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Hong L, Li J, Zeng W, Li Y, Yu C, Zhao S, Chen L, Feng Y. The seroprevalence of adenoviruses since 2000. Emerg Microbes Infect 2025:2475831. [PMID: 40035700 DOI: 10.1080/22221751.2025.2475831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Human adenoviruses (Ad) are increasingly used as vaccine vectors, especially after Ad5, Ad26, and ChAdY25 (ChAdOx1) were employed as vectors for SARS-CoV-2 vaccines. So far, more than 116 adenovirus genotypes have been identified, divided into 7 species (A-G). Most adenoviruses do not cause diseases or are mildly pathogenic, with only species B and E leading to acute respiratory infections or conjunctival inflammation and species F causing gastrointestinal infections. Previous studies have shown that the seroprevalence of neutralizing antibodies against adenoviruses can be limiting when applying adenoviral vectors. On the other hand, for highly pathogenic adenoviruses, neutralizing antibodies is beneficial for preventing the diseases caused by these adenoviruses. Here, we summarized the studies on the seroprevalence of adenoviruses, especially adenoviruses that may be utilized as vectors for vaccine and gene therapy. We also analyzed possible factors associated with the seroprevalence and neutralizing titers. Given the trend of increasing adenoviral vector application, it is necessary to continue the investigation of the seroprevalence of neutralizing antibodies against adenoviruses in different geographic locations and populations.
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Affiliation(s)
- Lingling Hong
- Department of Respiratory and Critical Care Medicine, Huadu District People's Hospital of Guangzhou, South China Medical University, Guangzhou 510800, China
| | - Jiashun Li
- Department of Respiratory and Critical Care Medicine, Huadu District People's Hospital of Guangzhou, South China Medical University, Guangzhou 510800, China
| | - Weikai Zeng
- Department of Respiratory and Critical Care Medicine, Huadu District People's Hospital of Guangzhou, South China Medical University, Guangzhou 510800, China
| | - Yuhua Li
- Department of Arboviruse vaccine, National Institutes for Food and Drug Control, Beijing 102629, China
| | - Changfa Yu
- Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Shutao Zhao
- Department of Respiratory and Critical Care Medicine, Huadu District People's Hospital of Guangzhou, South China Medical University, Guangzhou 510800, China
| | - Ling Chen
- Guangzhou National Laboratory, Guangzhou 510005, China
- Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Ying Feng
- Guangzhou National Laboratory, Guangzhou 510005, China
- Center for Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
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Nissilä E, Starck L, Aho E, Venerandi E, Jalkanen P, Leskinen K, Uvarov P, Saavalainen P, Julkunen I, Kotimaa J, Haapasalo K, Meri S. The COVID-19 vaccine ChAdOx1 is opsonized by anti-vector antibodies that activate complement and promote viral vector phagocytosis. Scand J Immunol 2025; 101:e70000. [PMID: 39891027 DOI: 10.1111/sji.70000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 12/22/2024] [Accepted: 01/07/2025] [Indexed: 02/03/2025]
Abstract
The ChAdOx1 nCoV-19 vaccine has been in large-scale use during the COVID-19 pandemic. Limited efficacy compared to mRNA vaccines and certain potential side effects raise the question of whether anti-adenoviral vector antibodies influence immune responses against the vaccine. Complement activation by ChAdOx1 and leukocyte phagocytosis of ChAdOx1 in vitro were studied. Plasma IgG levels against ChAdOx1 and human adenovirus 2 (hAdV2) hexon protein were determined (n = 20) and IgGs from high- and low-titre plasmas were isolated (n = 3). Complement activation was measured as cleavage of C3 by immunoblotting and generation of C3a and sC5b-9 by ELISA. pHrodo-labelled ChAdOx1 was opsonized with complement and IgG, and phagocytosis by isolated blood PMNs in vitro was studied by flow cytometry. The transcriptomic profile of PMN cells exposed to ChAdOx1 was analysed by RNA-seq. ChAdOx1 activated the classical complement pathway in an anti-adenovirus antibody-dependent manner. Generation of the terminal complement complex sC5b-9 in individual sera correlated with anti-hAdV2 hexon and anti-ChAdOx1 IgG levels. Phagocytosis of ChAdOx1 also correlated significantly with anti-hAdV2 hexon IgG, anti-ChAdOx1 IgG and serum sC5b-9 levels. High-titre anti-hAdv2 hexon IgG increased phagocytosis in the presence of normal serum. Anti-vector antibodies induced rapid complement activation and promoted phagocytosis of the ChAdOx1 vaccine by neutrophils. Moreover, transcriptomic analysis revealed upregulation of complement-related genes induced by the ChAdOx1 vaccine in vitro. Anti-adenovirus vector antibodies and complement activation may thus influence the efficacy of the ChAdOx1 vaccine against SARS-CoV-2 and be also involved in vaccine-related side effects.
