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Kanjo K, Lothe R, Nagar G, Rajurkar M, Rao H, Batwal S, Shaligram U, Varadarajan R. Destabilising Effect of Class B CpG Adjuvants on Different Proteins and Vaccine Candidates. Vaccines (Basel) 2025; 13:395. [PMID: 40333326 PMCID: PMC12031019 DOI: 10.3390/vaccines13040395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 03/19/2025] [Accepted: 04/02/2025] [Indexed: 05/09/2025] Open
Abstract
Background: Adjuvants function by enhancing the breadth, durability, and magnitude of the immune response, but little is known about their impact on vaccine stability. CpG is a widely used adjuvant that is included in several recently approved COVID-19 vaccines using Spike protein, RBD, or whole inactivated virus. Methods: Here, we investigate the in vitro stability of the Receptor-Binding Domain (RBD) of the SARS-CoV-2 Spike protein, as well as a number of other proteins formulated with a class B CpG adjuvant. Results: We show that RBD, BSA, and lysozyme proteins are less thermally stable, more aggregation-prone, and more protease-sensitive in the presence of CpG than without it, and that these effects are enhanced with prolonged incubation. For RBD, the effects of CpG are pH-independent but dependent on the salt concentration, with relative destabilisation decreasing with an increasing salt concentration, indicative of an electrostatic component to the interaction between CpG and the protein. The reduced thermal and proteolytic stability found in the presence of CpG is indicative of a preferential interaction of CpG with the unfolded state of the protein relative to its native state. It remains to be determined if these in vitro characteristics are unique to CpG or are also shared by other non-CpG commercial adjuvants, if they are antigen-dependent, and if and how they correlate with the in vivo immunogenicity of an adjuvanted vaccine. Conclusions: It is demonstrated that the CpG adjuvant is critical to enhancing immunogenicity and is a key reason for the success of multiple licensed commercial vaccines. Nonetheless, our work suggests that careful and systematic in vitro formulation studies may be warranted for the development of suitable, stable formulations of CpG-adjuvanted vaccine candidates.
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Affiliation(s)
- Kawkab Kanjo
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India;
| | - Rakesh Lothe
- Serum Institute of India Pvt. Ltd., Pune 411028, India; (R.L.); (G.N.); (M.R.); (H.R.); (S.B.); (U.S.)
| | - Gaurav Nagar
- Serum Institute of India Pvt. Ltd., Pune 411028, India; (R.L.); (G.N.); (M.R.); (H.R.); (S.B.); (U.S.)
| | - Meghraj Rajurkar
- Serum Institute of India Pvt. Ltd., Pune 411028, India; (R.L.); (G.N.); (M.R.); (H.R.); (S.B.); (U.S.)
| | - Harish Rao
- Serum Institute of India Pvt. Ltd., Pune 411028, India; (R.L.); (G.N.); (M.R.); (H.R.); (S.B.); (U.S.)
| | - Saurabh Batwal
- Serum Institute of India Pvt. Ltd., Pune 411028, India; (R.L.); (G.N.); (M.R.); (H.R.); (S.B.); (U.S.)
| | - Umesh Shaligram
- Serum Institute of India Pvt. Ltd., Pune 411028, India; (R.L.); (G.N.); (M.R.); (H.R.); (S.B.); (U.S.)
| | - Raghavan Varadarajan
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India;
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Lin F, Yin S, Zhang Z, Yu Y, Fang H, Liang Z, Zhu R, Zhou H, Li J, Cao K, Guo W, Qin S, Zhang Y, Lu C, Li H, Liu S, Zhang H, Ye B, Lin J, Li Y, Kang X, Xi JJ, Chen PR. Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment. Cell 2024; 187:7470-7491.e32. [PMID: 39504957 DOI: 10.1016/j.cell.2024.10.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2024] [Accepted: 10/11/2024] [Indexed: 11/08/2024]
Abstract
Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.
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Affiliation(s)
- Feng Lin
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Shenyi Yin
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
| | - Zijian Zhang
- National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China
| | - Ying Yu
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
| | - Haoming Fang
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
| | - Zhen Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Rujie Zhu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Haitao Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jianjie Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Kunxia Cao
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Weiming Guo
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Shan Qin
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
| | - Yuxuan Zhang
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Chenghao Lu
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Han Li
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
| | - Shibo Liu
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Heng Zhang
- Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Buqing Ye
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China
| | - Jian Lin
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China.
| | - Yan Li
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210061, China; National Resource Center for Mutant Mice, MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School of Nanjing University, Nanjing 210061, China.
| | - Xiaozheng Kang
- Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), First Department of Thoracic Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, China.
| | - Jianzhong Jeff Xi
- Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China.
| | - Peng R Chen
- Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Shenzhen Bay Laboratory, Shenzhen 518055, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
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Yu Y, Niu F, Sun B, Zhang S, Cai Z. Preclinical study of TLR stimulation combined PD-1 antibody enhance the therapeutic effect of microwave ablation on NSCLC. Clin Transl Oncol 2024:10.1007/s12094-024-03820-x. [PMID: 39702688 DOI: 10.1007/s12094-024-03820-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 11/26/2024] [Indexed: 12/21/2024]
Abstract
PURPOSE The purpose of this study was to investigate the therapeutic efficacy of the combination of microwave ablation (MWA) with immune checkpoints blockade and TLR9 stimulation in the treatment of non-small cell lung cancer (NSCLC) using the C57BL/6 tumor-bearing mice model. MATERIALS AND METHODS Tumor-bearing mice were treated with MWA, programmed cell death protein1 blockade (PD-1) plus MWA (MWA + P), TLR9 agonist CpG ODNs and MWA (MWA + C), PD-1 blockade and CpG ODNs (P + C), MWA plus PD-1 blockade and CpG ODNs (MWA + P + C), or untreated. Survival time was evaluated with the Kaplan-Meyer method comparing survival curves by log-rank test. On day 15 after MWA, ten mice from the combination therapy group received tumor rechallenge with LLC cells and the volumes of rechallenge tumor were calculated every 5 days. Immune cells were identified by immunohistochemistry and flow cytometry, and the concentrations of IFN-γ、TNF-α and TGF-β were identified by enzyme-linked immunosorbent assay (ELISA). RESULTS The MWA + P + C combination therapy significantly prolonged tumor-bearing mice survival and reduced tumor size compared to untreated group, MWA group, MWA + P group, M + C group, P + C group. The combination therapy also protected most surviving mice from LLC tumor rechallenge. CD8 + T-cell in tumor and spleen were remarkably induced by MWA + P + C and Treg cell further diminished by combination therapy. Both tumor necrosis factor-alpha (TNF-α) and interferon-gama (IFN-γ) concentrations in plasma were significantly elevated in the combination therapy group compared to other groups, while transforming growth factor Beta (TGF-β) was reduced. CONCLUSION MWA combined with immune checkpoints blockade and TLR stimulation could significantly enhance antitumor efficacy with augmented specific immune responses, and the combination therapy is a promising approach to treat non-small cell lung cancer (NSCLC).
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Affiliation(s)
- Ying Yu
- Hebei Key Laboratory of Respiratory Critical Care Medicine, The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Institute of Respiratory Diseases, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
- Department of Infectious Diseases, First hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, China
| | - Fu Niu
- Hebei Key Laboratory of Respiratory Critical Care Medicine, The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Institute of Respiratory Diseases, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Bo Sun
- Hebei Key Laboratory of Respiratory Critical Care Medicine, The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Institute of Respiratory Diseases, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Shusen Zhang
- Hebei Key Laboratory of Respiratory Critical Care Medicine, The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Institute of Respiratory Diseases, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Zhigang Cai
- Hebei Key Laboratory of Respiratory Critical Care Medicine, The First Department of Pulmonary and Critical Care Medicine, The Second Hospital of Hebei Medical University, Hebei Institute of Respiratory Diseases, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China.
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Woodworth JS, Contreras V, Christensen D, Naninck T, Kahlaoui N, Gallouët AS, Langlois S, Burban E, Joly C, Gros W, Dereuddre-Bosquet N, Morin J, Liu Olsen M, Rosenkrands I, Stein AK, Krøyer Wood G, Follmann F, Lindenstrøm T, Hu T, Le Grand R, Pedersen GK, Mortensen R. MINCLE and TLR9 agonists synergize to induce Th1/Th17 vaccine memory and mucosal recall in mice and non-human primates. Nat Commun 2024; 15:8959. [PMID: 39420177 PMCID: PMC11487054 DOI: 10.1038/s41467-024-52863-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Development of new vaccines tailored for difficult-to-target diseases is hampered by a lack of diverse adjuvants for human use, and none of the currently available adjuvants induce Th17 cells. Here, we develop a liposomal adjuvant, CAF®10b, that incorporates Mincle and Toll-like receptor 9 agonists. In parallel mouse and non-human primate studies comparing to CAF® adjuvants already in clinical trials, we report species-specific effects of adjuvant composition on the quality and magnitude of the responses. When combined with antigen, CAF®10b induces Th1 and Th17 responses and protection against a pulmonary infection with Mycobacterium tuberculosis in mice. In non-human primates, CAF®10b induces higher Th1 responses and robust Th17 responses detectable after six months, and systemic and pulmonary Th1 and Th17 recall responses, in a sterile model of local recall. Overall, CAF®10b drives robust memory antibody, Th1 and Th17 vaccine-responses via a non-mucosal immunization route across both rodent and primate species.
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Affiliation(s)
- Joshua S Woodworth
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark.
| | - Vanessa Contreras
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Dennis Christensen
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Thibaut Naninck
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Nidhal Kahlaoui
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Anne-Sophie Gallouët
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Sébastien Langlois
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Emma Burban
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Candie Joly
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Wesley Gros
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Nathalie Dereuddre-Bosquet
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Julie Morin
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Ming Liu Olsen
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Ida Rosenkrands
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Ann-Kathrin Stein
- Department of Vaccine Development, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Grith Krøyer Wood
- Department of Vaccine Development, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Frank Follmann
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Thomas Lindenstrøm
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Tu Hu
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Roger Le Grand
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184), 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Gabriel Kristian Pedersen
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark
| | - Rasmus Mortensen
- Department of Infectious Disease Immunology, Statens Serum Institut, Artillerivej 5, 2300, Copenhagen, Denmark.
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Gogoi H, Mani R, Bhatnagar R. Re-inventing traditional aluminum-based adjuvants: Insight into a century of advancements. Int Rev Immunol 2024; 44:58-81. [PMID: 39310923 DOI: 10.1080/08830185.2024.2404095] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 06/01/2023] [Accepted: 08/31/2024] [Indexed: 02/22/2025]
Abstract
Aluminum salt-based adjuvants like alum, alhydrogel and Adju-Phos are by far the most favored clinically approved vaccine adjuvants. They have demonstrated excellent safety profile and currently used in vaccines against diphtheria, tetanus, pertussis, hepatitis B, anthrax etc. These vaccinations cause minimal side effects like local inflammation at the injection site. Aluminum salt-based adjuvants primarily stimulate CD4+ T cells and B cell mediated Th2 immune response leading to generate a robust antibody response. In this review article, we have compiled the role of physio-chemical role of the two commonly used aluminum salt-based adjuvants alhydrogel and Adju-Phos, and the effect of surface properties, buffer composition, and adjuvant dosage on the immune response. After being studied for almost a century, researchers have come up with various mechanism by which these aluminum adjuvants activate the immune system. Firstly, we have covered the initial works of Glenny and his "repository effect" which paved the work for his successors to explore the involvement of cytokines, chemokines, recruitment of innate immune cells, enhanced antigen uptake by antigen presenting cells, and formation of NLRP3 inflammasome complex in mediating the immune response. It has been reported that aluminum adjuvants activate multiple immunological pathways which synergistically activates the immune system. We later discuss the recent developments in nanotechnology-based preparations of next generation aluminum based adjuvants which has enabled precise size control and morphology of the traditional aluminum adjuvants thereby manipulating the immune response as per our desire.
