of Pathogen and Biosecurity, Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
- *Correspondence: Chunjie Liu, ; Yanchun Wang,
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20
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Calado CRC. Antigenic and conserved peptides from diverse Helicobacter pylori antigens. Biotechnol Lett 2022; 44:535-545. [PMID: 35277779 PMCID: PMC8916697 DOI: 10.1007/s10529-022-03238-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 02/14/2022] [Indexed: 12/20/2022]
Abstract
Since the revolutionary finding of Helicobacter pylori as a common bacterial infection, that a high research effort for its eradication has been conducted. Epitope based-vaccine presents advantages over protein-based, as they can be designed to contain epitopes from diverse proteins, therefore, more easily representing the immune-variability of the bacterial population, while minimizing the toxicity associated to some whole proteins. In the present work, an iterative method, to design antigenic and conserved B-epitopes from diverse virulent factors of H. pylori, was established. The method considered the trade-off between epitopes antigenicity and conservation among the bacterial population. For the method validation, five virulent factors from H. pylori were selected. From each virulent factor, two epitopes were predicted, each with twelve residues of aminoacids. The corresponding ten peptides were synthesised and evaluated by enzyme-linked immunosorbent assay using polyclonal antibodies raised against a specific H. pylori strain. All ten peptides were recognised by the antibodies and were consequently antigenic and conserved. This result could strongly contribute to the design of a multivalent epitope-based vaccine, representing the immunogenetic variability within the bacterial population, leading to a sustained and effective immunogenic protection.
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Affiliation(s)
- Cecília R C Calado
- CIMOSM - Centro de Investigação em Modelação e Otimização de Sistemas Multifuncionais, ISEL - Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, R. Conselheiro Emídio Navarro 1, 1959-007, Lisboa, Portugal.
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21
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Barzigar R, Haraprasad N, Kumar BYS, Mehran MJ, Fakrudin B. Transient recombinant expression of highly immunogenic CagA, VacA and NapA in Nicotiana benthamiana. BIOTECHNOLOGY REPORTS (AMSTERDAM, NETHERLANDS) 2022; 33:e00699. [PMID: 35028298 PMCID: PMC8739878 DOI: 10.1016/j.btre.2021.e00699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 11/26/2022]
Abstract
Interest in the plant-based transient production of recombinant immunogenic antigens has tremendously progressed because plants are cost-effective, easily selectable, free of mammalian contamination, and support complex post-translational modifications. Nicotiana benthamiana is a convenient system for transient expression of recombinant antigens. The present study documented a platform for rapid production of Helicobacter pylori CagA, VacA and NapA antigens three days (first harvest, FH) and six days (second harvest, SH) after agro-infiltration using a syringe. In this study, CagA, VacA and NapA antigen genes from Helicobacter pylori were cloned into the binary vector pBI121 and transformed into Nicotiana benthamiana by the Agrobacterium-mediated process. Leaves of four to five weeks old Nicotiana benthamiana plants were agroinfiltrated with EHA105 subtype of Agrobacterium tumefaciens strain containing cloned CagA (pBI121-CagA), VacA (pBI121-VacA) and NapA (pBI121-NapA) constructs. The transient expression and accumulation of the recombinant genes containing CagA, VacA and NapA expression cassettes were confirmed using qRT-PCR by comparing the relative expression at FH and SH post-infiltration with the non-infiltrated (control) samples and using ELISA at 1/5 and 1/10 dilution ratios. The qRT-PCR findings showed that Agrobacterium-mediated syringe infiltration of leaves of four to five weeks old Nicotiana benthamiana plants produced significantly higher transcript levels of CagA (about 8-fold and 7-fold), VacA (38-fold and 24-fold) and NapA (7-fold and 5-fold) genes at FH and SH compared to the control sample. Besides, the maximum amount of CagA, VacA and NapA antigens were detected at the FH stage compared to the SH stage, when the antibody concentrations of the agro-infiltrated leaf extracts containing these recombinant antigens were diluted in a 1/5 ratio. This study has developed evidence to support that recombinant CagA, VacA and NapA can be transiently produced in Nicotiana benthamiana plants.
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Affiliation(s)
- Rambod Barzigar
- JSS Research Foundation, SJCE Technical Campus, Mysore 570006 India
| | | | - Basaralu Yadurappa Sathish Kumar
- JSS Research Foundation, SJCE Technical Campus, Mysore 570006 India
- Postgraduate Department of Biotechnology, JSS College, Ooty Road, Mysore 570025 India
| | | | - Bashasab Fakrudin
- Department of Biotechnology and Crop Improvement, College of Horticulture, University of Horticulture Sciences Campus, GKVK Post, Bengaluru 560065 India
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22
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Zhang L, Xiao Y, Ji L, Lin M, Zou Y, Zhao J, Zhao S. Potential Therapeutic Effects of Egg Yolk Antibody (IgY) in Helicobacter pylori Infections─A Review. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:13691-13699. [PMID: 34783242 DOI: 10.1021/acs.jafc.1c05398] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Currently, the infection with Helicobacter pylori affects about half of the world's population, and the most common therapy to treat H. pylori is the first line clarithromycin-based triple therapy or the quadruple therapy. However, drug resistance, eradication in a low level, high rate of reinfection, and gastrointestinal side effects among the causative organisms for H. pylori infection pose a critical challenge to the global health care community. Therefore, new approaches to treat H. pylori infections are urgently needed. Chicken egg yolk constituting a source of immunoglobulin Y (IgY) has attracted noticeable attention for its advantages of cost-effective extraction, minimization of animal harm and suffering, and induction of no specific resistance and is, therefore, being regarded as an alternative therapy for H. pylori infection. This review is intended to summarize various H. pylori antigens for IgY preparation in terms of their application, mechanism, and limitations.
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Affiliation(s)
- Leheng Zhang
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, People's Republic of China
| | - Yire Xiao
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, People's Republic of China
| | - Li Ji
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, People's Republic of China
| | - Mingxia Lin
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, People's Republic of China
| | - Yikui Zou
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, People's Republic of China
| | - Jingjing Zhao
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, People's Republic of China
| | - Suqing Zhao
- Department of Pharmaceutical Engineering, School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, People's Republic of China
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23
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Sousa C, Ferreira R, Azevedo NF, Oleastro M, Azeredo J, Figueiredo C, Melo LDR. Helicobacter pylori infection: from standard to alternative treatment strategies. Crit Rev Microbiol 2021; 48:376-396. [PMID: 34569892 DOI: 10.1080/1040841x.2021.1975643] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Helicobacter pylori is the major component of the gastric microbiome of infected individuals and one of the aetiological factors of chronic gastritis, peptic ulcer disease and gastric cancer. The increasing resistance to antibiotics worldwide has made the treatment of H. pylori infection a challenge. As a way to overhaul the efficacy of currently used H. pylori antibiotic-based eradication therapies, alternative treatment strategies are being devised. These include probiotics and prebiotics as adjuvants in H. pylori treatment, antimicrobial peptides as alternatives to antibiotics, photodynamic therapy ingestible devices, microparticles and nanoparticles applied as drug delivery systems, vaccines, natural products, and phage therapy. This review provides an updated synopsis of these emerging H. pylori control strategies and discusses the advantages, hurdles, and challenges associated with their development and implementation. An effective human vaccine would be a major achievement although, until now, projects regarding vaccine development have failed or were discontinued. Numerous natural products have demonstrated anti-H. pylori activity, mostly in vitro, but further clinical studies are needed to fully disclose their role in H. pylori eradication. Finally, phage therapy has the potential to emerge as a valid alternative, but major challenges remain, namely the isolation of more H. pylori strictly virulent bacterio(phages).