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Affiliation(s)
- Eija Nissilä
- Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland
- Human Microbiome Research Program University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Leo Starck
- Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Elias Aho
- Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Erika Venerandi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Pinja Jalkanen
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Katarzyna Leskinen
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Pavel Uvarov
- Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland
- Human Microbiome Research Program University of Helsinki, Helsinki, Finland
| | - Päivi Saavalainen
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
| | - Ilkka Julkunen
- Institute of Biomedicine, University of Turku, Turku, Finland
- Clinical Microbiology, Turku University Hospital, Turku, Finland
| | - Juha Kotimaa
- Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Karita Haapasalo
- Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland
- Human Microbiome Research Program University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology, Medicum, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
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Yudaeva A, Kostyusheva A, Kachanov A, Brezgin S, Ponomareva N, Parodi A, Pokrovsky VS, Lukashev A, Chulanov V, Kostyushev D. Clinical and Translational Landscape of Viral Gene Therapies. Cells 2024; 13:1916. [PMID: 39594663 PMCID: PMC11592828 DOI: 10.3390/cells13221916] [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: 09/23/2024] [Revised: 10/29/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Gene therapies hold significant promise for treating previously incurable diseases. A number of gene therapies have already been approved for clinical use. Currently, gene therapies are mostly limited to the use of adeno-associated viruses and the herpes virus. Viral vectors, particularly those derived from human viruses, play a critical role in this therapeutic approach due to their ability to efficiently deliver genetic material to target cells. Despite their advantages, such as stable gene expression and efficient transduction, viral vectors face numerous limitations that hinder their broad application. These limitations include small cloning capacities, immune and inflammatory responses, and risks of insertional mutagenesis. This review explores the current landscape of viral vectors used in gene therapy, discussing the different types of DNA- and RNA-based viral vectors, their characteristics, limitations, and current medical and potential clinical applications. The review also highlights strategies to overcome existing challenges, including optimizing vector design, improving safety profiles, and enhancing transgene expression both using molecular techniques and nanotechnologies, as well as by approved drug formulations.
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Affiliation(s)
- Alexandra Yudaeva
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (A.Y.); (A.K.); (A.K.); (S.B.); (N.P.); (A.L.)
| | - Anastasiya Kostyusheva
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (A.Y.); (A.K.); (A.K.); (S.B.); (N.P.); (A.L.)
| | - Artyom Kachanov
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (A.Y.); (A.K.); (A.K.); (S.B.); (N.P.); (A.L.)
| | - Sergey Brezgin
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (A.Y.); (A.K.); (A.K.); (S.B.); (N.P.); (A.L.)
- Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.P.); (V.S.P.)
| | - Natalia Ponomareva
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (A.Y.); (A.K.); (A.K.); (S.B.); (N.P.); (A.L.)
- Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.P.); (V.S.P.)
- Department of Pharmaceutical and Toxicological Chemistry, Sechenov First Moscow State Medical University, 119146 Moscow, Russia
| | - Alessandro Parodi
- Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.P.); (V.S.P.)
| | - Vadim S. Pokrovsky
- Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.P.); (V.S.P.)
- Blokhin National Medical Research Center of Oncology, 115478 Moscow, Russia
- Department of Biochemistry, People’s Friendship University, 117198 Moscow, Russia
| | - Alexander Lukashev
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (A.Y.); (A.K.); (A.K.); (S.B.); (N.P.); (A.L.)
- Research Institute for Systems Biology and Medicine, 117246 Moscow, Russia
| | - Vladimir Chulanov
- Department of Infectious Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
| | - Dmitry Kostyushev
- Laboratory of Genetic Technologies, Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases, First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (A.Y.); (A.K.); (A.K.); (S.B.); (N.P.); (A.L.)
- Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.P.); (V.S.P.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
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Fuchs J, Hübner J, Schmidt A, Irrgang P, Maier C, Vieira Antão A, Oltmanns F, Thirion C, Lapuente D, Tenbusch M. Evaluation of adenoviral vector Ad19a encoding RSV-F as novel vaccine against respiratory syncytial virus. NPJ Vaccines 2024; 9:205. [PMID: 39472590 PMCID: PMC11522487 DOI: 10.1038/s41541-024-01001-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 10/17/2024] [Indexed: 11/02/2024] Open
Abstract
Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants and toddlers. Since natural infections do not induce persistent immunity, there is the need of vaccines providing long-term protection. Here, we evaluated a new adenoviral vector (rAd) vaccine based on the rare serotype rAd19a and compared the immunogenicity and efficacy to the highly immunogenic rAd5. Given as an intranasal boost in DNA primed mice, both vectors encoding the F protein provided efficient protection against a subsequent RSV infection. However, intramuscular immunization with rAd19a vectors provoked vaccine-enhanced disease after RSV infection compared to non-vaccinated animals. While mucosal IgA antibodies and tissue-resident memory T-cells in intranasally vaccinated mice rapidly control RSV replication, a strong anamnestic systemic T-cell response in absence of local immunity might be the reason for immune-mediated enhanced disease. Our study highlighted the potential benefits of developing effective mucosal against respiratory pathogens.