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Affiliation(s)
- Himanshu Gogoi
- Amity Institute of Microbial Technology, Amity University Rajasthan, Jaipur, India
- Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
- Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad - Gurgaon Expressway, Faridabad, Haryana, India
| | - Rajesh Mani
- Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
- Department of Microbiology, Immunology and Molecular Genetics, University Kentucky College of Medicine, Lexington, KY, USA
| | - Rakesh Bhatnagar
- Amity Institute of Microbial Technology, Amity University Rajasthan, Jaipur, India
- Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
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Ezzemani W, Ouladlahsen A, Altawalah H, Saile R, Sarih M, Kettani A, Ezzikouri S. Identification of novel T-cell epitopes on monkeypox virus and development of multi-epitopes vaccine using immunoinformatics approaches. J Biomol Struct Dyn 2024; 42:5349-5364. [PMID: 37354141 DOI: 10.1080/07391102.2023.2226733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 06/10/2023] [Indexed: 06/26/2023]
Abstract
Monkeypox virus (MPV) is closely related to the smallpox virus, and previous data from Africa suggest that the smallpox vaccine (VARV) is at least 85% effective in preventing MPV. No multi-epitope vaccine has yet been developed to prevent MPV infection. In this work, we used in silico structural biology and advanced immunoinformatic strategies to design a multi-epitope subunit vaccine against MPV infection. The designed vaccine sequence is adjuvanted with CpG-ODN and includes HTL/CTL epitopes for similar proteins between vaccinia virus (VACV) that induced T-cell production in vaccinated volunteers and the first draft sequence of the MPV genome associated with the suspected outbreak in several countries, May 2022. In addition, the specific binding of the modified vaccine and the immune Toll-like receptor 9 (TLR9) was estimated by molecular interaction studies. Strong interaction in the binding groove as well as good docking scores confirmed the stringency of the modified vaccine. The stability of the interaction was confirmed by a classical molecular dynamics simulation and normal mode analysis. Then, the immune simulation also indicated the ability of this vaccine to induce an effective immune response against MPV. Codon optimization and in silico cloning of the vaccine into the pET-28a (+) vector also showed its expression potential in the E. coli K12 system. The promising data obtained from the various in silico studies indicate that this vaccine is effective against MPV. However, additional in vitro and in vivo studies are still needed to confirm its efficacy.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Wahiba Ezzemani
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
- Laboratoire de Biologie et Santé (URAC34), Départment de Biologie, Faculté des Sciences Ben Msik, Hassan II University of Casablanca, Casablanca, Morocco
| | - Ahd Ouladlahsen
- Faculté de médecine et de pharmacie, Université Hassan II, Casablanca, Morocco
- Service des maladies infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Haya Altawalah
- Department of Microbiology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
- Virology Unit, Yacoub Behbehani Center, Sabah Hospital, Ministry of Health, Kuwait City, Kuwait
| | - Rachid Saile
- Laboratoire de Biologie et Santé (URAC34), Départment de Biologie, Faculté des Sciences Ben Msik, Hassan II University of Casablanca, Casablanca, Morocco
| | - M'hammed Sarih
- Service de Parasitologie et des Maladies Vectorielles, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Anass Kettani
- Laboratoire de Biologie et Santé (URAC34), Départment de Biologie, Faculté des Sciences Ben Msik, Hassan II University of Casablanca, Casablanca, Morocco
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
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7
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Wang G, Wang Y, Ma F. Exploiting bacterial-origin immunostimulants for improved vaccination and immunotherapy: current insights and future directions. Cell Biosci 2024; 14:24. [PMID: 38368397 PMCID: PMC10874560 DOI: 10.1186/s13578-024-01207-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 02/06/2024] [Indexed: 02/19/2024] Open
Abstract
Vaccination is a valid strategy to prevent and control newly emerging and reemerging infectious diseases in humans and animals. However, synthetic and recombinant antigens are poor immunogenic to stimulate efficient and protective host immune response. Immunostimulants are indispensable factors of vaccines, which can promote to trigger fast, robust, and long-lasting immune responses. Importantly, immunotherapy with immunostimulants is increasing proved to be an effective and promising treatment of cancer, which could enhance the function of the immune system against tumor cells. Pattern recognition receptors (PRRs) play vital roles in inflammation and are central to innate and adaptive immune responses. Toll-like receptors (TLRs)-targeting immunostimulants have become one of the hotspots in adjuvant research and cancer therapy. Bacterial-origin immunoreactive molecules are usually the ligands of PRRs, which could be fast recognized by PRRs and activate immune response to eliminate pathogens. Varieties of bacterial immunoreactive molecules and bacterial component-mimicking molecules have been successfully used in vaccines and clinical therapy so far. This work provides a comprehensive review of the development, current state, mechanisms, and applications of bacterial-origin immunostimulants. The exploration of bacterial immunoreactive molecules, along with their corresponding mechanisms, holds immense significance in deepening our understanding of bacterial pathogenicity and in the development of promising immunostimulants.
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Affiliation(s)
- Guangyu Wang
- College of Food Science and Engineering, Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, Jiangsu, 210023, China
| | - Yongkang Wang
- College of Food Science and Engineering, Collaborative Innovation Center for Modern Grain Circulation and Safety/Key Laboratory of Grains and Oils Quality Control and Processing, Nanjing University of Finance and Economics, Nanjing, Jiangsu, 210023, China
| | - Fang Ma
- Institute of Veterinary Immunology & Engineering, National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, 210014, China.
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, 212013, China.
- GuoTai (Taizhou) Center of Technology Innovation for Veterinary Biologicals, Taizhou, 225300, China.
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8
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Gao F, Zheng M, Fan J, Ding Y, Liu X, Zhang M, Zhang X, Dong J, Zhou X, Luo J, Li X. A trimeric spike-based COVID-19 vaccine candidate induces broad neutralization against SARS-CoV-2 variants. Hum Vaccin Immunother 2023; 19:2186110. [PMID: 36882925 PMCID: PMC10026892 DOI: 10.1080/21645515.2023.2186110] [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: 03/09/2023] Open
Abstract
COVID-19 pandemic caused by SARS-CoV-2 infection has an impact on global public health and social economy. The emerging immune escape of SARS-CoV-2 variants pose great challenges to the development of vaccines based on original strains. The development of second-generation COVID-19 vaccines to induce immune responses with broad-spectrum protective effects is a matter of great urgency. Here, a prefusion-stabilized spike (S) trimer protein based on B.1.351 variant was expressed and prepared with CpG7909/aluminum hydroxide dual adjuvant to investigate the immunogenicity in mice. The results showed that the candidate vaccine could induce a significant receptor binding domain-specific antibody response and a substantial interferon-γ-mediated immune response. Furthermore, the candidate vaccine also elicited robust cross-neutralization against the pseudoviruses of the original strain, Beta variant, Delta variant and Omicron variant. The vaccine strategy of S-trimer protein formulated with CpG7909/aluminum hydroxide dual adjuvant may be considered a means to increase vaccine effectiveness against future variants.
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Affiliation(s)
- Feixia Gao
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Mei Zheng
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Jiangfeng Fan
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Yahong Ding
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Xueying Liu
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Min Zhang
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Xin Zhang
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Jinrong Dong
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Xu Zhou
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Jian Luo
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
| | - Xiuling Li
- Department of Research and Development, Shanghai Institute of Biological Products, Shanghai, China
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9
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Hongtu Q, BoLi L, Jianguo C, Shusheng P, Ming M. Immunogenicity of rabies virus G mRNA formulated with lipid nanoparticles and nucleic acid immunostimulators in mice. Vaccine 2023; 41:7129-7137. [PMID: 37866995 DOI: 10.1016/j.vaccine.2023.10.019] [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: 08/23/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/24/2023]
Abstract
Rabies is a preventable zoonotic disease caused by rabies virus (RABV) with high mortality. Messenger RNA (mRNA) vaccines have opened up new avenues for vaccine development and pandemic preparedness with potent scalability, which may overcome the only licensed rabies inactived vaccine' shortcoming of time and cost wasting. Here, we designed an RABV mRNA vaccines expressed RABV G protein and capsulated with lipid nanoparticle (LNP) and different nucleic acid immunostimulator (CPG 1018, CPG 2395 and Poly I:C) and then assessed the immunogenicity and protective capacity in mice. While RABV mRNA capsulated with LNP and CPG 1018 could induce more potent humoral response with highest and durable RABV-G specific IgG titers and virus neutralizing titers, but also induced stronger RABV G-specific cell-mediated immunity (CMI) responses, including the highest proportions of interferon-γ (IFN-γ) and tumor necrosis factor alpha (TNFα)- producing CD4+/CD8 + T cells according to a flow cytometry assay in mice. In addition, in the pre- and post-exposure challenge assays, LNP + CPG 1018 capsulated RABV G mRNA induced 100 % protection against 25 LD50 of RABV infection with highest inhibition efficacy of viral replication with the decreased virus genome detected by qRT-PCR. These results showed that RABV G mRNA capsulated with LNP immune-stimulating nucleic acids CPG 1018 showed promise as a safe and economical rabies vaccine candidate.
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Affiliation(s)
- Qiao Hongtu
- Scientific Research Department, Chengdu Qingbaijiang District People's Hospital, Chengdu, China.
| | - Liu BoLi
- Emergency Department, Chengdu Qingbaijiang District People's Hospital, Chengdu, China
| | - Chen Jianguo
- Medical Laboratory, Chengdu Qingbaijiang District People's Hospital, Chengdu, China
| | - Peng Shusheng
- Medical Laboratory, Chengdu Qingbaijiang District People's Hospital, Chengdu, China
| | - Min Ming
- Medical Laboratory, Chengdu Qingbaijiang District People's Hospital, Chengdu, China
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10
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Zhao T, Cai Y, Jiang Y, He X, Wei Y, Yu Y, Tian X. Vaccine adjuvants: mechanisms and platforms. Signal Transduct Target Ther 2023; 8:283. [PMID: 37468460 PMCID: PMC10356842 DOI: 10.1038/s41392-023-01557-7] [Citation(s) in RCA: 236] [Impact Index Per Article: 118.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/19/2023] [Accepted: 06/27/2023] [Indexed: 07/21/2023] Open
Abstract
Adjuvants are indispensable components of vaccines. Despite being widely used in vaccines, their action mechanisms are not yet clear. With a greater understanding of the mechanisms by which the innate immune response controls the antigen-specific response, the adjuvants' action mechanisms are beginning to be elucidated. Adjuvants can be categorized as immunostimulants and delivery systems. Immunostimulants are danger signal molecules that lead to the maturation and activation of antigen-presenting cells (APCs) by targeting Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) to promote the production of antigen signals and co-stimulatory signals, which in turn enhance the adaptive immune responses. On the other hand, delivery systems are carrier materials that facilitate antigen presentation by prolonging the bioavailability of the loaded antigens, as well as targeting antigens to lymph nodes or APCs. The adjuvants' action mechanisms are systematically summarized at the beginning of this review. This is followed by an introduction of the mechanisms, properties, and progress of classical vaccine adjuvants. Furthermore, since some of the adjuvants under investigation exhibit greater immune activation potency than classical adjuvants, which could compensate for the deficiencies of classical adjuvants, a summary of the adjuvant platforms under investigation is subsequently presented. Notably, we highlight the different action mechanisms and immunological properties of these adjuvant platforms, which will provide a wide range of options for the rational design of different vaccines. On this basis, this review points out the development prospects of vaccine adjuvants and the problems that should be paid attention to in the future.
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Affiliation(s)
- Tingmei Zhao
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yulong Cai
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yujie Jiang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xuemei He
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yifan Yu
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohe Tian
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China.
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11
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Estephan L, Liu LTC, Lien CE, Smith ER, Gurwith M, Chen RT. A Brighton Collaboration standardized template with key considerations for a benefit/risk assessment for the Medigen COVID-19 protein vaccine. Vaccine 2023; 41:2615-2629. [PMID: 36925422 PMCID: PMC9981522 DOI: 10.1016/j.vaccine.2023.02.083] [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: 02/17/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023]
Abstract
The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group has prepared standardized templates to describe the key considerations for the benefit-risk assessment of several vaccine platform technologies, including protein subunit vaccines. This article uses the BRAVATO template to review the features of the MVC-COV1901 vaccine, a recombinant protein subunit vaccine based on the stabilized pre-fusion SARS-CoV-2 spike protein S-2P, adjuvanted with CpG 1018 and aluminum hydroxide, manufactured by Medigen Vaccine Biologics Corporation in Taiwan. MVC-COV1901 vaccine is indicated for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 12 years of age and older. The template offers details on basic vaccine information, target pathogen and population, characteristics of antigen and adjuvant, preclinical data, human safety and efficacy data, and overall benefit-risk assessment. The clinical development program began in September 2020 and based on demonstration of favorable safety and immunogenicity profiles in 11 clinical trials in over 5,000 participants, it has been approved for emergency use based on immunobridging results for adults in Taiwan, Estwatini, Somaliland, and Paraguay. The main clinical trials include placebo-controlled phase 2 studies in healthy adults (CT-COV-21), adolescents (CT-COV-22), and elderly population (CT-COV-23) as well as 3 immunobridging phase 3 trials (CT-COV-31, CT-COV-32, and CT-COV-34) in which MVC-COV1901 was compared to AZD1222. There are also clinical trials studying MVC-COV1901 as homologous and heterologous boosters (CT-COV-24 and CT-COV-25). The totality of evidence based on ∼3 million vaccinees to date includes a mostly clean safety profile, with adverse events mostly being mild and self-limiting in both clinical development and post-marketing experience, proven immunogenic response, and real-world effectiveness data. The immunogenic profile demonstrates that MVC-COV1901 induces high levels of neutralizing and binding antibodies against SARS-CoV-2. There is a dose-dependent response and a significant correlation between binding and neutralizing antibody activity. Antigen-specific T-cell responses, particularly a Th1-biased immune response characterized by high levels of interferon gamma and IL-2 cytokines, have also been observed. Coupled with this, MVC-COV1901 has favorable thermostability and better safety profiles when compared to other authorized vaccines from different platforms, which make it potentially a good candidate for vaccine supply chains in global markets.
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Affiliation(s)
| | | | - Chia En Lien
- Medigen Vaccine Biologics Corp., Taipei, Taiwan; Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Emily R Smith
- Brighton Collaboration, A Program of the Task Force for Global Health, Decatur, GA, USA.
| | - Marc Gurwith
- Brighton Collaboration, A Program of the Task Force for Global Health, Decatur, GA, USA
| | - Robert T Chen
- Brighton Collaboration, A Program of the Task Force for Global Health, Decatur, GA, USA
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12
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Ito D, Ito H, Ando T, Sakai Y, Ideta T, Ishii KJ, Ishikawa T, Shimizu M. Spermidine enhances the efficacy of adjuvant in HBV vaccination in mice. Hepatol Commun 2023; 7:02009842-202304010-00022. [PMID: 36972390 PMCID: PMC10043579 DOI: 10.1097/hc9.0000000000000104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 01/15/2023] [Indexed: 03/29/2023] Open
Abstract
Background: Various vaccine adjuvants have been developed to eliminate HBV from patients with chronic HBV infection. In addition, spermidine (SPD), a type of polyamine, has been reported to enhance the activity of immune cells. In the present study, we investigated whether the combination of SPD and vaccine adjuvant enhances the HBV antigen-specific immune response to HBV vaccination. Methods: Wild-type and HBV-transgenic (HBV-Tg) mice were vaccinated 2 or 3 times. SPD was orally administered in drinking water. Cyclic guanosine monophosphate-AMP (cGAMP) and nanoparticulate CpG-ODN (K3-SPG) were used as the HBV vaccine adjuvants. The HBV antigen-specific immune response was evaluated by measuring the HBsAb titer in blood collected over time and the number of interferon-γ producing cells by enzyme-linked immunospot assay. Results: The administration of HBsAg + cGAMP + SPD or HBsAg + K3-SPG + SPD significantly enhanced HBsAg-specific interferon-γ production by CD8 T cells from wild-type and HBV-Tg mice. The administration of HBsAg, cGAMP, and SPD increased serum HBsAb levels in wild-type and HBV-Tg mice. In HBV-Tg mice, the administration of SPD + cGAMP or SPD + K3-SPG with HBV vaccination significantly reduced HBsAg levels in the liver and serum. CONCLUSIONS These results indicate that the combination of HBV vaccine adjuvant and SPD induces a stronger humoral and cellular immune response through T-cell activation. These treatments may support the development of a strategy to completely eliminate HBV.