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Affiliation(s)
- Cláudia Sousa
- Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Rute Ferreira
- Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Nuno F Azevedo
- Faculty of Engineering, LEPABE - Department of Chemical Engineering, University of Porto, Porto, Portugal
| | - Mónica Oleastro
- Department of Infectious Diseases, National Institute of Health Dr Ricardo Jorge, Lisbon, Portugal
| | - Joana Azeredo
- Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Ceu Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Faculty of Medicine, Department of Pathology, University of Porto, Porto, Portugal
| | - Luís D R Melo
- Centre of Biological Engineering, University of Minho, Braga, Portugal
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24
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Dos Santos Viana I, Cordeiro Santos ML, Santos Marques H, Lima de Souza Gonçalves V, Bittencourt de Brito B, França da Silva FA, Oliveira E Silva N, Dantas Pinheiro F, Fernandes Teixeira A, Tanajura Costa D, Oliveira Souza B, Lima Souza C, Vasconcelos Oliveira M, Freire de Melo F. Vaccine development against Helicobacter pylori: from ideal antigens to the current landscape. Expert Rev Vaccines 2021; 20:989-999. [PMID: 34139141 DOI: 10.1080/14760584.2021.1945450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022]
Abstract
Introduction: The interest of the world scientific community for an effective vaccine against Helicobacter pylori infection arises from its high prevalence and association with many diseases. Moreover, with an immunological response that is not always effective for the eradication of the bacteria and an increasing antibiotic resistance in the treatment of this infection, the search for a vaccine and new therapeutic modalities to control this infection is urgent.Areas covered: We bring an overview of the infection worldwide, discussing its prevalence, increasing resistance to antibiotics used in its therapy, in addition to the response of the immune system to the infection registered so far. Moreover, we address the most used antigens and their respective immunological responses expected or registered up to now. Finally, we address the trials and their partial results in development for such vaccines.Expert opinion: Although several studies for the development of an effective vaccine against this pathogen are taking place, many are still in the preclinical phase or even without updated information. In this sense, taking into account the high prevalence and association with important comorbidities, the interest of the pharmaceutical industry in developing an effective vaccine against this pathogen is questioned.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Davi Tanajura Costa
- Instituto Multidisciplinar Em Saúde, Universidade Federal da Bahia, Bahia, Brazil
| | - Briza Oliveira Souza
- Instituto Multidisciplinar Em Saúde, Universidade Federal da Bahia, Bahia, Brazil
| | - Cláudio Lima Souza
- Instituto Multidisciplinar Em Saúde, Universidade Federal da Bahia, Bahia, Brazil
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25
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Karbalaei M, Sahebkar A, Keikha M. Helicobacter pylori infection and susceptibility to cardiac syndrome X: A systematic review and meta-analysis. World J Meta-Anal 2021; 9:208-219. [DOI: 10.13105/wjma.v9.i2.208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/03/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
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26
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Karbalaei M, Sahebkar A, Keikha M. Helicobacter pylori infection and susceptibility to cardiac syndrome X: A systematic review and meta-analysis. World J Meta-Anal 2021; 9:207-218. [DOI: 10.13105/wjma.v9.i2.207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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27
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Abass OA, Timofeev VI, Sarkar B, Onobun DO, Ogunsola SO, Aiyenuro AE, Aborode AT, Aigboje AE, Omobolanle BN, Imolele AG, Abiodun AA. Immunoinformatics analysis to design novel epitope based vaccine candidate targeting the glycoprotein and nucleoprotein of Lassa mammarenavirus (LASMV) using strains from Nigeria. J Biomol Struct Dyn 2021; 40:7283-7302. [PMID: 33719908 DOI: 10.1080/07391102.2021.1896387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Lassa mammarenavirus (LASMV) is responsible for a specific type of acute viral hemorrhagic fever known as Lassa fever. Lack of effective treatments and counter-measures against the virus has resulted in a high mortality rate in its endemic regions. Therefore, in this study, a novel epitope-based vaccine has been designed using the methods of immunoinformatics targeting the glycoprotein and nucleoprotein of the virus. After numerous robust analyses, two CTL epitopes, eight HTL epitopes and seven B-cell epitopes were finally selected for constructing the vaccine. All these most promising epitopes were found to be antigenic, non-allergenic, nontoxic and non-human homolog, which made them suitable for designing the subunit vaccine. Furthermore, the selected T-cell epitopes which were found to be fully conserved across different isolates of the virus, were also considered for final vaccine construction. After that, numerous validation experiments, i.e. molecular docking, molecular dynamics simulation and immune simulation were conducted, which predicted that our designed vaccine should be stable within the biological environment and effective in combating the LASMV infection. In the end, codon adaptation and in silico cloning studies were performed to design a recombinant plasmid for producing the vaccine industrially. However, further in vitro and in vivo assessments should be done on the constructed vaccine to finally confirm its safety and efficacy.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Ohilebo Abdulateef Abass
- Department of Bioinformatics & Computational Biology, Centre for BioCode, Benin, Nigeria.,Department of Biochemistry, Faculty of Life Sciences, Ambrose Alli University, Ekpoma, Nigeria
| | - Vladimir I Timofeev
- Shubnikov Institute of Crystallography of Federal Scientific Research Centre "Crystallography and Photonics" of Russian Academy of Sciences, Moscow, Russian Federation
| | - Bishajit Sarkar
- Department of Biotechnology & Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Dhaka, Bangladesh
| | - Desmond Odiamehi Onobun
- Department of Bioinformatics & Computational Biology, Centre for BioCode, Benin, Nigeria.,Department of Biochemistry, Faculty of Life Sciences, Ambrose Alli University, Ekpoma, Nigeria
| | | | | | - Abdullahi Tunde Aborode
- Research & Development, Shaping Women in STEM (SWIS) Africa, Lagos, Nigeria.,Research & Development, Healthy Africans Platform, Ibadan, Nigeria
| | | | | | | | - Alade Adebowale Abiodun
- Bio-Computing Research Unit, Molecular Biology & Simulations (Mols & Sims) Centre, Ado-Ekiti, Nigeria
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28
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Crowley E, Hussey S. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:275-292.e12. [DOI: 10.1016/b978-0-323-67293-1.00027-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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29
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Zhou A, Li L, Zhao G, Min L, Liu S, Zhu S, Guo Q, Liu C, Zhang S, Li P. Vitamin D3 Inhibits Helicobacter pylori Infection by Activating the VitD3/VDR-CAMP Pathway in Mice. Front Cell Infect Microbiol 2020; 10:566730. [PMID: 33194806 PMCID: PMC7646218 DOI: 10.3389/fcimb.2020.566730] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/27/2020] [Indexed: 01/10/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is closely associated with the occurrence and development of gastric diseases. Therefore, eliminating H. pylori infection should help to prevent gastric diseases. Vitamin D3 (VitD3, 1,25(OH)2D3) was previously observed to exhibit anti-H. pylori infection activity in clinic, but these results were reported in heterogeneous in vivo studies without elucidation of the underlying mechanisms. In the present study, we established H. pylori infection models in both wild-type and VDR knockdown (VDR-KD) mice, which were used to demonstrate that VitD3 inhibits H. pylori infection by enhancing the expression of VitD receptor (VDR) and cathelicidin antimicrobial peptide (CAMP). Furthermore, VDR-KD mice that exhibited lower VDR expression were more susceptible to H. pylori infection. In cultured mouse primary gastric epithelial cells, we further demonstrated that the VitD3/VDR complex binds to the CAMP promoter region to increase its expression. These data provide a mechanistic explanation of the anti-H. pylori infection activity of VitD3 at the molecular level in mice and suggest a new avenue for the clinical management of H. pylori eradication therapy.