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Affiliation(s)
- Jana Fuchs
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | - Julian Hübner
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | - Anna Schmidt
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | - Pascal Irrgang
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | - Clara Maier
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | - Ana Vieira Antão
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | - Friederike Oltmanns
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | | | - Dennis Lapuente
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany
| | - Matthias Tenbusch
- Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossgarten 4, 91054, Erlangen, Germany.
- FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossplatz 1, D-91054, Erlangen, Germany.
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Koizumi N, Hirai T, Kano J, Sato A, Suzuki Y, Sasaki A, Nomura T, Utoguchi N. Utilizing Adenovirus Knob Proteins as Carriers in Cancer Gene Therapy Amidst the Presence of Anti-Knob Antibodies. Int J Mol Sci 2024; 25:10679. [PMID: 39409008 PMCID: PMC11476472 DOI: 10.3390/ijms251910679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/28/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
Numerous gene therapy drugs for cancer have received global approval, yet their efficacy against solid tumors remains inadequate. Our previous research indicated that the fiber protein, a component of the adenovirus capsid, can propagate from infected cells to neighboring cells that express the adenovirus receptor. We hypothesize that merging this fiber protein with an anti-cancer protein could enable the anti-cancer protein to disseminate around the transfected cells, presenting a novel approach to cancer gene therapy. In our study, we discovered that the knob region of the adenovirus type 5 fiber protein is the smallest unit capable of spreading to adjacent cells in a receptor-specific manner. We also showed that the recombinant knob protein infiltrates cells after dispersing to surrounding cells. To assess the potential of the knob protein to augment gene therapy for solid tumors in mice, we expressed a fusion gene of the A subunit of cytotoxic cholera toxin and the knob region in mouse tumors. We found that this fusion protein only inhibited tumor growth in receptor-expressing mouse melanomas, and this inhibitory effect persisted even in mice with anti-knob antibodies. Our study's findings propose a novel cancer gene therapy strategy that enhances therapeutic effects by specifically delivering therapeutic proteins, expressed from in vivo administered genes, to target molecules. This outcome offers a fresh perspective on gene therapy for solid cancers, and we anticipate that knob proteins will serve as a platform for this method.
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Affiliation(s)
- Naoya Koizumi
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
| | - Takamasa Hirai
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki 210-9501, Japan
| | - Junpei Kano
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
| | - Anna Sato
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
| | - Yurika Suzuki
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
| | - Arisa Sasaki
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
| | - Tetsuya Nomura
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
| | - Naoki Utoguchi
- Laboratory of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Tokyo 194-8543, Japan; (T.H.); (T.N.); (N.U.)
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Ward C, Beharry A, Tennakoon R, Rozik P, Wilhelm SDP, Heinemann IU, O’Donoghue P. Mechanisms and Delivery of tRNA Therapeutics. Chem Rev 2024; 124:7976-8008. [PMID: 38801719 PMCID: PMC11212642 DOI: 10.1021/acs.chemrev.4c00142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/11/2024] [Accepted: 04/26/2024] [Indexed: 05/29/2024]
Abstract
Transfer ribonucleic acid (tRNA) therapeutics will provide personalized and mutation specific medicines to treat human genetic diseases for which no cures currently exist. The tRNAs are a family of adaptor molecules that interpret the nucleic acid sequences in our genes into the amino acid sequences of proteins that dictate cell function. Humans encode more than 600 tRNA genes. Interestingly, even healthy individuals contain some mutant tRNAs that make mistakes. Missense suppressor tRNAs insert the wrong amino acid in proteins, and nonsense suppressor tRNAs read through premature stop signals to generate full length proteins. Mutations that underlie many human diseases, including neurodegenerative diseases, cancers, and diverse rare genetic disorders, result from missense or nonsense mutations. Thus, specific tRNA variants can be strategically deployed as therapeutic agents to correct genetic defects. We review the mechanisms of tRNA therapeutic activity, the nature of the therapeutic window for nonsense and missense suppression as well as wild-type tRNA supplementation. We discuss the challenges and promises of delivering tRNAs as synthetic RNAs or as gene therapies. Together, tRNA medicines will provide novel treatments for common and rare genetic diseases in humans.