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Affiliation(s)
- Daisuke Ito
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu City, Japan
| | - Hiroyasu Ito
- Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Aichi, Japan
| | - Tatsuya Ando
- Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Aichi, Japan
| | - Yasuhiro Sakai
- Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Aichi, Japan
| | - Takayasu Ideta
- Department of Gastroenterology, Central Japan International Medical Center, Gifu, Japan
| | - Ken J Ishii
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Tetsuya Ishikawa
- Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu City, Japan
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13
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Woodworth JS, Contreras V, Christensen D, Naninck T, Kahlaoui N, Gallouët AS, Langlois S, Burban E, Joly C, Gros W, Dereuddre-Bosquet N, Morin J, Olsen ML, Rosenkrands I, Stein AK, Wood GK, Follmann F, Lindenstrøm T, LeGrand R, Pedersen GK, Mortensen R. A novel adjuvant formulation induces robust Th1/Th17 memory and mucosal recall responses in Non-Human Primates. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.23.529651. [PMID: 36865310 PMCID: PMC9980079 DOI: 10.1101/2023.02.23.529651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
After clean drinking water, vaccination is the most impactful global health intervention. However, development of new vaccines against difficult-to-target diseases is hampered by the lack of diverse adjuvants for human use. Of particular interest, none of the currently available adjuvants induce Th17 cells. Here, we develop and test an improved liposomal adjuvant, termed CAF®10b, that incorporates a TLR-9 agonist. In a head-to-head study in non-human primates (NHPs), immunization with antigen adjuvanted with CAF®10b induced significantly increased antibody and cellular immune responses compared to previous CAF® adjuvants, already in clinical trials. This was not seen in the mouse model, demonstrating that adjuvant effects can be highly species specific. Importantly, intramuscular immunization of NHPs with CAF®10b induced robust Th17 responses that were observed in circulation half a year after vaccination. Furthermore, subsequent instillation of unadjuvanted antigen into the skin and lungs of these memory animals led to significant recall responses including transient local lung inflammation observed by Positron Emission Tomography-Computed Tomography (PET-CT), elevated antibody titers, and expanded systemic and local Th1 and Th17 responses, including >20% antigen-specific T cells in the bronchoalveolar lavage. Overall, CAF®10b demonstrated an adjuvant able to drive true memory antibody, Th1 and Th17 vaccine-responses across rodent and primate species, supporting its translational potential.
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Affiliation(s)
- Joshua S Woodworth
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Vanessa Contreras
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Dennis Christensen
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Thibaut Naninck
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Nidhal Kahlaoui
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Anne-Sophie Gallouët
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Sébastien Langlois
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Emma Burban
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Candie Joly
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Wesley Gros
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Nathalie Dereuddre-Bosquet
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Julie Morin
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Ming Liu Olsen
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Ida Rosenkrands
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Ann-Kathrin Stein
- Department of Vaccine Development, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Grith Krøyer Wood
- Department of Vaccine Development, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Frank Follmann
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Thomas Lindenstrøm
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Roger LeGrand
- Université Paris-Saclay, Inserm, CEA, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB/IDMIT/UMR1184); 92265, Fontenay-aux-Roses & Kremlin Bicêtre, France
| | - Gabriel Kristian Pedersen
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
| | - Rasmus Mortensen
- Department of Infectious Disease Immunology, Statens Serum Institut; Artillerivej 5, 2300 Copenhagen, Denmark
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14
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Zhang Y, Luo MT, Wu Q, Wang YX, Ma X, Yan G, Zhang SH, Chen Y, Wan N, Zhang L, You D, Wei J, Zhang Z, Zhou TC. Long-term and effective neutralization against omicron sublineages elicited by four platform COVID-19 vaccines as a booster dose. Cell Discov 2023; 9:17. [PMID: 36754955 PMCID: PMC9907876 DOI: 10.1038/s41421-023-00518-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 01/02/2023] [Indexed: 02/10/2023] Open
Affiliation(s)
- Yuemiao Zhang
- grid.440773.30000 0000 9342 2456Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan China ,grid.506261.60000 0001 0706 7839Renal Division, Department of Medicine, Peking University First Hospital, Renal Pathology Center, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China ,grid.410726.60000 0004 1797 8419State Key Laboratory of Genetic Resources and Evolution, and Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming and College of Life Science, University of Chinese Academy of Sciences, Beijing, China ,grid.440773.30000 0000 9342 2456State Key Laboratory for Conservation and Utilization of Bio-resource and School of Life Sciences, Yunnan University, Kunming, Yunnan China
| | - Meng-Ting Luo
- grid.440773.30000 0000 9342 2456Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan China
| | - Qingqin Wu
- grid.440773.30000 0000 9342 2456State Key Laboratory for Conservation and Utilization of Bio-resource and School of Life Sciences, Yunnan University, Kunming, Yunnan China
| | - Yun-Xia Wang
- grid.440773.30000 0000 9342 2456Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan China
| | - Xupu Ma
- grid.440773.30000 0000 9342 2456State Key Laboratory for Conservation and Utilization of Bio-resource and School of Life Sciences, Yunnan University, Kunming, Yunnan China
| | - Guanghong Yan
- grid.285847.40000 0000 9588 0960School of Public Health, Kunming Medical University, Kunming, Yunnan China
| | - Si-Hang Zhang
- grid.440773.30000 0000 9342 2456Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan China
| | - Yanli Chen
- grid.440773.30000 0000 9342 2456State Key Laboratory for Conservation and Utilization of Bio-resource and School of Life Sciences, Yunnan University, Kunming, Yunnan China ,grid.506261.60000 0001 0706 7839Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan China
| | - Na Wan
- grid.440773.30000 0000 9342 2456State Key Laboratory for Conservation and Utilization of Bio-resource and School of Life Sciences, Yunnan University, Kunming, Yunnan China
| | - Liang Zhang
- grid.440773.30000 0000 9342 2456Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan China
| | - Dingyun You
- grid.285847.40000 0000 9588 0960School of Public Health, Kunming Medical University, Kunming, Yunnan China ,grid.285847.40000 0000 9588 0960Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Biomedical Engineering, Kunming Medical University, Kunming, Yunnan China ,grid.285847.40000 0000 9588 0960Yunnan Key Laboratory of Stomatology, Kunming Medical University, Kunming, Yunnan China
| | - Jia Wei
- Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan, China.
| | - Zijie Zhang
- Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan, China. .,State Key Laboratory for Conservation and Utilization of Bio-resource and School of Life Sciences, Yunnan University, Kunming, Yunnan, China.
| | - Tai-Cheng Zhou
- Central Laboratory, Liver Disease Research Center and Department of Infectious Disease, The Affiliated Hospital of Yunnan University, Kunming, Yunnan, China.
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15
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Ahmad T, Baig M, Othman SS, Malibary H, Ahmad S, Rasheed SM, Al Bataineh MT, Al-Omari B. Bibliometric Analysis and Visualization Mapping of Anthrax Vaccine Publications from 1991 through 2021. Vaccines (Basel) 2022; 10:1007. [PMID: 35891169 PMCID: PMC9316950 DOI: 10.3390/vaccines10071007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/18/2022] [Accepted: 06/20/2022] [Indexed: 02/01/2023] Open
Abstract
PURPOSE This study aims to analyze and characterize anthrax vaccine-related research, key developments, global research trends, and mapping of published scientific research articles during the last three decades (1991-2021). METHODS A bibliometric and visualized study was conducted. The Web of Science Core Collection database (WoSCC) was searched using relevant keywords ("Anthrax" OR "Anthrax bacterium" OR "Bacillus anthracis" OR "Bacteridium anthracis" OR "Bacillus cereus var. Anthracis" (Topic)) AND ("Vaccine" OR "Vaccines" OR "Immunization" OR "Immunisation" OR "Immunizations" OR "Immunisations" (Topic)) with specific restrictions. The data was analyzed and plotted by using different bibliometric software and tools (HistCiteTM software, version 12.3.17, Bibliometrix: An R-tool version 3.2.1, and VOSviewer software, version 1.6.17). RESULTS The initial search yielded 1750 documents. After screening the titles and abstracts of the published studies, a total of 1090 articles published from 1991 to 2021 were included in the final analysis. These articles were published in 334 journals and were authored by 4567 authors from 64 countries with a collaboration index of 4.32. The annual scientific production growth rate was found to be 9.68%. The analyzed articles were cited 31335 times. The most productive year was 2006 (n = 77, 7.06%), while the most cited year was 2007 (2561 citations). The leading authors and journals in anthrax research were Rakesh Bhatnagar from Jawaharlal Nehru University, India (n = 35, 3.21%), and Vaccine (n = 1830, 16.51%), while the most cited author and journal were Arthur M. Friedlander from the United States Department of Defense (n = 2762), and Vaccine (n = 5696), respectively. The most studied recent research trend topics were lethal, double-blind, epidemiology, B surface antigen, disease, and toxin. The United States of America (USA) was the most dominant country in terms of publications, citations, corresponding author country, and global collaboration in anthrax vaccine research. The USA had the strongest collaboration with the United Kingdom (UK), China, Canada, Germany, and France. CONCLUSION This is the first bibliometric study that provides a comprehensive historical overview of scientific studies. From 2006 to 2008, more than 20% of the total articles were published; however, a decrease was observed since 2013 in anthrax vaccine research. The developed countries made significant contributions to anthrax vaccine-related research, especially the USA. Among the top 10 leading authors, six authors are from the USA. The majority of the top leading institutions are also from the USA. About 90% of the total studies were funded by the United States Department of Health and Human Services (HHS), National Institutes of Health (NIH), USA, and the National Institute of Allergy and Infectious Diseases (NIAID), USA.
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Affiliation(s)
- Tauseef Ahmad
- Vanke School of Public Health, Tsinghua University, Beijing 100084, China
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing 210096, China
| | - Mukhtiar Baig
- Department of Clinical Biochemistry, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah 25289, Saudi Arabia;
| | - Sahar Shafik Othman
- Department of Family Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 25289, Saudi Arabia;
| | - Husam Malibary
- Department of Internal Medicine, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah 25289, Saudi Arabia;
| | - Shabir Ahmad
- Department of Agriculture, Bacha Khan University Charsadda, P.O. Box 20, Charsadda 24420, Khyber Pakhtunkhwa, Pakistan; (S.A.); (S.M.R.)
| | - Syed Majid Rasheed
- Department of Agriculture, Bacha Khan University Charsadda, P.O. Box 20, Charsadda 24420, Khyber Pakhtunkhwa, Pakistan; (S.A.); (S.M.R.)
| | - Mohammad T. Al Bataineh
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi P.O. Box 127788, United Arab Emirates;
- Emirates Bio-Research Center, Ministry of Interior, Abu Dhabi P.O. Box 127788, United Arab Emirates
| | - Basem Al-Omari
- Department of Epidemiology and Population Health, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
- K.U. Research and Data Intelligence Support Center (RDISC) AW 8474000331, Khalifa University of Science and Technology, Abu Dhabi P.O. Box 127788, United Arab Emirates
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Liu B, Yin Y, Liu Y, Wang T, Sun P, Ou Y, Gong X, Hou X, Zhang J, Ren H, Luo S, Ke Q, Yao Y, Xu J, Wu J. A Vaccine Based on the Receptor-Binding Domain of the Spike Protein Expressed in Glycoengineered Pichia pastoris Targeting SARS-CoV-2 Stimulates Neutralizing and Protective Antibody Responses. ENGINEERING (BEIJING, CHINA) 2022; 13:107-115. [PMID: 34457370 PMCID: PMC8378774 DOI: 10.1016/j.eng.2021.06.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/05/2021] [Accepted: 06/11/2021] [Indexed: 05/24/2023]
Abstract
In 2020 and 2021, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, caused a global pandemic. Vaccines are expected to reduce the pressure of prevention and control, and have become the most effective strategy to solve the pandemic crisis. SARS-CoV-2 infects the host by binding to the cellular receptor angiotensin converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the surface spike (S) glycoprotein. In this study, a candidate vaccine based on a RBD recombinant subunit was prepared by means of a novel glycoengineered yeast Pichia pastoris expression system with characteristics of glycosylation modification similar to those of mammalian cells. The candidate vaccine effectively stimulated mice to produce high-titer anti-RBD specific antibody. Furthermore, the specific antibody titer and virus-neutralizing antibody (NAb) titer induced by the vaccine were increased significantly by the combination of the double adjuvants Al(OH)3 and CpG. Our results showed that the virus-NAb lasted for more than six months in mice. To summarize, we have obtained a SARS-CoV-2 vaccine based on the RBD of the S glycoprotein expressed in glycoengineered Pichia pastoris, which stimulates neutralizing and protective antibody responses. A technical route for fucose-free complex-type N-glycosylation modified recombinant subunit vaccine preparation has been established.