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Affiliation(s)
- Anni Zhou
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lei Li
- Department of Digestive Diseases, Affiliated Hospital for Wei Fang Medical University, Weifang, China
| | - Guiping Zhao
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Li Min
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Si Liu
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shengtao Zhu
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qingdong Guo
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Chunjie Liu
- Institute of Biomedical Engineering, Academy of Military Medical Sciences of the Chinese PLA, Beijing, China
| | - Shutian Zhang
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Peng Li
- Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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30
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Chen Q, Chen R, Dong Y. Inhibitory effect of endostar combined with radiotherapy on gastric cancer animal models. World J Surg Oncol 2020; 18:165. [PMID: 32669133 PMCID: PMC7364530 DOI: 10.1186/s12957-020-01937-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/29/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Inhibitory effect of endostar combined with radiotherapy on gastric cancer (GC) animal models and its effect on transforming growth factor-β1 (TGF-β1) and inter-leukin-10 (IL-10) were evaluated. METHODS Forty mice of GC model xenograft tumors were prepared and randomly divided into blank control group, endostar group, radiotherapy group, and endostar combined with radiotherapy group (combination group). From the 14th day, a vernier caliper was used for measuring the long and short diameters of the xenograft tumors. The formula V = ab2/2 was used for calculating the tumor volume and to obtain its average value. Tumor growth curves were plotted to calculate the tumor inhibition rate. The growth of xenograft tumors and the behavioral changes of mice were observed. Enzyme-linked immunosorbent assay (ELISA) was used for detecting the expression levels of IL-10 and TGF-β1. RESULTS The tumor growth in the combination group was significantly inhibited, and the tumor volume was the smallest compared with the other groups (p < 0.05). Compared to the blank control group, the tumor inhibition rate was 11.8% in endostar group, 33.0% in radiotherapy group, and 52.1% in combination group (p < 0.01). Endostar combined with radiotherapy had an interaction in decreasing the expression levels of TGF-β1 and IL-10 (F = 4.35 and 5.12, p < 0.05). Leucocyte count was significantly higher in control and combination groups than that in endostar and radiotherapy groups. The body weight of mice in endostar and radiotherapy groups decreased after treatment (p < 0.05). The body weight of mice after treatment in control and combination groups increased, with a statistically significant difference compared to that before treatment (p < 0.05). There was a statistically significant difference among all groups after treatment (F = 198.1, p < 0.01). CONCLUSIONS Endostar combined with radiotherapy can inhibit tumor growth and downregulate the expression levels of TGF-β1 and IL-10 through synergistic action.
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Affiliation(s)
- Qitian Chen
- Department of Oncology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, 15 Jiefang Road, Xiangyang, 441000, Hubei, People's Republic of China
| | - Ran Chen
- Department of Oncology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, 15 Jiefang Road, Xiangyang, 441000, Hubei, People's Republic of China
| | - Youhong Dong
- Department of Oncology, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, 15 Jiefang Road, Xiangyang, 441000, Hubei, People's Republic of China.
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31
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Abstract
As one of the most prevalent infections globally, Helicobacter pylori (H. pylori) continues to present diagnostic and therapeutic challenges for clinicians worldwide. Diagnostically, the "test-and-treat" strategy is the recommended approach for healthcare practitioners when managing this potentially curable disease. The choice of testing method should be based on several factors including patient age, presenting symptoms, and medication use, as well as test reliability, availability, and cost. With rising antibiotic resistance, particularly of macrolides, care must be taken to ensure that therapy is selected based on regional resistance patterns and prior antibiotic exposure. In the USA, macrolide antibiotic resistance rates in some areas have reached or exceeded a generally accepted threshold, such that clarithromycin triple therapy may no longer be an appropriate first-line empiric treatment. Instead, bismuth quadruple therapy should be considered, while levofloxacin-based or alternative macrolide-containing therapies are also options. Once treated, it is essential to test for eradication as untreated H. pylori is associated with serious complications including peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. This review article aims to consolidate current knowledge of H. pylori infection with a particular emphasis on diagnostic and treatment strategies.
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Affiliation(s)
- Bernardo Guevara
- Department of Internal Medicine, University of California Davis School of Medicine, 4150 V Street, Suite 1100, Sacramento, CA, 95817, USA
| | - Asha Gupta Cogdill
- Division of Gastroenterology and Hepatology, UC Davis Medical Center, University of California Davis School of Medicine, 4150 V Street, Suite 3500, Sacramento, CA, 95817, USA.
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32
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Paydarnia N, Mansoori B, Esmaeili D, Kazemi T, Aghapour M, Hajiasgharzadeh K, Alizadeh N, Baradaran B. Helicobacter pylori Recombinant CagA Regulates Th1/Th2 Balance in a BALB/c Murine Model. Adv Pharm Bull 2020; 10:264-270. [PMID: 32373495 PMCID: PMC7191242 DOI: 10.34172/apb.2020.031] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/17/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022] Open
Abstract
Purpose:Helicobacter pylori is recognized as one of the prevalent causes of human gastricinfection. In the present study, the role of mixed immunization with H. pylori lipopolysaccharide(LPS) and recombinant cytotoxin-associated gene A (rCagA) as a stimulator of host immuneresponses was determined. Methods: BALB/c mice were immunized with different formulations by the systemic administrationat 14-day intervals. The effects of the formulations plus CpG adjuvants were assessed before andpost-immunization in separated studies. Moreover, the expression of Th1/Th2 cytokines wasquantified in sera of immunized mice using reverse transcription polymerase chain reaction (RTPCR)test and the protein levels confirmed with enzyme linked immunosorbent assay (ELISA).Finally, the specific antibody levels in sera were studied by ELISA and the tendency of cellularresponse was examined by IgG1/IgG2a ratio. Results: Data of Western blotting verified the presence of constructed protein. Analysisof lymphocyte proliferation showed that CpG-conjugated rCagA increases lymphocytesproliferation compared to the control group. Also, it was shown that formulations containing LPSand rCagA promote a Th1 response indicated by interferon-gamma expression and induced Th1/Th2 balance. Additionally, the specific IgG1, total IgG and IgG2a levels elevated in response toall treatments. Ultimately, the IgG2a/IgG1 ratio in the mice immunized with rCagA-containingformulations increased. Conclusion: These results indicated that rCagA protein carried with CpG adjuvant not onlymaintained its antigenicity throughout the experiment but also induced robust Th1-biasedimmune responses. Therefore, it holds promise for the production of an efficient vaccine against H. pylori infection.