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Affiliation(s)
- Cian Ward
- Department of Biochemistry, Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Aruun Beharry
- Department of Biochemistry, Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Rasangi Tennakoon
- Department of Biochemistry, Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Peter Rozik
- Department of Biochemistry, Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Sarah D. P. Wilhelm
- Department of Biochemistry, Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Ilka U. Heinemann
- Department of Biochemistry, Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Patrick O’Donoghue
- Department of Biochemistry, Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada
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Göttig L, Schreiner S. E4orf1: The triple agent of adenovirus - Unraveling its roles in oncogenesis, infectious obesity and immune responses in virus replication and vector therapy. Tumour Virus Res 2024; 17:200277. [PMID: 38428735 PMCID: PMC10937242 DOI: 10.1016/j.tvr.2024.200277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/20/2024] [Accepted: 02/20/2024] [Indexed: 03/03/2024] Open
Abstract
Human Adenoviruses (HAdV) are nearly ubiquitous pathogens comprising numerous sub-types that infect various tissues and organs. Among many encoded proteins that facilitate viral replication and subversion of host cellular processes, the viral E4orf1 protein has emerged as an intriguing yet under-investigated player in the complex interplay between the virus and its host. E4orf1 has gained attention as a metabolism activator and oncogenic agent, while recent research is showing that E4orf1 may play a more important role in modulating cellular pathways such as PI3K-Akt-mTOR, Ras, the immune response and further HAdV replication stages than previously anticipated. In this review, we aim to explore the structure, molecular mechanisms, and biological functions of E4orf1, shedding light on its potentially multifaceted roles during HAdV infection, including metabolic diseases and oncogenesis. Furthermore, we discuss the role of functional E4orf1 in biotechnological applications such as Adenovirus (AdV) vaccine vectors and oncolytic AdV. By dissecting the intricate relationships between HAdV types and E4orf1 proteins, this review provides valuable insights into viral pathogenesis and points to promising areas of future research.
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Affiliation(s)
- Lilian Göttig
- Institute of Virology, School of Medicine, Technical University of Munich, Germany
| | - Sabrina Schreiner
- Institute of Virology, School of Medicine, Technical University of Munich, Germany; Institute of Virology, Hannover Medical School, Hannover, Germany; Cluster of Excellence RESIST (Resolving Infection Susceptibility; EXC 2155), Hannover, Germany; Institute of Virology, Medical Center - University of Freiburg, Freiburg, Germany.
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8
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Shirazi MMA, Saedi TA, Moghaddam ZS, Nemati M, Shiri R, Negahdari B, Goradel NH. Nanotechnology and nano-sized tools: Newer approaches to circumvent oncolytic adenovirus limitations. Pharmacol Ther 2024; 256:108611. [PMID: 38387653 DOI: 10.1016/j.pharmthera.2024.108611] [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: 10/19/2023] [Revised: 01/03/2024] [Accepted: 02/14/2024] [Indexed: 02/24/2024]
Abstract
Oncolytic adenoviruses (OAds), engineered Ads preferentially infect and lyse tumor cells, have attracted remarkable attention as immunotherapy weapons for the treatment of various malignancies. Despite hopeful successes in preclinical investigations and translation into clinical phases, they face some challenges that thwart their therapeutic effectiveness, including low infectivity of cancer cells, liver sequestration, pre-existing neutralizing antibodies, physical barriers to the spread of Ads, and immunosuppressive TME. Nanotechnology and nano-sized tools provide several advantages to overcome these limitations of OAds. Nano-sized tools could improve the therapeutic efficacy of OAds by enhancing infectivity and cellular uptake, targeting and protecting from pre-existing immune responses, masking and preventing liver tropism, and co-delivery with other therapeutic agents. Herein, we reviewed the constructs of various OAds and their application in clinical trials, as well as the limitations they have faced. Furthermore, we emphasized the potential applications of nanotechnology to solve the constraints of OAds to improve their anti-tumor activities.
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Affiliation(s)
| | - Tayebeh Azam Saedi
- Department of Genetics, Faculty of Science, Islamic Azad University, Tonekabon Branch, Tonekabon, Iran
| | - Zahra Samadi Moghaddam
- Department of Medical Biotechnology, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Mahnaz Nemati
- Amir Oncology Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Shiri
- Department of Basic Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, Maragheh University of Medical Sciences, Maragheh, Iran; Arthropod-Borne Diseases Research Centre, Ardabil University of Medical Sciences, Ardabil, Iran.