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Affiliation(s)
- Bo Liu
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Ying Yin
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Yuxiao Liu
- Medical Innovation Research Division & Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
- Department of Neurosurgery, First Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
| | - Tiantian Wang
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Peng Sun
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Yangqin Ou
- Shenzhen Taihe Biotechnology Co. Ltd., Shenzhen 518001, China
| | - Xin Gong
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Xuchen Hou
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Jun Zhang
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Hongguang Ren
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Shiqiang Luo
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
- Institute of Physical Science and Information Technology, Anhui University, Hefei 230000, China
| | - Qian Ke
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
- Institute of Physical Science and Information Technology, Anhui University, Hefei 230000, China
| | - Yongming Yao
- Medical Innovation Research Division & Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
| | - Junjie Xu
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
| | - Jun Wu
- Department of Microorganism Engineering, Beijing Institute of Biotechnology, Beijing 100071, China
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Ushach I, Zhu R, Rosler E, Pandey RK, De Costa NTS, Pourshahian S, Han Q, Li C, Beigelman L, Gryaznov SM, Yun T. Targeting TLR9 agonists to secondary lymphoid organs induces potent immune responses against HBV infection. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 27:1103-1115. [PMID: 35228903 PMCID: PMC8857595 DOI: 10.1016/j.omtn.2022.01.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 01/28/2022] [Indexed: 11/17/2022]
Abstract
Despite the existence of a prophylactic vaccine against hepatitis B virus (HBV), chronic hepatitis B virus (CHB) infection remains the leading cause of cirrhosis and liver cancer in developing countries. Because HBV persistence is associated with insufficient host immune responses to the infection, development of an immunomodulator as a component of therapeutic vaccination may become an important strategy for treatment CHB. In the present study, we aimed to design a novel immunomodulator with the capacity to subvert immune tolerance to HBV. We developed a lymphoid organ-targeting immunomodulator by conjugating a naturally occurring, lipophilic molecule, α-tocopherol, to a potent CpG oligonucleotide adjuvant pharmacophore. This approach resulted in preferential trafficking of the α-tocopherol-conjugated oligonucleotide to lymphoid organs where it was internalized by antigen-presenting cells (APCs). Moreover, we show that conjugation of the oligonucleotides to α-tocopherol results in micelle-like structure formation, which improved cellular internalization and enhanced immunomodulatory properties of the conjugates. In a mouse model of chronic HBV infection, targeting CpG oligonucleotide to lymphoid organs induced strong cellular and humoral immune responses that resulted in sustained control of the virus. Given the potency and tolerability of an α-tocopherol-conjugated CpG oligonucleotide, this modality could potentially be broadly applied for therapeutic vaccine development.
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Affiliation(s)
- Irina Ushach
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
- Corresponding author Irina Ushach, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
| | - Ren Zhu
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
- China R&D, Janssen Pharmaceuticals, 4560 Jinke Road, Pudong, Shanghai 200010, China
| | - Elen Rosler
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
| | - Rajendra K. Pandey
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
| | - N. Tilani S. De Costa
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
| | - Soheil Pourshahian
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
| | - Qinglin Han
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
- China R&D, Janssen Pharmaceuticals, 4560 Jinke Road, Pudong, Shanghai 200010, China
| | - Chris Li
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
- China R&D, Janssen Pharmaceuticals, 4560 Jinke Road, Pudong, Shanghai 200010, China
| | - Leonid Beigelman
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
| | - Sergei M. Gryaznov
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
| | - Theodore Yun
- Janssen Pharmaceutical Companies of Johnson & Johnson, 260 E. Grand Avenue, 169 Harbor Boulevard, South San Francisco, CA 94080, USA
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18
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Yan Y, Qiu Y, Davgadorj C, Zheng C. Novel Molecular Therapeutics Targeting Signaling Pathway to Control Hepatitis B Viral Infection. Front Cell Infect Microbiol 2022; 12:847539. [PMID: 35252042 PMCID: PMC8894711 DOI: 10.3389/fcimb.2022.847539] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Numerous canonical cellular signaling pathways modulate hepatitis B virus (HBV) replication. HBV genome products are known to play a significant role in regulating these cellular pathways for the liver’s viral-related pathology and physiology and have been identified as the main factor in hepatocarcinogenesis. Signaling changes during viral replication ultimately affect cellular persistence, multiplication, migration, genome instability, and genome damage, leading to proliferation, evasion of apoptosis, block of differentiation, and immortality. Recent studies have documented that numerous signaling pathway agonists or inhibitors play an important role in reducing HBV replication in vitro and in vivo, and some have been used in phase I or phase II clinical trials. These optional agents as molecular therapeutics target cellular pathways that could limit the replication and transcription of HBV or inhibit the secretion of the small surface antigen of HBV in a signaling-independent manner. As principle-based available information, a combined strategy including antiviral therapy and immunomodulation will be needed to control HBV infection effectively. In this review, we summarize recent findings on interventions of molecular regulators in viral replication and the interactions of HBV proteins with the components of the various targeting cellular pathways, which may assist in designing novel agents to modulate signaling pathways to prevent HBV replication or carcinogenesis.
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Affiliation(s)
- Yan Yan
- Laboratory for Infection and Immunity, Hepatology Institute of Wuxi, The Fifth People’s Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China
- *Correspondence: Yan Yan, ; Chunfu Zheng,
| | - Yuanwang Qiu
- Laboratory for Infection and Immunity, Hepatology Institute of Wuxi, The Fifth People’s Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Chantsalmaa Davgadorj
- Laboratory for Infection and Immunity, Hepatology Institute of Wuxi, The Fifth People’s Hospital of Wuxi, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Chunfu Zheng
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
- *Correspondence: Yan Yan, ; Chunfu Zheng,
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19
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Yang JX, Tseng JC, Yu GY, Luo Y, Huang CYF, Hong YR, Chuang TH. Recent Advances in the Development of Toll-like Receptor Agonist-Based Vaccine Adjuvants for Infectious Diseases. Pharmaceutics 2022; 14:pharmaceutics14020423. [PMID: 35214155 PMCID: PMC8878135 DOI: 10.3390/pharmaceutics14020423] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 02/06/2023] Open
Abstract
Vaccines are powerful tools for controlling microbial infections and preventing epidemic diseases. Efficient inactive, subunit, or viral-like particle vaccines usually rely on a safe and potent adjuvant to boost the immune response to the antigen. After a slow start, over the last decade there has been increased developments on adjuvants for human vaccines. The development of adjuvants has paralleled our increased understanding of the molecular mechanisms for the pattern recognition receptor (PRR)-mediated activation of immune responses. Toll-like receptors (TLRs) are a group of PRRs that recognize microbial pathogens to initiate a host’s response to infection. Activation of TLRs triggers potent and immediate innate immune responses, which leads to subsequent adaptive immune responses. Therefore, these TLRs are ideal targets for the development of effective adjuvants. To date, TLR agonists such as monophosphoryl lipid A (MPL) and CpG-1018 have been formulated in licensed vaccines for their adjuvant activity, and other TLR agonists are being developed for this purpose. The COVID-19 pandemic has also accelerated clinical research of vaccines containing TLR agonist-based adjuvants. In this paper, we reviewed the agonists for TLR activation and the molecular mechanisms associated with the adjuvants’ effects on TLR activation, emphasizing recent advances in the development of TLR agonist-based vaccine adjuvants for infectious diseases.
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Affiliation(s)
- Jing-Xing Yang
- Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; (J.-X.Y.); (J.-C.T.)
| | - Jen-Chih Tseng
- Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; (J.-X.Y.); (J.-C.T.)
| | - Guann-Yi Yu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 35053, Taiwan;
| | - Yunping Luo
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China;
| | - Chi-Ying F. Huang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
| | - Yi-Ren Hong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Tsung-Hsien Chuang
- Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; (J.-X.Y.); (J.-C.T.)
- Department of Life Sciences, National Central University, Taoyuan City 32001, Taiwan
- Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +886-37-246166 (ext. 37611)
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20
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Nanishi E, Borriello F, O’Meara TR, McGrath ME, Saito Y, Haupt RE, Seo HS, van Haren SD, Cavazzoni CB, Brook B, Barman S, Chen J, Diray-Arce J, Doss-Gollin S, De Leon M, Prevost-Reilly A, Chew K, Menon M, Song K, Xu AZ, Caradonna TM, Feldman J, Hauser BM, Schmidt AG, Sherman AC, Baden LR, Ernst RK, Dillen C, Weston SM, Johnson RM, Hammond HL, Mayer R, Burke A, Bottazzi ME, Hotez PJ, Strych U, Chang A, Yu J, Sage PT, Barouch DH, Dhe-Paganon S, Zanoni I, Ozonoff A, Frieman MB, Levy O, Dowling DJ. An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice. Sci Transl Med 2022; 14:eabj5305. [PMID: 34783582 PMCID: PMC10176044 DOI: 10.1126/scitranslmed.abj5305] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.
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Affiliation(s)
- Etsuro Nanishi
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
| | - Francesco Borriello
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
- Division of Immunology, Boston Children’s Hospital, Boston, MA, USA 02115
- Present address: Generate Biomedicines, Cambridge, MA, USA 02139
| | - Timothy R. O’Meara
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Marisa E. McGrath
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA 21201
| | - Yoshine Saito
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Robert E. Haupt
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA 21201
| | - Hyuk-Soo Seo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02115
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA 02115
| | - Simon D. van Haren
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
| | - Cecilia B. Cavazzoni
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 02115
| | - Byron Brook
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
| | - Soumik Barman
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
| | - Jing Chen
- Research Computing Group, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Joann Diray-Arce
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
| | - Simon Doss-Gollin
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Maria De Leon
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Alejandra Prevost-Reilly
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Katherine Chew
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Manisha Menon
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Kijun Song
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02115
| | - Andrew Z. Xu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02115
| | | | - Jared Feldman
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA 02139
| | - Blake M. Hauser
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA 02139
| | - Aaron G. Schmidt
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA 02139
- Department of Microbiology, Harvard Medical School, Boston, MA, USA 02115
| | - Amy C. Sherman
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA 02115
| | - Lindsey R. Baden
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA 02115
| | - Robert K. Ernst
- Department of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, MD, USA 21201
| | - Carly Dillen
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA 21201
| | - Stuart M. Weston
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA 21201
| | - Robert M. Johnson
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA 21201
| | - Holly L. Hammond
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA 21201
| | - Romana Mayer
- Department of Pathology, University of Maryland Medical Center, Baltimore, MD, USA 21201
| | - Allen Burke
- Department of Pathology, University of Maryland Medical Center, Baltimore, MD, USA 21201
| | - Maria E. Bottazzi
- Texas Children’s Hospital Center for Vaccine Development, Baylor College of Medicine, Houston, TX, USA 77030
- National School of Tropical Medicine and Departments of Pediatrics and Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA 77030
| | - Peter J. Hotez
- Texas Children’s Hospital Center for Vaccine Development, Baylor College of Medicine, Houston, TX, USA 77030
- National School of Tropical Medicine and Departments of Pediatrics and Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA 77030
| | - Ulrich Strych
- Texas Children’s Hospital Center for Vaccine Development, Baylor College of Medicine, Houston, TX, USA 77030
- National School of Tropical Medicine and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 77030
| | - Aiquan Chang
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 02115
| | - Jingyou Yu
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 02115
| | - Peter T. Sage
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 02115
| | - Dan H. Barouch
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 02115
| | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA 02115
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA 02115
| | - Ivan Zanoni
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
- Division of Immunology, Boston Children’s Hospital, Boston, MA, USA 02115
| | - Al Ozonoff
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
| | - Matthew B. Frieman
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA 21201
| | - Ofer Levy
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
- Broad Institute of MIT & Harvard, Cambridge, MA, USA 02142
| | - David J. Dowling
- Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA 02115
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA 02115
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21
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Firdaus FZ, Skwarczynski M, Toth I. Developments in Vaccine Adjuvants. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2412:145-178. [PMID: 34918245 DOI: 10.1007/978-1-0716-1892-9_8] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Vaccines, including subunit, recombinant, and conjugate vaccines, require the use of an immunostimulator/adjuvant for maximum efficacy. Adjuvants not only enhance the strength and longevity of immune responses but may also influence the type of response. In this chapter, we review the adjuvants that are available for use in human vaccines, such as alum, MF59, AS03, and AS01. We extensively discuss their composition, characteristics, mechanism of action, and effects on the immune system. Additionally, we summarize recent trends in adjuvant discovery, providing a brief overview of saponins, TLRs agonists, polysaccharides, nanoparticles, cytokines, and mucosal adjuvants.
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Affiliation(s)
- Farrhana Ziana Firdaus
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Mariusz Skwarczynski
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| | - Istvan Toth
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia. .,Institute of Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia. .,School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia.
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22
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Liu H, Zhou C, An J, Song Y, Yu P, Li J, Gu C, Hu D, Jiang Y, Zhang L, Huang C, Zhang C, Yang Y, Zhu Q, Wang D, Liu Y, Miao C, Cao X, Ding L, Zhu Y, Zhu H, Bao L, Zhou L, Yan H, Fan J, Xu J, Hu Z, Xie Y, Liu J, Liu G. Development of recombinant COVID-19 vaccine based on CHO-produced, prefusion spike trimer and alum/CpG adjuvants. Vaccine 2021; 39:7001-7011. [PMID: 34750014 PMCID: PMC8556577 DOI: 10.1016/j.vaccine.2021.10.066] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 12/23/2022]
Abstract
COVID-19 pandemic has severely impacted the public health and social economy worldwide. A safe, effective, and affordable vaccine against SARS-CoV-2 infections/diseases is urgently needed. We have been developing a recombinant vaccine based on a prefusion-stabilized spike trimer of SARS-CoV-2 and formulated with aluminium hydroxide and CpG 7909. The spike protein was expressed in Chinese hamster ovary (CHO) cells, purified, and prepared as a stable formulation with the dual adjuvant. Immunogenicity studies showed that candidate vaccines elicited robust neutralizing antibody responses and substantial CD4+ T cell responses in both mice and non-human primates. And vaccine-induced neutralizing antibodies persisted at high level for at least 6 months. Challenge studies demonstrated that candidate vaccine reduced the viral loads and inflammation in the lungs of SARS-CoV-2 infected golden Syrian hamsters significantly. In addition, the vaccine-induced antibodies showed cross-neutralization activity against B.1.1.7 and B.1.351 variants. These data suggest candidate vaccine is efficacious in preventing SARS-CoV-2 infections and associated pneumonia, thereby justifying ongoing phase I/II clinical studies in China (NCT04982068 and NCT04990544).