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Affiliation(s)
- Nafiseh Paydarnia
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Tabriz University of Medical Sciences, International Branch (Aras), Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davoud Esmaeili
- Department of Medical Microbiology, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahyar Aghapour
- Department of Pathobiology, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | | | - Nazila Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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33
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Meyer TF, Morey P. A Future for a Vaccine Against the Cancer-Inducing Bacterium Helicobacter pylori? MUCOSAL VACCINES 2020:579-596. [DOI: 10.1016/b978-0-12-811924-2.00033-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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34
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Keikha M, Eslami M, Yousefi B, Ghasemian A, Karbalaei M. Potential antigen candidates for subunit vaccine development against Helicobacter pylori infection. J Cell Physiol 2019; 234:21460-21470. [PMID: 31188484 DOI: 10.1002/jcp.28870] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 02/05/2023]
Abstract
Helicobacter pylori (H. pylori) is a resident bacterium in the stomach that accounts for 75% cases of gastric cancer. In this review, we comprehensively studied published papers on H. pylori vaccines using Google Scholar and NCBI databases to gather information about vaccines against H. pylori. Considering the pivotal roles of the enzyme urease (in production of NH3 and neutralization of the acidic medium of the stomach), cytotoxin-associated gene A, and vacuolating cytotoxin A proteins in H. pylori infection, they could be the best candidates for the construction of recombinant vaccines. The outer membrane porins (Hop), blood group antigen-binding adhesin (BabA), sialic acid-binding adhesin (SabA), and outer inflammatory protein A, play significant roles in binding of bacterium to human gastric tissues, and because binding is the first step in bacterial fixation and colonization, these antigens also can be considered as suitable candidates for designing vaccines. Likely, other significant bacterial antigens, such as NapA (chemotactic factor for recruitment of human neutrophils and monocytes to the site of infection), duodenal ulcer promoting protein A (to promote duodenal ulcer), and Hsp60 (as a molecular chaperon for activation of urease enzyme), can be used in the construction of subunit vaccines. New vaccines in use currently, such as DNA vaccines and subunit vaccines, can efficiently replace the dead and attenuated vaccines. Nonetheless, the results show that urease enzyme is most used compared with bacterial components in the designing and construction of recombinant vaccines. The BabA and SabA antigens belong to the outer membrane porins family in H. pylori and are required for binding and fixation of the bacterium to the human gastric tissues.
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Affiliation(s)
- Masoud Keikha
- Antimicrobial Resistance Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Abdolmajid Ghasemian
- Department of Biology, Tehran Central Branch, Islamic Azad University, Tehran, Iran
| | - Mohsen Karbalaei
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
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Walduck AK, Raghavan S. Immunity and Vaccine Development Against Helicobacter pylori. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:257-275. [PMID: 31016627 DOI: 10.1007/5584_2019_370] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Helicobacter pylori is a highly-adapted gastrointestinal pathogen of humans and the immunology of this chronic infection is extremely complex. Despite the availability of antibiotic therapy, the global incidence of H. pylori infection remains high, particularly in low to middle-income nations. Failure of therapy and the spread of antibiotic resistance among the bacteria are significant problems and provide impetus for the development of new therapies and vaccines to treat or prevent gastric ulcer, and gastric carcinoma. The expansion of knowledge on gastric conventional and regulatory T cell responses, and the role of TH17 in chronic gastritis from studies in mouse models and patients have provided valuable insights into how gastritis is initiated and maintained. The development of human challenge models for testing candidate vaccines has meant a unique opportunity to study acute infection, but the field of vaccine development has not progressed as rapidly as anticipated. One clear lesson learned from previous studies is that we need a better understanding of the immune suppressive mechanisms in vivo to be able to design vaccine strategies. There is still an urgent need to identify practical surrogate markers of protection that could be deployed in future field vaccine trials. Important developments in our understanding of the chronic inflammatory response, progress and problems arising from human studies, and an outlook for the future of clinical vaccine trials will be discussed.
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Affiliation(s)
- Anna K Walduck
- School of Science, RMIT University, Melbourne, VIC, Australia.
| | - Sukanya Raghavan
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
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36
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Urrutia-Baca VH, Gomez-flores R, De La Garza-Ramos MA, Tamez-guerra P, Lucio-sauceda DG, Rodríguez-padilla MC. Immunoinformatics Approach to Design a Novel Epitope-Based Oral Vaccine Against Helicobacter pylori. J Comput Biol 2019; 26:1177-1190. [PMID: 31120321 PMCID: PMC6786345 DOI: 10.1089/cmb.2019.0062] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Helicobacter pylori is an infectious agent that colonizes the gastric mucosa of half of the population worldwide. This bacterium has been recognized as belonging to group 1 carcinogen by the World Health Organization for the role in development of gastritis, peptic ulcers, and cancer. Due to the increase in resistance to antibiotics used in the anti-H. pylori therapy, the development of an effective vaccine is an alternative of great interest, which remains a challenge. Therefore, a rational, strategic, and efficient vaccine design against H. pylori is necessary where the use of the most current bioinformatics tools could help achieve it. In this study, immunoinformatics approach was used to design a novel multiepitope oral vaccine against H. pylori. Our multiepitope vaccine is composed of cholera toxin subunit B (CTB) that is used as a mucosal adjuvant to enhance vaccine immunogenicity for oral immunization. CTB fused to 11 epitopes predicted of pathogenic (UreB170-189, VacA459-478, CagA1103-1122, GGT106-126, NapA30-44, and OipA211-230) and colonization (HpaA33-52, FlaA487-506, FecA437-456, BabA129-149, and SabA540-559) proteins from H. pylori. CKS9 peptide (CKSTHPLSC) targets epithelial microfold cells to enhance vaccine uptake from the gut barrier. All sequences were joined to each other by proper linkers. The vaccine was modeled and validated to achieve a high-quality three-dimensional structure. The vaccine design was evaluated as nonallergenic, antigenic, soluble, and with an appropriate molecular weight and isoelectric point. Our results suggest that our newly designed vaccine could serve as a promising anti-H. pylori vaccine candidate.