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9
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Wettengel JM, Naka H, Dissen GA, Torgerson J, Pounder M, Mueller SF, Mueller E, Hagen P, Brandt M, Protzer U, Burwitz BJ. High-Throughput Screening for the Prevalence of Neutralizing Antibodies against Human Adenovirus Serotype 5. Vaccines (Basel) 2024; 12:155. [PMID: 38400138 PMCID: PMC10891882 DOI: 10.3390/vaccines12020155] [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: 12/12/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Adenoviral vectors based on the human adenovirus species C serotype 5 (HAdV-C5) are commonly used for vector-based gene therapies and vaccines. In the preclinical stages of development, their safety and efficacy are often validated in suitable animal models. However, pre-existing neutralizing antibodies may severely influence study outcomes. Here, we generated a new HAdV-C5-based reporter vector and established a high-throughput screening assay for the multivalent detection of HAdV-C5-neutralizing antibodies in serum. We screened the sera of rhesus macaques at different primate centers, and of rabbits, horses, cats, and dogs, showing that HAdV-C5-neutralizing antibodies can be found in all species, albeit at different frequencies. Our results emphasize the need to prescreen model animals in HAdV-C5-based studies.
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Affiliation(s)
- Jochen M. Wettengel
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; (J.M.W.)
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
- German Center for Infection Research, Munich Partner Site, 81675 Munich, Germany
| | - Hiroaki Naka
- Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA;
| | - Gregory A. Dissen
- Molecular Virology Core, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; (G.A.D.); (J.T.)
| | - Jeffrey Torgerson
- Molecular Virology Core, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; (G.A.D.); (J.T.)
| | - Michelle Pounder
- Molecular Virology Core, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; (G.A.D.); (J.T.)
| | | | | | - Philipp Hagen
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Micah Brandt
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; (J.M.W.)
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich, 81675 Munich, Germany
- German Center for Infection Research, Munich Partner Site, 81675 Munich, Germany
| | - Benjamin J. Burwitz
- Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA; (J.M.W.)
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10
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Kwon T. Utilizing non-human primate models to combat recent COVID-19/SARS-CoV-2 and viral infectious disease outbreaks. J Med Primatol 2024; 53:e12689. [PMID: 38084001 DOI: 10.1111/jmp.12689] [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: 10/05/2023] [Revised: 11/01/2023] [Accepted: 12/01/2023] [Indexed: 02/13/2024]
Abstract
In recent times, global viral outbreaks and diseases, such as COVID-19 (SARS-CoV-2), Zika (ZIKV), monkeypox (MPOX), Ebola (EBOV), and Marburg (MARV), have been extensively documented. Swiftly deciphering the mechanisms underlying disease pathogenesis and devising vaccines or therapeutic interventions to curtail these outbreaks stand as paramount imperatives. Amidst these endeavors, animal models emerge as pivotal tools. Among these models, non-human primates (NHPs) hold a position of particular importance. Their proximity in evolutionary lineage and physiological resemblances to humans render them a primary model for comprehending human viral infections. This review encapsulates the pivotal role of various NHP species-such as rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), african green monkeys (Chlorocebus sabaeus/aethiops), pigtailed macaques (Macaca nemestrina/Macaca leonina), baboons (Papio hamadryas/Papio anubis), and common marmosets (Callithrix jacchus)-in investigations pertaining to the abovementioned viral outbreaks. These NHP models play a pivotal role in illuminating key aspects of disease dynamics, facilitating the development of effective countermeasures, and contributing significantly to our overall understanding of viral pathogenesis.
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Affiliation(s)
- Taeho Kwon
- Primate Resources Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-si, Jeonbuk, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea National University of Science and Technology (UST), Daejeon, Korea
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11
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Sallard E, Schulte L, van den Boom A, Klimovitskii A, Knierer J, Hagedorn C, Knocks M, Zhang W, Kreppel F, Ehrhardt A, Ehrke-Schulz E. Development of oncolytic and gene therapy vectors based on adenovirus serotype 4 as an alternative to adenovirus serotype 5. J Gene Med 2024; 26:e3576. [PMID: 37580111 DOI: 10.1002/jgm.3576] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/13/2023] [Accepted: 07/14/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND Adenoviral vectors are among the most frequently used vectors for gene therapy and cancer treatment. Most vectors are derived from human adenovirus (Ad) serotype 5 despite limited applicability caused by pre-existing immunity and unfavorable liver tropism, whereas the other more than 100 known human serotypes remain largely unused. Here, we screened a library of human Ad types and identified Ad4 as a promising candidate vector. METHODS Reporter-gene-expressing viruses representative of the natural human Ad diversity were used to transduce an array of muscle cell lines and two- or three-dimensional tumor cultures. The time-course of transgene expression was monitored by fluorescence or luminescence measurements. To generate replication-deficient Ad4 vector genomes, successive homologous recombination was applied. RESULTS Ad4, 17 and 50 transduced human cardiomyocytes more efficiently than Ad5, whereas Ad37 was found to be superior in rhabdomyocytes. Despite its moderate transduction efficiency, Ad4 showed efficient and long-lasting gene expression in papillomavirus (HPV) positive tumor organoids. Therefore, we aimed to harness the potential of Ad4 for improved muscle transduction or oncolytic virotherapy of HPV-positive tumors. We deleted the E1 and E3 transcription units to produce first generation Ad vectors for gene therapy. The E1- and E1/E3-deleted vectors were replication-competent in HEK293 cells stably expressing E1 but not in the other cell lines tested. Furthermore, we show that the Ad5 E1 transcription unit can complement the replication of E1-deleted Ad4 vectors. CONCLUSIONS Our Ad4-based gene therapy vector platform contributes to the development of improved Ad vectors based on non-canonical serotypes for a broad range of applications.