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Affiliation(s)
- Haitao Liu
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | | | - Jiao An
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Yujiao Song
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Pin Yu
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Jiadai Li
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Chenjian Gu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dongdong Hu
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | | | - Lingli Zhang
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Chuanqi Huang
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Chao Zhang
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Yunqi Yang
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Qianjun Zhu
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Dekui Wang
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Yuqiang Liu
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Chenyang Miao
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Xiayao Cao
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Longfei Ding
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yuanfei Zhu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hua Zhu
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Linlin Bao
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Lingyun Zhou
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Huan Yan
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Jiang Fan
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China
| | - Jianqing Xu
- Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Zhongyu Hu
- National Institute for Food and Drug Control (NIFDC), Beijing, China.
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Jiangning Liu
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.
| | - Ge Liu
- Shanghai Zerun Biotechnology Co., Ltd., Shanghai, China.
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23
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Orlacchio A, Mazzone P. The Role of Toll-like Receptors (TLRs) Mediated Inflammation in Pancreatic Cancer Pathophysiology. Int J Mol Sci 2021; 22:12743. [PMID: 34884547 PMCID: PMC8657588 DOI: 10.3390/ijms222312743] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most lethal forms of cancer, characterized by its aggressiveness and metastatic potential. Despite significant improvements in PC treatment and management, the complexity of the molecular pathways underlying its development has severely limited the available therapeutic opportunities. Toll-like receptors (TLRs) play a pivotal role in inflammation and immune response, as they are involved in pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Activation of TLRs initiates a signaling cascade, which in turn, leads to the transcription of several genes involved in inflammation and anti-microbial defense. TLRs are also deregulated in several cancers and can be used as prognostic markers and potential targets for cancer-targeted therapy. In this review we discuss the current knowledge about the role of TLRs in PC progression, focusing on the available TLRs-targeting compounds and their possible use in PC therapy.
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Affiliation(s)
- Arturo Orlacchio
- NYU Grossman School of Medicine, NYU Langone Health, New York, NY 10016, USA
| | - Pellegrino Mazzone
- Biogem Scarl, Istituto di Ricerche Genetiche Gaetano Salvatore, 83031 Ariano Irpino, Italy
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24
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Rao VV, Godin CS, Lacy MJ, Inglefield JR, Park S, Blauth B, Reece JJ, Ionin B, Savransky V. Evaluation of the AV7909 Anthrax Vaccine Toxicity in Sprague Dawley Rats Following Three Intramuscular Administrations. Int J Toxicol 2021; 40:442-452. [PMID: 34281421 PMCID: PMC8532110 DOI: 10.1177/10915818211031239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
AV7909 is a next-generation anthrax vaccine under development for post-exposure prophylaxis following suspected or confirmed Bacillus anthracis exposure, when administered in conjunction with the recommended antibacterial regimen. AV7909 consists of the FDA-approved BioThrax® vaccine (anthrax vaccine adsorbed) and an immunostimulatory Toll-like receptor 9 agonist oligodeoxynucleotide adjuvant, CPG 7909. The purpose of this study was to evaluate the potential systemic and local toxicity of AV7909 when administered via repeat intramuscular injection to the right thigh muscle (biceps femoris) to male and female Sprague Dawley rats. The vaccine was administered on Days 1, 15, and 29 and the animals were assessed for treatment-related effects followed by a 2-week recovery period to evaluate the persistence or reversibility of any toxic effects. The AV7909 vaccine produced no apparent systemic toxicity based on evaluation of clinical observations, body weights, body temperature, clinical pathology, and anatomic pathology. Necrosis and inflammation were observed at the injection sites as well as in regional lymph nodes and adjacent tissues and were consistent with immune stimulation. Antibodies against B. anthracis protective antigen (PA) were detected in rats treated with the AV7909 vaccine, confirming relevance of this animal model for the assessment of systemic toxicity of AV7909. In contrast, sera of rats that received saline or soluble CPG 7909 alone were negative for anti-PA antibodies. Overall, 3 intramuscular immunizations of Sprague Dawley rats with AV7909 were well tolerated, did not induce mortality or any systemic adverse effects, and did not result in any delayed toxicity.
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Affiliation(s)
| | | | | | - Jon R. Inglefield
- Frederick National Laboratory for Cancer Research, Frederick, MD (current affiliation; JRI was affiliated with the Emergent BioSolutions Inc, Gaithersburg, MD at the time of the work)
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25
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Li Y, Yin S, Issa R, Tong X, Wang G, Xia J, Huang R, Chen G, Weng D, Chen C, Wu C, Chen Y. B Cell-mediated Humoral Immunity in Chronic Hepatitis B Infection. J Clin Transl Hepatol 2021; 9:592-597. [PMID: 34447690 PMCID: PMC8369012 DOI: 10.14218/jcth.2021.00051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/24/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.
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Affiliation(s)
- Yang Li
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rahma Issa
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guiyang Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guangmei Chen
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dan Weng
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Chen Chen
- Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
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26
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Nanishi E, Borriello F, O'Meara TR, McGrath ME, Saito Y, Haupt RE, Seo HS, van Haren SD, Brook B, Chen J, Diray-Arce J, Doss-Gollin S, Leon MD, Chew K, Menon M, Song K, Xu AZ, Caradonna TM, Feldman J, Hauser BM, Schmidt AG, Sherman AC, Baden LR, Ernst RK, Dillen C, Weston SM, Johnson RM, Hammond HL, Mayer R, Burke A, Bottazzi ME, Hotez PJ, Strych U, Chang A, Yu J, Barouch DH, Dhe-Paganon S, Zanoni I, Ozonoff A, Frieman MB, Levy O, Dowling DJ. Alum:CpG adjuvant enables SARS-CoV-2 RBD-induced protection in aged mice and synergistic activation of human elder type 1 immunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021. [PMID: 34031655 DOI: 10.1101/2021.05.20.444848] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic especially for low- and middle-income countries. While vaccines against SARS-CoV-2 based on mRNA and adenoviral-vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are needed to meet global demand. In this context, protein subunit vaccines formulated with appropriate adjuvants represent a promising approach to address this urgent need. Receptor-binding domain (RBD) is a key target of neutralizing antibodies (Abs) but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists, including those activating STING, TLR3, TLR4 and TLR9, alone or formulated with aluminum hydroxide (AH), and benchmarked them to AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that the AH and CpG adjuvant formulation (AH:CpG) demonstrated the highest enhancement of anti-RBD neutralizing Ab titers in both age groups (∼80-fold over AH), and protected aged mice from the SARS-CoV-2 challenge. Notably, AH:CpG-adjuvanted RBD vaccine elicited neutralizing Abs against both wild-type SARS-CoV-2 and B.1.351 variant at serum concentrations comparable to those induced by the authorized mRNA BNT162b2 vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and synergistically enhanced cytokine and chemokine production in human young adult and elderly mononuclear cells. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups. One Sentence Summary Alum and CpG enhance SARS-CoV-2 RBD protective immunity, variant neutralization in aged mice and Th1-polarizing cytokine production by human elder leukocytes.
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27
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Tay BQ, Wright Q, Ladwa R, Perry C, Leggatt G, Simpson F, Wells JW, Panizza BJ, Frazer IH, Cruz JLG. Evolution of Cancer Vaccines-Challenges, Achievements, and Future Directions. Vaccines (Basel) 2021; 9:vaccines9050535. [PMID: 34065557 PMCID: PMC8160852 DOI: 10.3390/vaccines9050535] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/14/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.
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Affiliation(s)
- Ban Qi Tay
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Quentin Wright
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Rahul Ladwa
- Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia;
- Faculty of Medicine, University of Queensland, Woolloongabba, QLD 4102, Australia; (C.P.); (B.J.P.)
| | - Christopher Perry
- Faculty of Medicine, University of Queensland, Woolloongabba, QLD 4102, Australia; (C.P.); (B.J.P.)
- Department of Otolaryngology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
| | - Graham Leggatt
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Fiona Simpson
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - James W. Wells
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Benedict J. Panizza
- Faculty of Medicine, University of Queensland, Woolloongabba, QLD 4102, Australia; (C.P.); (B.J.P.)
- Department of Otolaryngology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
| | - Ian H. Frazer
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
| | - Jazmina L. G. Cruz
- Faculty of Medicine, Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia; (B.Q.T.); (Q.W.); (G.L.); (F.S.); (J.W.W.); (I.H.F.)
- Correspondence: ; Tel.: +61-0478912737
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28
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Tong J, Zhu C, Lai H, Feng C, Zhou D. Potent Neutralization Antibodies Induced by a Recombinant Trimeric Spike Protein Vaccine Candidate Containing PIKA Adjuvant for COVID-19. Vaccines (Basel) 2021; 9:296. [PMID: 33810026 PMCID: PMC8004863 DOI: 10.3390/vaccines9030296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 12/11/2022] Open
Abstract
The structures of immunogens that elicit the most potent neutralization antibodies to prevent COVID-19 infection are still under investigation. In this study, we tested the efficacy of a recombinant trimeric Spike protein containing polyI:C (PIKA) adjuvant in mice immunized by a 0-7-14 day schedule. The results showed that a Spike protein-specific antibody was induced at Day 21 with titer of above 50,000 on average, as measured by direct binding. The neutralizing titer was above 1000 on average, as determined by a pseudo-virus using monoclonal antibodies (40592-MM57 and 40591-MM43) with IC50 at 1 μg/mL as standards. The protein/peptide array-identified receptor-binding domain (RBD) was considered as immunodominant. No linear epitopes were found in the RBD, although several linear epitopes were found in the C-terminal domain right after the RBD and heptad repeat regions. Our study supports the efficacy of a recombinant trimeric Spike protein vaccine candidate for COVID-19 that is safe and ready for storage and distribution in developing countries.
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Affiliation(s)
- Jiao Tong
- Tongji University School of Medicine, Shanghai 200092, China; (J.T.); (C.Z.); (H.L.); (C.F.)
- Shanghai Pudong New Area Mental Health Center Affiliated with Tongji University School of Medicine, 165 Sanlin Road, Shanghai 200124, China
| | - Chenxi Zhu
- Tongji University School of Medicine, Shanghai 200092, China; (J.T.); (C.Z.); (H.L.); (C.F.)
- Shanghai Pudong New Area Mental Health Center Affiliated with Tongji University School of Medicine, 165 Sanlin Road, Shanghai 200124, China
| | - Hanyu Lai
- Tongji University School of Medicine, Shanghai 200092, China; (J.T.); (C.Z.); (H.L.); (C.F.)
- Shanghai Pudong New Area Mental Health Center Affiliated with Tongji University School of Medicine, 165 Sanlin Road, Shanghai 200124, China
| | - Chunchao Feng
- Tongji University School of Medicine, Shanghai 200092, China; (J.T.); (C.Z.); (H.L.); (C.F.)
- Shanghai Pudong New Area Mental Health Center Affiliated with Tongji University School of Medicine, 165 Sanlin Road, Shanghai 200124, China
| | - Dapeng Zhou
- Tongji University School of Medicine, Shanghai 200092, China; (J.T.); (C.Z.); (H.L.); (C.F.)
- Shanghai Pudong New Area Mental Health Center Affiliated with Tongji University School of Medicine, 165 Sanlin Road, Shanghai 200124, China
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Abstract
CpG Oligonucleotides (ODN) are immunomodulatory synthetic oligonucleotides specifically designed to stimulate Toll-like receptor 9. TLR9 is expressed on human plasmacytoid dendritic cells and B cells and triggers an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. This chapter reviews recent progress in understanding the mechanism of action of CpG ODN and provides an overview of human clinical trial results using CpG ODN to improve vaccines for the prevention/treatment of cancer, allergy, and infectious disease.
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Affiliation(s)
| | | | - Dennis M Klinman
- National Cancer Institute, NIH, Frederick, MD, USA.
- Leitman Klinman Consulting, Potomac, MD, USA.
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30
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Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology 2021; 1:699-716. [PMID: 22934262 PMCID: PMC3429574 DOI: 10.4161/onci.20696] [Citation(s) in RCA: 170] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.