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Affiliation(s)
- Victor Hugo Urrutia-Baca
- Laboratory of Immunology and Virology, School of Biological Sciences, Autonomous University of Nuevo Leon, Monterrey, Mexico
| | - Ricardo Gomez-flores
- Laboratory of Immunology and Virology, School of Biological Sciences, Autonomous University of Nuevo Leon, Monterrey, Mexico
| | - Myriam Angélica De La Garza-Ramos
- Integral Dentistry Unit and Specialties, Center for Research and Development in Health Sciences, Autonomous University of Nuevo Leon, Monterrey, Mexico
| | - Patricia Tamez-guerra
- Laboratory of Immunology and Virology, School of Biological Sciences, Autonomous University of Nuevo Leon, Monterrey, Mexico
| | - Daniela Guadalupe Lucio-sauceda
- Laboratory of Immunology and Virology, School of Biological Sciences, Autonomous University of Nuevo Leon, Monterrey, Mexico
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Doohan D, Miftahussurur M, Matsuo Y, Kido Y, Akada J, Matsuhisa T, Yee TT, Htet K, Aftab H, Vilaichone RK, Mahachai V, Ratanachu-Ek T, Tshering L, Waskito LA, Fauzia KA, Uchida T, Syam AF, Rezkitha YAA, Yamaoka Y. Characterization of a novel Helicobacter pylori East Asian-type CagA ELISA for detecting patients infected with various cagA genotypes. Med Microbiol Immunol 2019; 209:29-40. [PMID: 31549252 DOI: 10.1007/s00430-019-00634-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 09/06/2019] [Indexed: 12/17/2022]
Abstract
Currently, Western-type CagA is used in most commercial Helicobacter pylori CagA ELISA kits for CagA detection rather than East Asian-type CagA. We evaluated the ability of the East Asian-type CagA ELISA developed by our group to detect anti-CagA antibody in patients infected with different cagA genotypes of H. pylori from four different countries in South Asia and Southeast Asia. The recombinant CagA protein was expressed and later purified using GST-tag affinity chromatography. The East Asian-type CagA-immobilized ELISA was used to measure the levels of anti-CagA antibody in 750 serum samples from Bhutan, Indonesia, Myanmar, and Bangladesh. The cutoff value of the serum antibody in each country was determined via Receiver-Operating Characteristic (ROC) analysis. The cutoff values were different among the four countries studied (Bhutan, 18.16 U/mL; Indonesia, 6.01 U/mL; Myanmar, 10.57 U/mL; and Bangladesh, 6.19 U/mL). Our ELISA had better sensitivity, specificity, and accuracy of anti-CagA antibody detection in subjects predominantly infected with East Asian-type CagA H. pylori (Bhutan and Indonesia) than in those infected with Western-type CagA H. pylori predominant (Myanmar and Bangladesh). We found positive correlations between the anti-CagA antibody and antral monocyte infiltration in subjects from all four countries. There was no significant association between bacterial density and the anti-CagA antibody in the antrum or the corpus. The East Asian-type CagA ELISA had improved detection of the anti-CagA antibody in subjects infected with East Asian-type CagA H. pylori. The East Asian-type CagA ELISA should, therefore, be used in populations predominantly infected with East Asian-type CagA.
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Affiliation(s)
- Dalla Doohan
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, 879-5593, Japan.,Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Muhammad Miftahussurur
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115, Indonesia.,Gastroentero-Hepatology Division, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, 60131, Indonesia
| | - Yuichi Matsuo
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, 879-5593, Japan.,Department of Host-Defense Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
| | - Yasutoshi Kido
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, 879-5593, Japan.,Department of Parasitology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Junko Akada
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, 879-5593, Japan
| | - Takeshi Matsuhisa
- Department of Gastroenterology, Tama-Nagayama University Hospital of Nippon Medical School, Tama, Japan
| | - Than Than Yee
- Department of GI and HBP Surgery, No (2), Defense Service General Hospital (1000 Bedded), Nay Pyi Taw, Myanmar
| | - Kyaw Htet
- Department of GI and HBP Surgery, No (1), Defense Service General Hospital (1000 Bedded), Mingalodon, Yangon, Myanmar
| | - Hafeza Aftab
- Department of Gastroenterology, Dhaka Medical College and Hospital, Dhaka, Bangladesh
| | - Ratha-Korn Vilaichone
- Gastroenterology Unit, Department of Medicine, Thammasat University Hospital, Pathum Thani, Thailand
| | - Varocha Mahachai
- GI and Liver Center, Bangkok Medical Center, Bangkok, 10310, Thailand
| | | | - Lotay Tshering
- Department of Surgery, Jigme Dorji Wangchuck National Referral Hospital, Thimphu, 11001, Bhutan
| | - Langgeng Agung Waskito
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, 879-5593, Japan.,Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Kartika Afrida Fauzia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, 879-5593, Japan.,Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115, Indonesia
| | - Tomohisa Uchida
- Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu, 879-5593, Japan
| | - Ari Fahrial Syam
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Yudith Annisa Ayu Rezkitha
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, 60115, Indonesia.,Faculty of Medicine, University of Muhammadiyah Surabaya, Surabaya, 60113, Indonesia
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, 879-5593, Japan. .,Gastroentero-Hepatology Division, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, 60131, Indonesia. .,Department of Gastroenterology and Hepatology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, 77030, USA.
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Abstract
Chronic inflammation induced by Helicobacter pylori infection is a critical factor in the development of peptic ulcer disease and gastric cancer. Central to this inflammation is the initiation of pro-inflammatory signaling cascades within epithelial cells, in particular those mediated by two sensors of bacterial cell wall components, nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and alpha-protein kinase 1 (ALPK1). H pylori is, however, also highly adept at mitigating inflammation in the host, thereby restricting tissue damage and favoring bacterial persistence. H pylori modulates host immune responses by altering cytokine signaling in epithelial and myeloid cells, which results in increased proliferation of regulatory T cells and downregulation of effector T-cell responses. H pylori vacuolating cytotoxin A (VacA) has been shown to play an important role in the dampening of immune responses and induction of immune tolerance capable of protecting against asthma. It is also possible to generate protective immune responses by immunization with various H pylori antigens or their epitopes, in combination with an adjuvant, though this for now has only been shown in mouse models. Novel non-toxic adjuvants, consisting of modified bacterial enterotoxins or nanoparticles, have recently been developed that may not only enhance vaccine efficacy, but also help translate candidate vaccines to the clinic. This review will summarize the main discoveries in the past year regarding host immune responses to H pylori infection, as well as the design of new vaccine approaches against this infection.