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Affiliation(s)
- Erwan Sallard
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Lukas Schulte
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Alexander van den Boom
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Alexander Klimovitskii
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Julius Knierer
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Claudia Hagedorn
- Institute for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Maximilian Knocks
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Wenli Zhang
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Florian Kreppel
- Institute for Biochemistry and Molecular Medicine, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Anja Ehrhardt
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Eric Ehrke-Schulz
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany
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12
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Francisco AG, Reyes JCB, Tabios IKB, Cruz CJG, Ang MAC, Heralde FM, Lacuna ARG, de Paz-Silava SLM. Seroprevalence of human adenovirus type 5 neutralizing antibodies in the Philippines. PLoS One 2023; 18:e0293046. [PMID: 38039314 PMCID: PMC10691707 DOI: 10.1371/journal.pone.0293046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/16/2023] [Indexed: 12/03/2023] Open
Abstract
Human adenovirus (HAdV), particularly the HAdV type 5 (HAdV-5), has been extensively utilized in the development of vector vaccines due to its high immunogenicity, good safety profile, and ease of propagation. However, one of the main challenges in its use is the presence of pre-existing immunity among vaccine recipients. Pre-existing neutralizing antibodies (NAbs) can prevent the uptake of HAdV-5 vectors and reduce vaccine efficacy. Hence, this study investigated the seroprevalence of NAbs against HAdV-5 in urban and rural regions of the Philippines. Luciferase-based neutralization assay was performed on 391 plasma/serum samples. Out of these samples, 346 or 88.5% were positive for HAdV-5 NAbs, and the majority of them (56.8%) had high titers against the virus. Among the regions included in this study, Bicol (Region V) had the highest seroprevalence rate (94.1%). Our findings show that a significant number of adults in the Philippines have pre-existing immunity against HAdV-5. This supports the recommendation that vaccination programs in the country should consider implementing vaccination techniques, such as a prime-boost regimen or addition of booster doses, to address the potential negative effects of pre-existing HAdV-5 immunity in the efficacy of adenoviral vector-based vaccines.
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Affiliation(s)
- Abialbon G. Francisco
- Department of Medical Microbiology, College of Public Health, University of the Philippines Manila, Manila, Philippines
| | - John Carlo B. Reyes
- Department of Laboratories, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines
| | - Ian Kim B. Tabios
- Institute of Biology, College of Science, University of the Philippines Diliman, Quezon City, Philippines
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Criselda Jean G. Cruz
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
- College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Mark Angelo C. Ang
- Department of Laboratories, Philippine General Hospital, University of the Philippines Manila, Manila, Philippines
- Department of Pathology, College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Francisco M. Heralde
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Azita Racquel G. Lacuna
- Department of Medical Microbiology, College of Public Health, University of the Philippines Manila, Manila, Philippines
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13
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Leikas AJ, Ylä-Herttuala S, Hartikainen JEK. Adenoviral Gene Therapy Vectors in Clinical Use-Basic Aspects with a Special Reference to Replication-Competent Adenovirus Formation and Its Impact on Clinical Safety. Int J Mol Sci 2023; 24:16519. [PMID: 38003709 PMCID: PMC10671366 DOI: 10.3390/ijms242216519] [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: 11/05/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Adenoviral vectors are commonly used in clinical gene therapy. Apart from oncolytic adenoviruses, vector replication is highly undesired as it may pose a safety risk for the treated patient. Thus, careful monitoring for the formation of replication-competent adenoviruses (RCA) during vector manufacturing is required. To render adenoviruses replication deficient, their genomic E1 region is deleted. However, it has been known for a long time that during their propagation, some viruses will regain their replication capability by recombination in production cells, most commonly HEK293. Recently developed RCA assays have revealed that many clinical batches contain more RCA than previously assumed and allowed by regulatory authorities. The clinical significance of the higher RCA content has yet to be thoroughly evaluated. In this review, we summarize the biology of adenovirus vectors, their manufacturing methods, and the origins of RCA formed during HEK293-based vector production. Lastly, we share our experience using minimally RCA-positive serotype 5 adenoviral vectors based on observations from our clinical cardiovascular gene therapy studies.
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Affiliation(s)
- Aleksi J. Leikas
- Heart Center, Kuopio University Hospital, 70200 Kuopio, Finland; (S.Y.-H.); (J.E.K.H.)