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Affiliation(s)
- Lorenzo Galluzzi
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Institut Gustave Roussy; Villejuif, France
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Jia X, Guo J, Guo S, Zhao T, Liu X, Cheng C, Wang L, Zhang B, Meng C, Jia H, Luo E. Antitumor effects and mechanisms of CpG ODN combined with attenuated Salmonella-delivered siRNAs against PD-1. Int Immunopharmacol 2021; 90:107052. [PMID: 33310296 DOI: 10.1016/j.intimp.2020.107052] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/11/2022]
Abstract
Numerous studies have focused on the treatment of melanoma, but the current therapies for melanoma have limited therapeutic effects. To find a more effective therapy for melanoma, we combined artificially designed CpG ODN (cytosine-phosphate-guanine oligodeoxynucleotides) and siRNAs (small-interfering ribonucleic acids) targeting PD-1 (programmed cell death protein 1), which were delivered by attenuated Salmonella to treat melanoma in mice, and explored the underlying antitumor mechanisms. We found that mice receiving the combination therapy had the smallest tumor size and the longest survival time. The possible mechanisms underlying this phenomenon include pathways mediated by cyclin D1, p-STAT3 (phosphorylated signal transducers and activators of transcription protein 3), MMP2 (matrix metallopeptidase 2) and cleaved caspase 3, since after treatment, the expression of cyclin D1, p-STAT3, and MMP2 decreased but that of cleaved caspase 3 increased; additional mechanisms include increases in the recruitment of immune cells to tumor sites and in the number of immune cells in mouse spleens and the upregulation of TNF-α (tumor necrosis factor) and IL-6 (interleukin 6). We demonstrated that the combination therapy composed of CpG ODN and PD-1-siRNA delivered by attenuated Salmonella exhibited a strong ability to inhibit melanoma and improve the antitumor immune responses of tumor-bearing mice.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Cell Line, Tumor
- Combined Modality Therapy
- Cytokines/blood
- Female
- Gene Expression Regulation, Neoplastic
- Genetic Vectors
- Male
- Melanoma, Experimental/genetics
- Melanoma, Experimental/immunology
- Melanoma, Experimental/metabolism
- Melanoma, Experimental/therapy
- Mice, Inbred C57BL
- Oligodeoxyribonucleotides/pharmacology
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/metabolism
- RNA, Small Interfering/administration & dosage
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- RNAi Therapeutics
- Salmonella/genetics
- Time Factors
- Toll-Like Receptor 9/agonists
- Toll-Like Receptor 9/metabolism
- Tumor Burden
- Mice
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Affiliation(s)
- Xiaolong Jia
- Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, 77 Puhe Road, Shenyang 110122, PR China
| | - Jing Guo
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, PR China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China
| | - Sheng Guo
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, PR China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China
| | - Tiesuo Zhao
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453000, PR China; Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, 5 Xinxiang, Henan 453000, PR China
| | - Xiaoming Liu
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China
| | - Chenchen Cheng
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China
| | - Lei Wang
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China
| | - Beibei Zhang
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China
| | - Chenchen Meng
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China
| | - Huijie Jia
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan 453000, PR China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, 5 Xinxiang, Henan 453000, PR China; Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453000, PR China.
| | - Enjie Luo
- Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, 77 Puhe Road, Shenyang 110122, PR China.
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32
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Bianchi S, Martínez Allo VC, Massimino M, Lavignolle Heguy MDR, Borzone FR, Gomez Bustillo S, Chasseing NA, Libertun C, Montaner AD, Rabinovich GA, Toscano MA, Lux-Lantos VA, Bianchi MS. Oligonucleotide IMT504 Improves Glucose Metabolism and Controls Immune Cell Mediators in Female Diabetic NOD Mice. Nucleic Acid Ther 2020; 31:155-171. [PMID: 33347786 DOI: 10.1089/nat.2020.0901] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Type 1 diabetes occurs as a consequence of progressive autoimmune destruction of beta cells. A potential treatment for this disease should address the immune attack on beta cells and their preservation/regeneration. The objective of this study was to elucidate whether the immunomodulatory synthetic oligonucleotide IMT504 was able to ameliorate diabetes in NOD mice and to provide further understanding of its mechanism of action. We found that IMT504 restores glucose homeostasis in a diabetes mouse model similar to human type 1 diabetes, by regulating expression of immune modulatory factors and improving beta cell function. IMT504 treatment markedly improved fasting glycemia, insulinemia, and homeostatic model assessment of beta cell function (HOMA-Beta cell) index. Moreover, this treatment increased islet number and decreased apoptosis, insulitis, and CD45+ pancreas-infiltrating leukocytes. In a long-term treatment, we observed improvement of glucose metabolism up to 9 days after IMT504 cessation and increased survival after 15 days of the last IMT504 injection. We postulate that interleukin (IL)-12B (p40), possibly acting as a homodimer, and Galectin-3 (Gal-3) may function as mediators of this immunomodulatory action. Overall, these results validate the therapeutic activity of IMT504 as a promising drug for type 1 diabetes and suggest possible downstream mediators of its immunomodulatory effect.
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Affiliation(s)
- Stefania Bianchi
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Verónica C Martínez Allo
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Milena Massimino
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María Del R Lavignolle Heguy
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Francisco R Borzone
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Sofía Gomez Bustillo
- Instituto de Ciencia y Tecnología César Milstein-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación Pablo Cassará, Buenos Aires, Argentina
| | - Norma A Chasseing
- Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Carlos Libertun
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.,Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Alejandro D Montaner
- Instituto de Ciencia y Tecnología César Milstein-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Fundación Pablo Cassará, Buenos Aires, Argentina
| | - Gabriel A Rabinovich
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.,Departmento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marta A Toscano
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Victoria A Lux-Lantos
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - María S Bianchi
- Laboratoio de Neuroendocrinología, Instituto de Biología y Medicina Experimental (IBYME)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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Cai Y, Yin W. The Multiple Functions of B Cells in Chronic HBV Infection. Front Immunol 2020; 11:582292. [PMID: 33381113 PMCID: PMC7767983 DOI: 10.3389/fimmu.2020.582292] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the main causes of liver diseases, of which the natural history and clinical outcomes are associated with the role of B cells. As humoral immune cells, B cells play a critical role in the process of anti-HBV antibody production. In addition, some studies have also characterized other B cell subsets involved in antigen presentation and regulating the immune response beyond antibody secretion. However, not all B cell subsets play a positive role in the immune response to chronic HBV infection, and various B cell subsets jointly mediate persistent HBV infection, tolerance, and liver damage. Thus, we further sought to elucidate the multiple functions of B cells to gain novel insight into the understanding of chronic hepatitis B (CHB) pathogenesis. We also reviewed the current immunotherapies targeting B cells to explore novel therapeutic interventions for the treatment of chronic HBV infection.
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Affiliation(s)
- Ying Cai
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wenwei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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34
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Clark A, Wolfe DN. Current State of Anthrax Vaccines and Key R&D Gaps Moving Forward. Microorganisms 2020; 8:microorganisms8050651. [PMID: 32365729 PMCID: PMC7285291 DOI: 10.3390/microorganisms8050651] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/25/2020] [Accepted: 04/27/2020] [Indexed: 11/16/2022] Open
Abstract
A licensed anthrax vaccine has been available for pre-exposure prophylaxis in the United States since 1970, and it was approved for use as a post-exposure prophylaxis, in combination with antibiotic treatment, in 2015. A variety of other vaccines are available in other nations, approved under various regulatory frameworks. However, investments in anthrax vaccines continue due to the severity of the threat posed by this bacterium, as both a naturally occurring pathogen and the potential for use as a bioweapon. In this review, we will capture the current landscape of anthrax vaccine development, focusing on those lead candidates in clinical development. Although approved products are available, a robust pipeline of candidate vaccines are still in development to try to address some of the key research gaps in the anthrax vaccine field. We will then highlight some of the most pressing needs in terms of anthrax vaccine research.
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35
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Bower WA, Schiffer J, Atmar RL, Keitel WA, Friedlander AM, Liu L, Yu Y, Stephens DS, Quinn CP, Hendricks K. Use of Anthrax Vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices, 2019. MMWR Recomm Rep 2019; 68:1-14. [PMID: 31834290 PMCID: PMC6918956 DOI: 10.15585/mmwr.rr6804a1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
This report updates the 2009 recommendations from the CDC Advisory Committee on Immunization Practices (ACIP) regarding use of anthrax vaccine in the United States (Wright JG, Quinn CP, Shadomy S, Messonnier N. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices [ACIP)], 2009. MMWR Recomm Rep 2010;59[No. RR-6]). The report 1) summarizes data on estimated efficacy in humans using a correlates of protection model and safety data published since the last ACIP review, 2) provides updated guidance for use of anthrax vaccine adsorbed (AVA) for preexposure prophylaxis (PrEP) and in conjunction with antimicrobials for postexposure prophylaxis (PEP), 3) provides updated guidance regarding PrEP vaccination of emergency and other responders, 4) summarizes the available data on an investigational anthrax vaccine (AV7909), and 5) discusses the use of anthrax antitoxins for PEP. Changes from previous guidance in this report include the following: 1) a booster dose of AVA for PrEP can be given every 3 years instead of annually to persons not at high risk for exposure to Bacillus anthracis who have previously received the initial AVA 3-dose priming and 2-dose booster series and want to maintain protection; 2) during a large-scale emergency response, AVA for PEP can be administered using an intramuscular route if the subcutaneous route of administration poses significant materiel, personnel, or clinical challenges that might delay or preclude vaccination; 3) recommendations on dose-sparing AVA PEP regimens if the anthrax vaccine supply is insufficient to vaccinate all potentially exposed persons; and 4) clarification on the duration of antimicrobial therapy when used in conjunction with vaccine for PEP. These updated recommendations can be used by health care providers and guide emergency preparedness officials and planners who are developing plans to provide anthrax vaccine, including preparations for a wide-area aerosol release of B. anthracis spores. The recommendations also provide guidance on dose-sparing options, if needed, to extend the supply of vaccine to increase the number of persons receiving PEP in a mass casualty event.
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36
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Ma Z, Zhang E, Gao S, Xiong Y, Lu M. Toward a Functional Cure for Hepatitis B: The Rationale and Challenges for Therapeutic Targeting of the B Cell Immune Response. Front Immunol 2019; 10:2308. [PMID: 31608073 PMCID: PMC6769125 DOI: 10.3389/fimmu.2019.02308] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022] Open
Abstract
The central role of the cellular immune response in the control and clearance of the hepatitis B virus (HBV) infection has been well-established. The contribution of humoral immunity, including B cell and antibody responses against HBV, has been investigated for a long time but has attracted increasing attention again in recent years. The anti-HBs antibody was first recognized as a marker of protective immunity after the acute resolution of the HBV infection (or vaccination) and is now defined as a biomarker for the functional cure of chronic hepatitis B (CHB). In this way, therapies targeting HBV-specific B cells and the induction of an anti-HBs antibody response are essential elements of a rational strategy to terminate chronic HBV infection. However, a high load of HBsAg in the blood, which has been proposed to induce antigen-specific immune tolerance, represents a major obstacle to curing CHB. Long-term antiviral treatment by nucleoside analogs, by targeting viral translation by siRNA, by inhibiting HBsAg release via nucleic acid polymers, or by neutralizing HBsAg via specific antibodies could potentially reduce the HBsAg load in CHB patients. A combined strategy including a reduction of the HBsAg load via the above treatments and the therapeutic targeting of B cells by vaccination may induce the appearance of anti-HBs antibodies and lead to a functional cure of CHB.
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Affiliation(s)
- Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ejuan Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Shicheng Gao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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37
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Rudicell RS, Garinot M, Kanekiyo M, Kamp HD, Swanson K, Chou TH, Dai S, Bedel O, Simard D, Gillespie RA, Yang K, Reardon M, Avila LZ, Besev M, Dhal PK, Dharanipragada R, Zheng L, Duan X, Dinapoli J, Vogel TU, Kleanthous H, Mascola JR, Graham BS, Haensler J, Wei CJ, Nabel GJ. Comparison of adjuvants to optimize influenza neutralizing antibody responses. Vaccine 2019; 37:6208-6220. [PMID: 31493950 DOI: 10.1016/j.vaccine.2019.08.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/26/2019] [Accepted: 08/17/2019] [Indexed: 12/14/2022]
Abstract
Seasonal influenza vaccines represent a positive intervention to limit the spread of the virus and protect public health. Yet continual influenza evolution and its ability to evade immunity pose a constant threat. For these reasons, vaccines with improved potency and breadth of protection remain an important need. We previously developed a next-generation influenza vaccine that displays the trimeric influenza hemagglutinin (HA) on a ferritin nanoparticle (NP) to optimize its presentation. Similar to other vaccines, HA-nanoparticle vaccine efficacy is increased by the inclusion of adjuvants during immunization. To identify the optimal adjuvants to enhance influenza immunity, we systematically analyzed TLR agonists for their ability to elicit immune responses. HA-NPs were compatible with nearly all adjuvants tested, including TLR2, TLR4, TLR7/8, and TLR9 agonists, squalene oil-in-water mixtures, and STING agonists. In addition, we chemically conjugated TLR7/8 and TLR9 ligands directly to the HA-ferritin nanoparticle. These TLR agonist-conjugated nanoparticles induced stronger antibody responses than nanoparticles alone, which allowed the use of a 5000-fold-lower dose of adjuvant than traditional admixtures. One candidate, the oil-in-water adjuvant AF03, was also tested in non-human primates and showed strong induction of neutralizing responses against both matched and heterologous H1N1 viruses. These data suggest that AF03, along with certain TLR agonists, enhance strong neutralizing antibody responses following influenza vaccination and may improve the breadth, potency, and ultimately vaccine protection in humans.
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Affiliation(s)
| | | | - Masaru Kanekiyo
- Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | | | | | | | | | | | | | - Rebecca A Gillespie
- Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | | | | | | | | | | | | | | | | | | | | | | | - John R Mascola
- Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Barney S Graham
- Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Laws TR, Taylor AW, Russell P, Williamson D. The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review. Expert Rev Anti Infect Ther 2019; 17:957-967. [PMID: 30626237 DOI: 10.1080/14787210.2018.1496330] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Melioidosis is a significant health problem within endemic areas such as Southeast Asia and Northern Australia. The varied presentation of melioidosis and the intrinsic antibiotic resistance of Burkholderia pseudomallei, the causative organism, make melioidosis a difficult infection to manage. Often prolonged courses of antibiotic treatments are required with no guarantee of clinical success.Areas covered: B. pseudomallei is able to enter phagocytic cells, affect immune function, and replicate, via manipulation of the caspase system. An examination of this mechanism, and a look at other factors in the pathogenesis of melioidosis, shows that there are multiple potential points of therapeutic intervention, some of which may be complementary. These include the directed use of antimicrobial compounds, blocking virulence mechanisms, balancing or modulating cytokine responses, and ameliorating sepsis.Expert commentary: There may be therapeutic options derived from drugs in clinical use for unrelated conditions that may have benefit in melioidosis. Key compounds of interest primarily affect the disequilibrium of the cytokine response, and further preclinical work is needed to explore the utility of this approach and encourage the clinical research needed to bring these into beneficial use.