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Affiliation(s)
- Philippe Lehours
- INSERM UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, Université de Bordeaux, Bordeaux, France.,French National Reference Centre for Campylobacters and Helicobacters, Pellegrin Hospital, Bordeaux, France
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.,Department of Molecular and Translational Science, Monash University, Melbourne, Victoria, Australia.,Biomedical Discovery Institute, Department of Microbiology, Monash University, Melbourne, Victoria, Australia
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39
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Guo L, Hong D, Wang S, Zhang F, Tang F, Wu T, Chu Y, Liu H, He M, Yang H, Yin R, Liu K. Therapeutic Protection Against H. pylori Infection in Mongolian Gerbils by Oral Immunization With a Tetravalent Epitope-Based Vaccine With Polysaccharide Adjuvant. Front Immunol 2019; 10:1185. [PMID: 31191547 PMCID: PMC6546824 DOI: 10.3389/fimmu.2019.01185] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 05/09/2019] [Indexed: 12/28/2022] Open
Abstract
Urease is an effective target for design of a therapeutic epitope vaccine against Helicobacter pylori (H. pylori). In our previous studies, an epitope vaccine CTB-UE containing Th and B epitopes from H. pylori urease was constructed, and the CTB-UE vaccine could provide therapeutic effect on H. pylori infection in mice. However, a multivalent vaccine, combining different antigens participating in different aspects of H. pylori colonization and pathogenesis, may be more effective as a therapeutic vaccine than a univalent vaccine targetting urease. Therefore, a multivalent epitope vaccine FVpE, containing Th1-type immune adjuvant NAP, three selected functional fragments from CagA and VacA, and an urease multi-epitope peptide (UE) from CTB-UE, was constructed in this study and expected to obtain better sterilizing immunity than the univalent epitope vaccine CTB-UE. The therapeutic effect of multivalent epitope vaccine FVpE with polysaccharide adjuvant (PA) was evaluated in H. pylori-infected Mongolian gerbil model. The results showed that both FvpE and CTB-UE vaccine could induce similar levels of specific antibodies against H. pylori urease, and had similar inhibition effect on H. pylori urease activity. However, only FVpE could induce high levels of specific antibodies to CagA, VacA, and NAP. In addition, oral therapeutic immunization with FVpE plus PA significantly reduced the number of H. pylori colonies in the stomach of Mongolian gerbils compared with oral immunization with CTB-UE plus PA, or FVpE only, and the FVpE vaccine with PA even exhibited sterilizing immunity. The protection of FVpE was related to the mixed CD4+ T cell responses and epitope-specific antibodies against various H. pylori antigens. These results indicate that a multivalent epitope vaccine targetting various H. pylori antigens could be a promising candidate against H. pylori infection.
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Affiliation(s)
- Le Guo
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, China.,Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China.,Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Dantong Hong
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Shue Wang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Fan Zhang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Feng Tang
- Research Center for High Altitude Medicine, Qinghai University, Xining, China
| | - Tao Wu
- Clinical Laboratory, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Yuankui Chu
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Hongpeng Liu
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Meng He
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Hua Yang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Runting Yin
- Center for Cell Therapy, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Kunmei Liu
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China.,Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
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40
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Current and Future Treatment of Helicobacter pylori Infections. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1149:211-225. [PMID: 31016626 DOI: 10.1007/5584_2019_367] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Helicobacter pylori is one of the most common human pathogens and it has been estimated that about 50% of the world's population is currently infected. The present consensus is that, unless there are compelling reasons, all H. pylori infections should be cured. Since the 1990s, different national and international guidelines for the management of H. pylori-related diseases have been published and periodically updated regarding indications for treatment, diagnostic procedures, and preferred treatment regimens. Most guidelines provide sophisticated meta-analyses examining the outcome of different regimens done in regions with variable, often high rates of resistance to antibiotics, for which the prevalence and effects of resistance was often ignored. Although successful antimicrobial therapy must be susceptibility-based, increasing antimicrobial resistance and general unavailability of susceptibility testing have required clinicians to generally rely on empiric regimens. Antibiotics resistance of H. pylori has reached alarming high levels worldwide, which has an effect to efficacy of treatment. The recommendations should provide regimes for multi-resistant infections or for those where susceptibility testing is unavailable or refused. The first rule is to use only proven locally effective therapies. Because of patient intolerances, drug allergies, and local experiences, the clinicians should have at least two options for first-line therapy. As with any antimicrobial therapy, a thorough review of prior antibiotic use is invaluable to identify the presence of probably resistance. The second key is patient education regarding potential and expected side-effects and the importance of completing the course of antibiotics. We also review here triple therapies, sequential-concomitant, hybrid therapies, bismuth therapies, dual therapy, vonoprazan, modern antibiotic treatments, probiotics and vaccination.
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41
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Karkhah A, Ebrahimpour S, Rostamtabar M, Koppolu V, Darvish S, Vasigala VKR, Validi M, Nouri HR. Helicobacter pylori evasion strategies of the host innate and adaptive immune responses to survive and develop gastrointestinal diseases. Microbiol Res 2018; 218:49-57. [PMID: 30454658 DOI: 10.1016/j.micres.2018.09.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Revised: 09/09/2018] [Accepted: 09/28/2018] [Indexed: 02/08/2023]
Abstract
Helicobacter pylori (H. pylori) is a bacterial pathogen that resides in more than half of the human population and has co-evolved with humans for more than 58,000 years. This bacterium is orally transmitted during childhood and is a key cause of chronic gastritis, peptic ulcers and two malignant cancers including MALT (mucosa-associated lymphoid tissue) lymphoma and adenocarcinoma. Despite the strong innate and adaptive immune responses, H. pylori has a long-term survival in the gastric mucosa. In addition to the virulence factors, survival of H. pylori is strongly influenced by the ability of bacteria to escape, disrupt and manipulate the host immune system. This bacterium can escape from recognition by innate immune receptors via altering its surface molecules. Moreover, H. pylori subverts adaptive immune response by modulation of effector T cell. In this review, we discuss the immune-pathogenicity of H. pylori by focusing on its ability to manipulate the innate and acquired immune responses to increase its survival in the gastric mucosa, leading up to gastrointestinal disorders. We also highlight the mechanisms that resulted to the persistence of H. pylori in gastric mucosa.
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Affiliation(s)
- Ahmad Karkhah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Soheil Ebrahimpour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Rostamtabar
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Veerendra Koppolu
- Scientist Biopharmaceutical Development Medimmune Gaithersburg, MD, 20878 USA
| | - Sorena Darvish
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | - Majid Validi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Hamid Reza Nouri
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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Malfertheiner P, Selgrad M, Wex T, Romi B, Borgogni E, Spensieri F, Zedda L, Ruggiero P, Pancotto L, Censini S, Palla E, Kanesa-Thasan N, Scharschmidt B, Rappuoli R, Graham DY, Schiavetti F, Del Giudice G. Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study. Lancet Gastroenterol Hepatol 2018; 3:698-707. [DOI: 10.1016/s2468-1253(18)30125-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/29/2018] [Accepted: 04/05/2018] [Indexed: 12/14/2022]
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43
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Stubljar D, Jukic T, Ihan A. How far are we from vaccination against Helicobacter pylori infection? Expert Rev Vaccines 2018; 17:935-945. [PMID: 30238819 DOI: 10.1080/14760584.2018.1526680] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Helicobacter pylori infection results in chronic gastritis, peptic ulcer, or gastric cancer; therefore, eradication of this bacterium is essential. The strategy for developing effective vaccines against H. pylori entails immunization of mice with a combination of classical and recombinant H. pylori antigens, but this has proven to be onerous in all cases. AREAS COVERED We have reviewed literature databases in PubMed and Scopus using the key words H. pylori, vaccine, and vaccination and have conducted a systematic review of published clinical trials and animal model studies on vaccines against H. pylori and have tried to summarize why the vaccines are not effective or only partially effective. EXPERT COMMENTARY This is the perfect time to review vaccine development against H. pylori as, after several failed attempts, promising results were reported by Zeng et al. in 2015. Successful vaccine development requires knowledge of both the immune mechanisms active during natural infection by H. pylori, owing to the complicated host response against the pathogen, and the factors that allow the persistence of bacteria, such as genetic diversity of H. pylori. Moreover, various clinical trials are needed to prove vaccine efficacy.