- Gene Therapy Unit, Kuopio University Hospital, 70200 Kuopio, Finland
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland
| | - Seppo Ylä-Herttuala
- Heart Center, Kuopio University Hospital, 70200 Kuopio, Finland; (S.Y.-H.); (J.E.K.H.)
- Gene Therapy Unit, Kuopio University Hospital, 70200 Kuopio, Finland
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland
| | - Juha E. K. Hartikainen
- Heart Center, Kuopio University Hospital, 70200 Kuopio, Finland; (S.Y.-H.); (J.E.K.H.)
- Gene Therapy Unit, Kuopio University Hospital, 70200 Kuopio, Finland
- School of Medicine, Faculty of Health Sciences, University of Eastern Finland, 70210 Kuopio, Finland
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14
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Zou P, Wang Q, Zhang P, Luo S, Wang C, Zhang E, Zhang L, Li C, Li T. Characterization of Pre-Existing Neutralizing Antibody to Human Adenovirus Types 5 and 49 and Simian Type 23 in Chinese Population. Viral Immunol 2023; 36:617-625. [PMID: 37903228 DOI: 10.1089/vim.2023.0023] [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: 11/01/2023] Open
Abstract
Recombinant adenovirus vector has been widely used in vaccine development. Due to the pre-existing immunity of human adenovirus type 5 (HAd5) in humans, a range of rare human and chimpanzee adenovirus vectors have been developed. In the previous study, we constructed novel adenovirus vector Sad23L and Ad49L based on simian adenovirus type 23 (SAd23) and human adenovirus type 49 (HAd49), which were used in the development of ZIKV and COVID-19 vaccines. However, the levels of pre-existing neutralizing antibody (NAb) of HAd49 and SAd23 remain unclear in China. In this study, we measured NAbs titers of HAd5, HAd49, and SAd23 in 600 healthy blood donors from 6 regions across China. NAb titer of HAd49 or SAd23 was significantly lower than that of HAd5 (p < 0.001). There was no significant difference in seroprevalence and NAb titers of three adenoviruses between male and female donors. The seropositive rates of HAd5 and SAd23 increased with age growth in a positive correlation (p < 0.01), while in contrast to HAd5, HAd49, and SAd23 had a low level of pre-existing immunity in Chinese population, which suggested that Ad49L and Sad23L vectors could be used in vaccine development for humans.
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Affiliation(s)
- Peng Zou
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Qi Wang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
- Department of Laboratory Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Panli Zhang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Shengxue Luo
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
- Department of Pediatrics, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Cong Wang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Enhui Zhang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Ling Zhang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Chengyao Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Tingting Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
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15
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Wong B, Birtch R, Rezaei R, Jamieson T, Crupi MJF, Diallo JS, Ilkow CS. Optimal delivery of RNA interference by viral vectors for cancer therapy. Mol Ther 2023; 31:3127-3145. [PMID: 37735876 PMCID: PMC10638062 DOI: 10.1016/j.ymthe.2023.09.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/28/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
In recent years, there has been a surge in the innovative modification and application of the viral vector-based gene therapy field. Significant and consistent improvements in the engineering, delivery, and safety of viral vectors have set the stage for their application as RNA interference (RNAi) delivery tools. Viral vector-based delivery of RNAi has made remarkable breakthroughs in the treatment of several debilitating diseases and disorders (e.g., neurological diseases); however, their novelty has yet to be fully applied and utilized for the treatment of cancer. This review highlights the most promising and emerging viral vector delivery tools for RNAi therapeutics while discussing the variables limiting their success and suitability for cancer therapy. Specifically, we outline different integrating and non-integrating viral platforms used for gene delivery, currently employed RNAi targets for anti-cancer effect, and various strategies used to optimize the safety and efficacy of these RNAi therapeutics. Most importantly, we provide great insight into what challenges exist in their application as cancer therapeutics and how these challenges can be effectively navigated to advance the field.
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Affiliation(s)
- Boaz Wong
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Rayanna Birtch
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Reza Rezaei
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Taylor Jamieson
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Mathieu J F Crupi
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Jean-Simon Diallo
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Carolina S Ilkow
- Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
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16
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Wang X, Hetzel M, Zhang W, Ehrhardt A, Bayer W. Comparative analysis of the impact of 40 adenovirus types on dendritic cell activation and CD8 + T cell proliferation capacity for the identification of favorable immunization vector candidates. Front Immunol 2023; 14:1286622. [PMID: 37915567 PMCID: PMC10616870 DOI: 10.3389/fimmu.2023.1286622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 10/04/2023] [Indexed: 11/03/2023] Open
Abstract
For the development of new adenovirus (AdV)-based vectors, it is important to understand differences in immunogenicity. In a side-by-side in vitro analysis, we evaluated the effect of 40 AdV types covering human AdV (HAdV) species A through G on the expression of 11 activation markers and the secretion of 12 cytokines by AdV-transduced dendritic cells, and the effect on CD8+ T cell proliferation capacity. We found that the expression of activation markers and cytokines differed widely between the different HAdV types, and many types were able to significantly impair the proliferation capacity of CD8+ T cells. Univariate and multivariate regression analyses suggested an important role of type I interferons in mediating this suppression of CD8+ T cells, which we confirmed experimentally in a proliferation assay using a type I interferon receptor blocking antibody. Using Bayesian statistics, we calculated a prediction model that suggests HAdV types HAdV-C1, -D8, -B7, -F41, -D33, -C2, -A31, -B3 and -D65 as the most favorable candidates for vaccine vector development.