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Affiliation(s)
- Thomas R Laws
- CBR Division, DSTL Porton Down, Salisbury, Wiltshire, UK
| | - Adam W Taylor
- CBR Division, DSTL Porton Down, Salisbury, Wiltshire, UK
| | - Paul Russell
- CBR Division, DSTL Porton Down, Salisbury, Wiltshire, UK
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39
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Virus-like particles in der Prophylaxe und Immuntherapie allergischer Erkrankungen. ALLERGO JOURNAL 2018. [DOI: 10.1007/s15007-018-1763-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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40
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Yu P, Yan J, Wu W, Tao X, Lu X, Liu S, Zhu W. A CpG oligodeoxynucleotide enhances the immune response to rabies vaccination in mice. Virol J 2018; 15:174. [PMID: 30424815 PMCID: PMC6234694 DOI: 10.1186/s12985-018-1089-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 11/01/2018] [Indexed: 11/27/2022] Open
Abstract
Background Rabies is a fatal disease that is preventable when post exposure prophylaxis (PEP) is administered in a timely fashion. CpG oligodeoxynucleotides (ODNs) can trigger cells that express Toll-like receptor 9, and their immunopotentiation activity in an inactivated aluminum-adjuvanted rabies vaccine for dogs has been identified using mouse and dog models. Methods A human diploid cell rabies vaccine (HDCV) of humans and a CpG ODNs with cross-immunostimulatory activity in humans and mice were used to evaluate the immunogenicity and protective efficacy of CpG ODN in a mouse model that simulates human PEP. Results HDCV combined with CpG ODN (HDCV–CpG) stimulated mice to produce rabies virus-specific neutralizing antibody (RVNA) earlier and increased the seroconversion rate. Compared with HDCV alone, either HDCV–1.25 μg CpG or HDCV–5 μg CpG increased the levels of RVNA. In particular, 5 μg CpG ODN per mouse significantly boosted the levels of RVNA compared with HDCV alone. IFN-γ producing splenocytes generated in the HDCV-5 μg CpG group were significantly increased compared to the group treated with HDCV alone. When the immunization regimen was reduced to three injections or the dose was reduced to half of the recommended HDCV combined with CpG ODN, the RVNA titers were still higher than those induced by HDCV alone. After viral challenge, 50% of mice immunized with a half-dose HDCV–CpG survived, while the survival rate of mice immunized with HDCV alone was 30%. Conclusions The immunopotentiation activity of CpG ODNs for a commercially available human rabies vaccine was first evaluated in a mouse model on the basis of the Essen regimen. Our results suggest that the CpG ODN used in this study is a potential adjuvant to rabies vaccines for human use. Electronic supplementary material The online version of this article (10.1186/s12985-018-1089-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Pengcheng Yu
- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jianghong Yan
- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Weicheng Wu
- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiaoyan Tao
- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xuexin Lu
- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Shuqing Liu
- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Wuyang Zhu
- Key Laboratory for Medical Virology, Ministry of Health, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
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41
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Shetab Boushehri MA, Lamprecht A. TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings. Mol Pharm 2018; 15:4777-4800. [DOI: 10.1021/acs.molpharmaceut.8b00691] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | - Alf Lamprecht
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, D-53121 Bonn, Germany
- PEPITE EA4267, Univ. Bourgonge Franch-Comte, 25030 Besançon, France
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42
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Kuznetsova TA, Persiyanova EV, Ermakova SP, Khotimchenko MY, Besednova NN. The Sulfated Polysaccharides of Brown Algae and Products of Their Enzymatic Transformation as Potential Vaccine Adjuvants. Nat Prod Commun 2018. [DOI: 10.1177/1934578x1801300837] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The review is devoted to critical analysis of literature data, deal with effects and mechanisms of action of sulfated polysaccharides (PSs) – fucoidans from brown algae and products of their enzymatic transformation as potential adjuvants for enhancement of anti-infective and antitumor immune response. Numerous experimental data indicate that sulfated PSs demonstrate properties of vaccine adjuvants. Application perspectiveness of fucoidans as vaccine adjuvants is defined by their high biocompatibility, low-toxicity, safety and good tolerance by macroorganism, and also mechanisms of their immunomodulatory action. In particular, fucoidans are agonists of receptors of innate immunity and strong inducers of cellular and humoral immune response. At presenting the data of structural - functional interrelations, attention focused to the defining role of degree of sulfation, uronic acids and polyphenols contents, and also molecular mass in actions of fucoidans to innate and adaptive immunity cells. Insufficiency of literary data on studying of correlation of structure – physicochemical characteristics with adjuvanticities of the sulfated PSs, and also the problem of standardization of their active fractions are noted. Special attention is paid to the analysis of immunomodulatory and adjuvant activity of fucoidan oligosaccharides. Presented here results of experimental trial indicate that, despite the difficulties due to preparation of highly purified structurally characterized fractions and complex structure of fucoidans, these substances can be used as safe and effective adjuvants in vaccines against various pathogens including viruses, and also in antitumor vaccines.
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Affiliation(s)
- Tatyana A. Kuznetsova
- Federal State Budgetary Scientific Institution «Research Somov Institute of Epidemiology and Microbiology», Sel'skaya street, 1, 690087, Vladivostok, Russian Federation
- Far Eastern Federal University, School of Biomedicine, bldg. M25 FEFU Campus, Ajax Bay, Russky Isl., 690922 Vladivostok, Russian Federation
| | - Elena V. Persiyanova
- Federal State Budgetary Scientific Institution «Research Somov Institute of Epidemiology and Microbiology», Sel'skaya street, 1, 690087, Vladivostok, Russian Federation
| | - Svetlana P. Ermakova
- G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-letya Vladivostoka 159, 690022, Vladivostok, Russian Federation
| | - Maxim Yu. Khotimchenko
- Far Eastern Federal University, School of Biomedicine, bldg. M25 FEFU Campus, Ajax Bay, Russky Isl., 690922 Vladivostok, Russian Federation
| | - Natalya N. Besednova
- Federal State Budgetary Scientific Institution «Research Somov Institute of Epidemiology and Microbiology», Sel'skaya street, 1, 690087, Vladivostok, Russian Federation
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Klimek L, Kündig T, Kramer MF, Guethoff S, Jensen-Jarolim E, Schmidt-Weber CB, Palomares O, Mohsen MO, Jakob T, Bachmann M. Virus-like particles (VLP) in prophylaxis and immunotherapy of allergic diseases. ALLERGO JOURNAL INTERNATIONAL 2018; 27:245-255. [PMID: 30546996 PMCID: PMC6267129 DOI: 10.1007/s40629-018-0074-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 05/17/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Apart from active allergen avoidance, immunotherapy is regarded as the most effective form of treatment available for type I allergies. Such treatments involve the administration of allergen preparations in various forms and by various routes. Virus-like particles (VLPs) offer a very effective platform for immunization with the allergen and are characterized by high immunogenicity, low allergenicity and high clinical efficacy. Formulations that include Toll-like receptor ligands, T cell stimulatory epitopes and/or depot-forming adjuvants appear to enhance activation of the relevant immune cells. Short nucleotide sequences including CpG motifs have also been intensively explored as potent stimulators of dendritic cells and B cells. METHODS The present paper is based on a systematic literature search in PubMed and MEDLINE, and focuses on the pertinent immunological processes and on clinical data relating to use of VLPs and CpG motifs for the treatment of allergic rhinitis (AR). RESULTS Many published studies have reported positive clinical results following administration of VLPs, either alone or in combination with CpG motifs and, in some cases, even in the absence of the allergen-specific allergen. CONCLUSIONS These results indicate that VLPs modulate immune responses in ways which underline their exceptional promise as a platform for the immunotherapy of allergic disorders. However, clinical evaluations remain limited, and further large-scale and longer-term studies will be necessary to substantiate the efficacy and safety of these novel therapies.
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Affiliation(s)
- Ludger Klimek
- Center for Rhinology & Allergology, Wiesbaden, Germany
| | - Thomas Kündig
- Department for Dermatology, University Hospital Zürich, Zurich, Switzerland
| | - Matthias F. Kramer
- Bencard Allergie GmbH, Munich, Germany
- Allergy Therapeutics plc, Worthing, UK
| | - Sonja Guethoff
- Bencard Allergie GmbH, Munich, Germany
- Allergy Therapeutics plc, Worthing, UK
| | - Erika Jensen-Jarolim
- Institute for Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
- Inter-University Messerli Science Institute, Veterinary University Vienna, Vienna, Austria
| | - Carsten B. Schmidt-Weber
- Center for Allergy and Environmental Resarch (ZAUM), Technical University and Helmholtz-Center, Munich, Germany
| | - Oskar Palomares
- Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain
| | | | - Thilo Jakob
- Department of Dermatology and Allergology, University Medical Center Gießen and Marburg, Campus Gießen, Justus-Liebig-University, Gießen, Germany
| | - Martin Bachmann
- Jenner Institute, University of Oxford, Oxford, UK
- Inselspital, University Department for Rheumatology, Immunology and Allergology, Sahlihaus 1, 3010 Bern, Switzerland
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Du K, Liu J, Broering R, Zhang X, Yang D, Dittmer U, Lu M. Recent advances in the discovery and development of TLR ligands as novel therapeutics for chronic HBV and HIV infections. Expert Opin Drug Discov 2018; 13:661-670. [PMID: 29772941 DOI: 10.1080/17460441.2018.1473372] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Toll-like receptor (TLR) ligands remain as promising antiviral drug candidates for the treatment of chronic viral infections. Basic research on the mechanisms of antiviral activity of TLR ligands in preclinical animal models and clinical testing of drug candidates have been carried out in recent years. Areas covered: This review provides an overview of the preclinical and clinical testing of TLR ligands in two major viral infections: hepatitis B virus (HBV) and human immunodeficiency virus (HIV). Recent results have further demonstrated the potent antiviral activity of various TLR ligands . A TLR7 agonist is in clinical trials for the treatment of chronic HBV infection while a HBV vaccine using a TLR9 ligand as an adjuvant has proven to be superior to conventional HBV vaccines and has been approved for clinical use. Generally, TLR activation may achieve viral control mainly by promoting adaptive immunity to viral proteins. Expert opinion: Recent research in this field indicates that TLR ligands could be developed as clinically effective drugs if the obstacles concerning toxicity and application routes are overcome. TLR-mediated promotion of adaptive immunity is a major issue for future studies and will determine the future development of TLR ligands as drugs for immunomodulation.
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Affiliation(s)
- Keye Du
- a Department of Infectious Disease , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Jia Liu
- a Department of Infectious Disease , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Ruth Broering
- b Department of Gastroenterology and Hepatology , University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Xiaoyong Zhang
- c Hepatology Unit and Department of Infectious Diseases , Nanfang Hospital, Southern Medical University , Guangzhou , China
| | - Dongliang Yang
- a Department of Infectious Disease , Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Ulf Dittmer
- d Institute of Virology , University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Mengji Lu
- d Institute of Virology , University Hospital Essen, University of Duisburg-Essen , Essen , Germany
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Tosi I, Bureau F, Farnir F, Denoix JM, Lekeux P, Art T. Effects of a P-class CpG-ODN administered by intramuscular injection on plasma cytokines and on white blood cells of healthy horses. Vet Immunol Immunopathol 2018; 201:57-61. [PMID: 29914683 DOI: 10.1016/j.vetimm.2018.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 05/11/2018] [Accepted: 05/13/2018] [Indexed: 12/31/2022]
Abstract
Cytosine-phosphate-guanosine (CpG-ODN) has been described as a potent immunostimulatory agent in different species. No study reported the effect of a P-class CpG when administered systemically in healthy horses. The aim of this study was to evaluate the tolerance and the effect of an intramuscularly administered P-class CpG-ODN on hematology and on plasma cytokines (IFN-α, IL-10, TNF-α, IFN-γ) in 8 healthy horses. Intra-muscular CpG-ODN or placebo (PBS) was administered twice at a 7 days-interval. Groups were inversed after 2 months of washout period. A physical examination, complete blood count (CBC) and plasma cytokine measurements were performed from 2 days before injection up to 21 days after injection. P-class CpG-ODN injection was well tolerated with minor side effects. After the first injection a significant transient drop in circulating total leukocytes, lymphocytes and an increase in monocytes were observed. A transient drop in eosinophils was also noted after each CpG injection. P-class CpG-ODN at a dose of 5 mg did not create major side effects in 7 horses, one horse showed transient pyrexia. A redistribution of white blood cells was observed in horses receiving CpG, but no change in plasma cytokines was observed at the indicated dose, route of administration and sampling times.