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Affiliation(s)
- David Stubljar
- a Department of Research & Development , In-Medico , Metlika , Slovenia
| | - Tomislav Jukic
- b Department of Biomedicine and Public Health , Faculty of Medicine Osijek , Osijek , Croatia
| | - Alojz Ihan
- c Medical Faculty of Ljubljana , Institute of Microbiology and Immunology , Ljubljana , Slovenia
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44
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Pan X, Ke H, Niu X, Li S, Lv J, Pan L. Protection Against Helicobacter pylori Infection in BALB/c Mouse Model by Oral Administration of Multivalent Epitope-Based Vaccine of Cholera Toxin B Subunit-HUUC. Front Immunol 2018; 9:1003. [PMID: 29867978 PMCID: PMC5951970 DOI: 10.3389/fimmu.2018.01003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 04/23/2018] [Indexed: 12/20/2022] Open
Abstract
Vaccination is an increasingly important alternative approach to control Helicobacter pylori infection, since H. pylori resistance to previously efficacious antibiotic regimens is increased, and H. pylori eradication treatment for upper gastrointestinal diseases is becoming less successful. Fortunately, an efficient oral monovalent H. pylori vaccine has been developed. However, compared with monovalent vaccines, multivalent vaccines have the potential to induce more effective and comprehensive protection against H. pylori infection. In this study, we designed and produced a multivalent epitope-based vaccine cholera toxin B subunit (CTB)-HUUC with the intramucosal adjuvant CTB and tandem copies of B-cell epitopes (HpaA132-141, UreA183-203, and UreB321-339) and T-cell epitopes (HpaA88-100, UreA27-53, UreB229-251, UreB317-329, UreB373-385, UreB438-452, UreB546-561, CagA149-164, and CagA196-217) from H. pylori adhesion A subunit (HpaA), urease A subunit (UreA), urease B subunit (UreB), and cytotoxin-associated antigen (CagA). Serum IgG, stomach, and intestine mucosal sIgA from mice after CTB-HUUC vaccination neutralized H. pylori urease activity in vitro. CTB-HUUC vaccination promoted H. pylori-specific lymphocyte responses and a mixed CD4+ T cell immune response as indicated by IFN-γ, interleukin-4, and interleukin-17 production in mice. Both oral prophylactic and therapeutic CTB-HUUC vaccinations reduced gastric urease activity and H. pylori infection and protected stomachs in mice. Taken together, CTB-HUUC is a promising potent and safe multivalent vaccine in controlling H. pylori infection in BALB/c mouse model.
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Affiliation(s)
- Xing Pan
- Institute of Infection and Immunity, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Hong Ke
- Department of Hemotology, People's Hospital, Hubei University of Medicine, Shiyan, China
| | - Xiaojuan Niu
- Department of Pharmacology, Hubei University of Medicine, Shiyan, China
| | - Shan Li
- Institute of Infection and Immunity, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Jun Lv
- Institute of Infection and Immunity, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Longrui Pan
- Department of Pharmacology, Hubei University of Medicine, Shiyan, China
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45
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Sutton P, Boag JM. Status of vaccine research and development for Helicobacter pylori. Vaccine 2018; 37:7295-7299. [PMID: 29627231 PMCID: PMC6892279 DOI: 10.1016/j.vaccine.2018.01.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 01/02/2018] [Indexed: 12/18/2022]
Abstract
Gastric adenocarcinoma is globally the third leading cause of death due to malignancy, with the bulk of this disease burden being suffered by low and middle income countries (LMIC), especially in Asia. The majority of these cancers develop as a result of a chronic gastritis that arises in response to infection with the stomach-dwelling bacterium, Helicobacter pylori. A vaccine against this pathogen would therefore be a powerful tool for preventing gastric adenocarcinoma. However, notwithstanding a proof-of-concept that vaccination can protect children from acquisition of H. pylori infection, there are currently no advanced vaccine candidates with only a single vaccine in Phase I clinical trial. Further, the development of a vaccine against H. pylori is not a current strategic priority of major pharmaceutical companies despite the large global disease burden. Given the involvement of such companies is likely to be critical for late stage development, there is therefore a need for an increased appreciation of the burden of this disease in LMIC and more investment to reinvigorate research in H. pylori vaccine Research and Development.
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Affiliation(s)
- Philip Sutton
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia; Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria 3010, Australia.
| | - Joanne M Boag
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia
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46
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Kienesberger S, Perez-Perez GI, Olivares AZ, Bardhan P, Sarker SA, Hasan KZ, Sack RB, Blaser MJ. When is Helicobacter pylori acquired in populations in developing countries? A birth-cohort study in Bangladeshi children. Gut Microbes 2018; 9:252-263. [PMID: 29494270 PMCID: PMC6219588 DOI: 10.1080/19490976.2017.1421887] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Helicobacter pylori colonization is prevalent throughout the world, and is predominantly acquired during childhood. In developing countries, >70% of adult populations are colonized with H. pylori and >50% of children become colonized before the age of 10 years. However, the exact timing of acquisition is unknown. We assessed detection of H. pylori acquisition among a birth cohort of 105 children in Mirzapur, Bangladesh. Blood samples collected at time 0 (cord blood), and at 6, 12, 18, and 24 months of life were examined for the presence of IgG and IgA antibodies to whole cell H. pylori antigen and for IgG antibodies to the CagA antigen using specific ELISAs and immunoblotting. Breast milk samples were analyzed for H. pylori-specific IgA antibodies. Cord blood was used to establish maternal colonization status. H. pylori seroprevalence in the mothers was 92.8%. At the end of the two-year follow-up period, 50 (47.6%) of the 105 children were positive for H. pylori in more than one assay. Among the colonized children, CagA prevalence was 78.0%. A total of 58 children seroconverted: 50 children showed persistent colonization and 8 (7.6%) children showed transient seroconversion, but immunoblot analysis suggested that the transient seroconversion observed by ELISA may represent falsely positive results. Acquisition of H. pylori was not influenced by the mother H. pylori status in serum or breastmilk. In this population with high H. pylori prevalence, we confirmed that H. pylori in developing countries is detectable mainly after the first year of life.