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Affiliation(s)
- I Tosi
- Equine Sports Medicine Center, Department of Functional Sciences, Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine, University of Liège, Avenue de Cureghem, 7A (B42), Quartier Vallée 2, Sart Tilman, B-4000, Liège, Belgium.
| | - F Bureau
- Laboratory of Cellular and Molecular Immunology, GIGA-Research, University of Liège, Avenue de l'Hôpital 1, Sart Tilman, B-4000, Liège, Belgium.
| | - F Farnir
- Department of Animal Productions, Biostatistics and Bioinformatics Applied to Veterinary Sciences, Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine, University of Liège, Avenue de Cureghem, 7A (B43), Quartier Vallée 2, Sart Tilman, B-4000, Liège, Belgium.
| | - J M Denoix
- CIRALE, National Veterinary School of Maisons-Alfort, R.D. 675, 14430, Goustranville, France.
| | - P Lekeux
- Equine Sports Medicine Center, Department of Functional Sciences, Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine, University of Liège, Avenue de Cureghem, 7A (B42), Quartier Vallée 2, Sart Tilman, B-4000, Liège, Belgium.
| | - T Art
- Equine Sports Medicine Center, Department of Functional Sciences, Fundamental and Applied Research for Animals & Health (FARAH), Faculty of Veterinary Medicine, University of Liège, Avenue de Cureghem, 7A (B42), Quartier Vallée 2, Sart Tilman, B-4000, Liège, Belgium.
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46
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Lawless OJ, Bellanti JA, Brown ML, Sandberg K, Umans JG, Zhou L, Chen W, Wang J, Wang K, Zheng SG. In vitro induction of T regulatory cells by a methylated CpG DNA sequence in humans: Potential therapeutic applications in allergic and autoimmune diseases. Allergy Asthma Proc 2018; 39:143-152. [PMID: 29490770 PMCID: PMC6479479 DOI: 10.2500/aap.2018.39.4113] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Allergic and autoimmune diseases comprise a group of inflammatory disorders caused by aberrant immune responses in which CD25+ Forkhead box P3-positive (FOXP3+) T regulatory (Treg) cells that normally suppress inflammatory events are often poorly functioning. This has stimulated an intensive investigative effort to find ways of increasing Tregs as a method of therapy for these conditions. One such line of investigation includes the study of how ligation of Toll-like receptors (TLRs) by CpG oligonucleotides (ODN) results in an immunostimulatory cascade that leads to induction of T-helper (Th) type 1 and Treg-type immune responses. OBJECTIVE The present study investigated the mechanisms by which calf thymus mammalian double-stranded DNA (CT-DNA) and a synthetic methylated DNA CpG ODN sequence suppress in vitro lymphoproliferative responses to antigens, mitogens, and alloantigens when measured by [3H]-thymidine incorporation and promote FoxP3 expression in human CD4+ T cells in the presence of transforming growth factor (TGF) beta and interleukin-2 (IL-2). METHODS Lymphoproliferative responses of peripheral blood mononuclear cells from four healthy subjects or nine subjects with systemic lupus erythematosus to CT-DNA or phytohemagglutinin (PHA) was measured by tritiated thymidine ([3H]-TdR) incorporation expressed as a stimulation index. Mechanisms of immunosuppressive effects of CT-DNA were evaluated by measurement of the degree of inhibition to lymphoproliferative responses to streptokinase-streptodornase, phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), or alloantigens by a Con A suppressor assay. The effects of CpG methylation on induction of FoxP3 expression in human T cells were measured by comparing inhibitory responses of synthetic methylated and nonmethylated 8-mer CpG ODN sequences by using cell sorting, in vitro stimulation, and suppressor assay. RESULTS Here, we showed that CT-DNA and a synthetic methylated DNA 8-mer sequence could suppress antigen-, mitogen-, and alloantigen-induced lymphoproliferation in vitro when measured by [3H]-thymidine. The synthetic methylated DNA CpG ODN but not an unmethylated CpG ODN sequence was shown to promote FoxP3 expression in human CD4+ T cells in the presence of TGF beta and IL-2. The induction of FoxP3+ suppressor cells is dose dependent and offers a potential clinical therapeutic application in allergic and autoimmune and inflammatory diseases. CONCLUSION The use of this methylated CpG ODN offers a broad clinical application as a novel therapeutic method for Treg induction and, because of its low cost and small size, should facilitate delivery via nasal, respiratory, gastrointestinal routes, and/or by injection, routes of administration important for vaccine delivery to target sites responsible for respiratory, gastrointestinal, and systemic forms of allergic and autoimmune disease.
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Affiliation(s)
- Oliver J. Lawless
- From the Department of Pediatrics, Georgetown University Medical Center, Washington, D.C
- International Center for Interdisciplinary Studies of Immunology, Georgetown University Medical Center, Washington, D.C
| | - Joseph A. Bellanti
- From the Department of Pediatrics, Georgetown University Medical Center, Washington, D.C
- International Center for Interdisciplinary Studies of Immunology, Georgetown University Medical Center, Washington, D.C
- Department of Microbiology-Immunology, Georgetown University Medical Center, Washington, D.C
| | - Milton L. Brown
- Inova Shar Cancer Institute, Center for Drug Discovery and Development, Fairfax, VA
| | - Kathryn Sandberg
- Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, D.C
| | - Jason G. Umans
- MedStar Health Research Institute, Hyattsville, MD
- Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, D.C
| | - Li Zhou
- Division of Rheumatology, Milton S. Hershey Medical Center at Penn State University, Hershey PA
| | - Weiqian Chen
- Division of Rheumatology, Milton S. Hershey Medical Center at Penn State University, Hershey PA
| | - Julie Wang
- Division of Rheumatology, Milton S. Hershey Medical Center at Penn State University, Hershey PA
| | - Kan Wang
- Inova Shar Cancer Institute, Center for Drug Discovery and Development, Fairfax, VA
| | - Song Guo Zheng
- Division of Rheumatology, Milton S. Hershey Medical Center at Penn State University, Hershey PA
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Masuta Y, Yamamoto T, Natsume-Kitatani Y, Kanuma T, Moriishi E, Kobiyama K, Mizuguchi K, Yasutomi Y, Ishii KJ. An Antigen-Free, Plasmacytoid Dendritic Cell-Targeting Immunotherapy To Bolster Memory CD8 + T Cells in Nonhuman Primates. THE JOURNAL OF IMMUNOLOGY 2018; 200:2067-2075. [PMID: 29431693 DOI: 10.4049/jimmunol.1701183] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 01/07/2018] [Indexed: 01/10/2023]
Abstract
The priming, boosting, and restoration of memory cytotoxic CD8+ T lymphocytes by vaccination or immunotherapy in vivo is an area of active research. Particularly, nucleic acid-based compounds have attracted attention due to their ability to elicit strong Ag-specific CTL responses as a vaccine adjuvant. Nucleic acid-based compounds have been shown to act as anticancer monotherapeutic agents even without coadministration of cancer Ag(s); however, so far they have lacked efficacy in clinical trials. We recently developed a second-generation TLR9 agonist, a humanized CpG DNA (K3) complexed with schizophyllan (SPG), K3-SPG, a nonagonistic Dectin-1 ligand. K3-SPG was previously shown to act as a potent monoimmunotherapeutic agent against established tumors in mice in vivo. In this study we extend the monoimmunotherapeutic potential of K3-SPG to a nonhuman primate model. K3-SPG activated monkey plasmacytoid dendritic cells to produce both IFN-α and IL-12/23 p40 in vitro and in vivo. A single injection s.c. or i.v. with K3-SPG significantly increased the frequencies of activated memory CD8+ T cells in circulation, including Ag-specific memory CTLs, in cynomolgus macaques. This increase did not occur in macaques injected with free CpG K3 or polyinosinic-polycytidylic acid. Injection of 2 mg K3-SPG induced mild systemic inflammation, however, levels of proinflammatory serum cytokines and circulating neutrophil influx were lower than those induced by the same dose of polyinosinic-polycytidylic acid. Therefore, even in the absence of specific Ags, we show that K3-SPG has potent Ag-specific memory CTL response-boosting capabilities, highlighting its potential as a monoimmunotherapeutic agent for chronic infectious diseases and cancer.
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Affiliation(s)
- Yuji Masuta
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan.,Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.,Laboratories of Discovery Research, Nippon Shinyaku Co., Ltd., Kyoto 601-8550, Japan
| | - Takuya Yamamoto
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan.,Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
| | - Yayoi Natsume-Kitatani
- Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
| | - Tomohiro Kanuma
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan.,Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
| | - Eiko Moriishi
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
| | - Kouji Kobiyama
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan.,Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.,Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and
| | - Kenji Mizuguchi
- Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
| | - Yasuhiro Yasutomi
- Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki 305-0843, Japan
| | - Ken J Ishii
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; .,Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
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48
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Meckes B, Banga RJ, Nguyen ST, Mirkin CA. Enhancing the Stability and Immunomodulatory Activity of Liposomal Spherical Nucleic Acids through Lipid-Tail DNA Modifications. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2018; 14:10.1002/smll.201702909. [PMID: 29226611 PMCID: PMC5815854 DOI: 10.1002/smll.201702909] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 10/06/2017] [Indexed: 05/22/2023]
Abstract
Liposomal spherical nucleic acids (LSNAs) are an attractive therapeutic platform for gene regulation and immunomodulation due to their biocompatibility, chemically tunable structures, and ability to enter cells rapidly without the need for ancillary transfection agents. Such structures consist of small (<100 nm) liposomal cores functionalized with a dense, highly oriented nucleic acid shell, both of which are key components in facilitating their biological activity. Here, the properties of LSNAs synthesized using conventional methods, anchoring cholesterol terminated oligonucleotides into a liposomal core, are compared to LSNAs made by directly modifying the surface of a liposomal core containing azide-functionalized lipids with dibenzocyclooctyl-terminated oligonucleotides. The surface densities of the oligonucleotides are measured for both types of LSNAs, with the lipid-modified structures having approximately twice the oligonucleotide surface coverage. The stabilities and cellular uptake properties of these structures are also evaluated. The higher density, lipid-functionalized structures are markedly more stable than conventional cholesterol-based structures in the presence of other unmodified liposomes and serum proteins as evidenced by fluorescence assays. Significantly, this new form of LSNA exhibits more rapid cellular uptake and increased sequence-specific toll-like receptor activation in immune reporter cell lines, making it a promising candidate for immunotherapy.
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Affiliation(s)
- Brian Meckes
- Department of Chemistry, International Institute for Nanotechnology, Evanston, IL, 60208, USA
| | - Resham J Banga
- Department of Chemical and Biological Engineering, Northwestern University, International Institute for Nanotechnology, Evanston, IL, 60208, USA
| | - SonBinh T Nguyen
- Department of Chemistry, International Institute for Nanotechnology, Evanston, IL, 60208, USA
| | - Chad A Mirkin
- Department of Chemistry, International Institute for Nanotechnology, Evanston, IL, 60208, USA
- Department of Chemical and Biological Engineering, Northwestern University, International Institute for Nanotechnology, Evanston, IL, 60208, USA
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49
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Ma Z, Cao Q, Xiong Y, Zhang E, Lu M. Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis B. Vaccines (Basel) 2018; 6:vaccines6010006. [PMID: 29337856 PMCID: PMC5874647 DOI: 10.3390/vaccines6010006] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 01/06/2018] [Accepted: 01/11/2018] [Indexed: 02/06/2023] Open
Abstract
Immune defense against infection with the hepatitis B virus (HBV) is complex and involves both host innate and adaptive immune systems. It is well accepted that the development of sufficient HBV-specific T cell and B cell responses are required for controlling an HBV infection. However, the contribution of innate immunity to removing HBV has been explored in recent years. Toll-like receptors (TLRs) are recognized as the first line of antiviral immunity because they initiate intracellular signaling pathways to induce antiviral mediators such as interferons (IFNs) and other cytokines. Recent studies show that the activation of TLR-mediated signaling pathways results in a suppression of HBV replication in vitro and in vivo. However, HBV has also evolved strategies to counter TLR responses including the suppression of TLR expression and the blockage of downstream signaling pathways. Antiviral treatment in chronic HBV-infected patients leads to an upregulation of TLR expression and the restoration of its innate antiviral functions. Thus, TLR activation may serve as an additional immunotherapeutic option for treating chronic HBV infection in combination with antiviral treatment.
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Affiliation(s)
- Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Qian Cao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Ejuan Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
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50
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Reeman S, Gates AJ, Pulford DJ, Krieg A, Ulaeto DO. Protection of Mice from Lethal Vaccinia Virus Infection by Vaccinia Virus Protein Subunits with a CpG Adjuvant. Viruses 2017; 9:v9120378. [PMID: 29232844 PMCID: PMC5744152 DOI: 10.3390/v9120378] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 12/03/2017] [Accepted: 12/04/2017] [Indexed: 12/23/2022] Open
Abstract
Smallpox vaccination carries a high risk of adverse events in recipients with a variety of contra-indications for live vaccines. Although alternative non-replicating vaccines have been described in the form of replication-deficient vaccine viruses, DNA vaccines, and subunit vaccines, these are less efficacious than replicating vaccines in animal models. DNA and subunit vaccines in particular have not been shown to give equivalent protection to the traditional replicating smallpox vaccine. We show here that combinations of the orthopoxvirus A27, A33, B5 and L1 proteins give differing levels of protection when administered in different combinations with different adjuvants. In particular, the combination of B5 and A27 proteins adjuvanted with CpG oligodeoxynucleotides (ODN) gives a level of protection in mice that is equivalent to the Lister traditional vaccine in a lethal vaccinia virus challenge model.
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Affiliation(s)
- Sarah Reeman
- Chemical, Biological & Radiological Division, Dstl Porton Down, Salisbury SP4 0JQ, UK.
| | - Amanda J Gates
- Chemical, Biological & Radiological Division, Dstl Porton Down, Salisbury SP4 0JQ, UK.
| | - David J Pulford
- Animal Health Laboratory, Ministry for Primary Industries, Wallaceville, Upper Hutt 5140, New Zealand.
| | - Art Krieg
- Checkmate Pharmaceuticals, One Broadway, 14th Floor, Cambridge, MA 02142, USA.
| | - David O Ulaeto
- Chemical, Biological & Radiological Division, Dstl Porton Down, Salisbury SP4 0JQ, UK.
- The Pirbright Institute, Pirbright GU24 0NF, UK.
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