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Affiliation(s)
- Sabine Kienesberger
- Departments of Medicine and Microbiology, New York University School of Medicine, New York, USA,Institute of Molecular Biosciences, University of Graz, Graz, Styria, Austria,BioTechMed-Graz, Graz, Styria, Austria
| | - Guillermo I. Perez-Perez
- Departments of Medicine and Microbiology, New York University School of Medicine, New York, USA,CONTACT Guillermo I. Perez-Perez Department of Medicine, University Langone Medical Center, 6027W 423 East 23th street, NY 10010, New York, USA
| | - Asalia Z. Olivares
- Departments of Medicine and Microbiology, New York University School of Medicine, New York, USA
| | - Pradip Bardhan
- Nutrition and Clinical Services Division, ICDDR, Dhaka, Bangladesh
| | | | - Kh. Zahid Hasan
- Nutrition and Clinical Services Division, ICDDR, Dhaka, Bangladesh
| | - R. Bradley Sack
- Department of International Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Martin J. Blaser
- Departments of Medicine and Microbiology, New York University School of Medicine, New York, USA,Veterans Administration Medical Center, New York, USA
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Nell S, Estibariz I, Krebes J, Bunk B, Graham DY, Overmann J, Song Y, Spröer C, Yang I, Wex T, Korlach J, Malfertheiner P, Suerbaum S. Genome and Methylome Variation in Helicobacter pylori With a cag Pathogenicity Island During Early Stages of Human Infection. Gastroenterology 2018; 154:612-623.e7. [PMID: 29066327 DOI: 10.1053/j.gastro.2017.10.014] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 09/22/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Helicobacter pylori is remarkable for its genetic variation; yet, little is known about its genetic changes during early stages of human infection, as the bacteria adapt to their new environment. We analyzed genome and methylome variations in a fully virulent strain of H pylori during experimental infection. METHODS We performed a randomized Phase I/II, observer-blind, placebo-controlled study of 12 healthy, H pylori-negative adults in Germany from October 2008 through March 2010. The volunteers were given a prophylactic vaccine candidate (n = 7) or placebo (n = 5) and then challenged with H pylori strain BCM-300. Biopsy samples were collected and H pylori were isolated. Genomes of the challenge strain and 12 reisolates, obtained 12 weeks after (or in 1 case, 62 weeks after) infection were sequenced by single-molecule, real-time technology, which, in parallel, permitted determination of genome-wide methylation patterns for all strains. Functional effects of genetic changes observed in H pylori strains during human infection were assessed by measuring release of interleukin 8 from AGS cells (to detect cag pathogenicity island function), neutral red uptake (to detect vacuolating cytotoxin activity), and adhesion assays. RESULTS The observed mutation rate was in agreement with rates previously determined from patients with chronic H pylori infections, without evidence of a mutation burst. A loss of cag pathogenicity island function was observed in 3 reisolates. In addition, 3 reisolates from the vaccine group acquired mutations in the vacuolating cytotoxin gene vacA, resulting in loss of vacuolization activity. We observed interstrain variation in methylomes due to phase variation in genes encoding methyltransferases. CONCLUSIONS We analyzed adaptation of a fully virulent strain of H pylori to 12 different volunteers to obtain a robust estimate of the frequency of genetic and epigenetic changes in the absence of interstrain recombination. Our findings indicate that the large amount of genetic variation in H pylori poses a challenge to vaccine development. ClinicalTrials.gov no: NCT00736476.
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Affiliation(s)
- Sandra Nell
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany
| | - Iratxe Estibariz
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany
| | - Juliane Krebes
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany
| | - Boyke Bunk
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - David Y Graham
- Baylor College of Medicine, Michael E. DeBakey VAMC, Houston, Texas
| | - Jörg Overmann
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - Yi Song
- Pacific Biosciences, Menlo Park, California
| | - Cathrin Spröer
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
| | - Ines Yang
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany
| | - Thomas Wex
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | | | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Sebastian Suerbaum
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany; Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, Faculty of Medicine, LMU Munich, München, Germany; National Reference Center for Helicobacter pylori, München, Germany.
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Zou X, Qin C, Pereira CL, Tian G, Hu J, Seeberger PH, Yin J. Synergistic Glycosylation as Key to the Chemical Synthesis of an Outer Core Octasaccharide ofHelicobacter pylori. Chemistry 2018; 24:2868-2872. [DOI: 10.1002/chem.201800049] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Xiaopeng Zou
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Chunjun Qin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Claney L. Pereira
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Guangzong Tian
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Jing Hu
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
| | - Peter H. Seeberger
- Department of Biomolecular Systems; Max Planck Institute of Colloids and Interfaces; Am Mühlenberg 1 14476 Potsdam Germany
| | - Jian Yin
- Key Laboratory of Carbohydrate Chemistry and Biotechnology; Ministry of Education; School of Biotechnology; Jiangnan University; Lihu Avenue 1800 Wuxi Jiangsu province 214122 P. R. China
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Sun H, Yuan H, Tan R, Li B, Guo G, Zhang J, Jing H, Qin Y, Zhao Z, Zou Q, Wu C. Immunodominant antigens that induce Th1 and Th17 responses protect mice against Helicobacter pylori infection. Oncotarget 2018; 9:12050-12063. [PMID: 29552292 PMCID: PMC5844728 DOI: 10.18632/oncotarget.23927] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/30/2017] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori has infected more than half of the world's population, causing gastritis, gastric ulcers, gastric mucosa-associated lymphoid tissue lymphoma and gastric cancer. The oral recombinant Helicobacter pylori vaccine currently used has made great progress in addressing this problem, however, its efficacy and longevity still need to be improved. Th1 and Th17 cells play essential roles in local protection against Helicobacter pylori in the stomach mucosa. Additionally, protective immunodominant antigens are the preferred for a vaccine. In this work, Helicobacter pylori whole cell lysate was separated into 30 groups based on molecular weight by molecular sieve chromatography. The group best promoting CD4 T cells proliferation was selected and evaluated by immunization. The detail proteins were then analyzed by LC-MS/MS and expressed in Escherichia coli. Eleven proteins were selected and the dominant ones were demonstrated. As a result, three protective immunodominant antigens, inosine 5'-monophosphate dehydrogenase, type II citrate synthase, and urease subunit beta, were selected from Helicobacter pylori whole cell. Two of them (inosine 5'-monophosphate dehydrogenase and type II citrate synthase) were newly identified, and one (urease subunit beta) was confirmed as previously reported. The mixture of the three antigens showed satisfactory protective efficiency, with significant lower H. pylori colonization level (P < 0.001) and stronger Th1 (P < 0.001) and Th17 (P < 0.001) responses than PBS control group. Thus, inosine 5'-monophosphate dehydrogenase, type II citrate synthase, and urease subunit beta are three protective antigens inducing dominant Th1 and Th17 responses to defend against Helicobacter pylori infection.
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Affiliation(s)
- Heqiang Sun
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Hanmei Yuan
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Ranjing Tan
- Department of Dermatology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Bin Li
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Gang Guo
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Jinyong Zhang
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Haiming Jing
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Yi Qin
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Zhuo Zhao
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Quanming Zou
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
| | - Chao Wu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China
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