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Affiliation(s)
- Xiaoyan Wang
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Mario Hetzel
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Wenli Zhang
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Anja Ehrhardt
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Wibke Bayer
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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17
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Bates EA, Lovatt C, Plein AR, Davies JA, Siebzehnrubl FA, Parker AL. Engineering Adenoviral Vectors with Improved GBM Selectivity. Viruses 2023; 15:v15051086. [PMID: 37243172 DOI: 10.3390/v15051086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/21/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (HAdV-C5) has been the most utilised clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to HAdV-C5 coupled with the infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an HAdV-C5-based platform using the fibre knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptor coxsackie, adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at a low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance the specificity of transgene expression to GBM, we assessed the potential for tumour-specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tight GBM-specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour-specific promoter approaches may enable the development of efficacious therapies better suited to GBM.
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Affiliation(s)
- Emily A Bates
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Charlotte Lovatt
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Alice R Plein
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - James A Davies
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
| | - Florian A Siebzehnrubl
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Maindy Road, Cardiff CF24 4HQ, UK
| | - Alan L Parker
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
- Systems Immunity University Research Institute, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
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18
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Rzymski P. Guillain-Barré syndrome and COVID-19 vaccines: focus on adenoviral vectors. Front Immunol 2023; 14:1183258. [PMID: 37180147 PMCID: PMC10169623 DOI: 10.3389/fimmu.2023.1183258] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
COVID-19 vaccination is a life-saving intervention. However, it does not come up without a risk of rare adverse events, which frequency varies between vaccines developed using different technological platforms. The increased risk of Guillain-Barré syndrome (GBS) has been reported for selected adenoviral vector vaccines but not for other vaccine types, including more widely used mRNA preparations. Therefore, it is unlikely that GBS results from the cross-reactivity of antibodies against the SARS-CoV-2 spike protein generated after the COVID-19 vaccination. This paper outlines two hypotheses according to which increased risk of GBS following adenoviral vaccination is due to (1) generation of anti-vector antibodies that may cross-react with proteins involved in biological processes related to myelin and axons, or (2) neuroinvasion of selected adenovirus vectors to the peripheral nervous system, infection of neurons and subsequent inflammation and neuropathies. The rationale behind these hypotheses is outlined, advocating further epidemiological and experimental research to verify them. This is particularly important given the ongoing interest in using adenoviruses in developing vaccines against various infectious diseases and cancer immunotherapeutics.
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Affiliation(s)
- Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznan, Poland
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19
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Yang Z, Paes BCMF, Fulber JPC, Tran MY, Farnós O, Kamen AA. Development of an Integrated Continuous Manufacturing Process for the rVSV-Vectored SARS-CoV-2 Candidate Vaccine. Vaccines (Basel) 2023; 11:vaccines11040841. [PMID: 37112753 PMCID: PMC10143285 DOI: 10.3390/vaccines11040841] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
The administration of viral vectored vaccines remains one of the most effective ways to respond to the ongoing novel coronavirus disease 2019 (COVID-19) pandemic. However, pre-existing immunity to the viral vector hinders its potency, resulting in a limited choice of viral vectors. Moreover, the basic batch mode of manufacturing vectored vaccines does not allow one to cost-effectively meet the global demand for billions of doses per year. To date, the exposure of humans to VSV infection has been limited. Therefore, a recombinant vesicular stomatitis virus (rVSV), which expresses the spike protein of SARS-CoV-2, was selected as the vector. To determine the operating upstream process conditions for the most effective production of an rVSV-SARS-CoV-2 candidate vaccine, a set of critical process parameters was evaluated in an Ambr 250 modular system, whereas in the downstream process, a streamlined process that included DNase treatment, clarification, and a membrane-based anion exchange chromatography was developed. The design of the experiment was performed with the aim to obtain the optimal conditions for the chromatography step. Additionally, a continuous mode manufacturing process integrating upstream and downstream steps was evaluated. rVSV-SARS-CoV-2 was continuously harvested from the perfusion bioreactor and purified by membrane chromatography in three columns that were operated sequentially under a counter-current mode. Compared with the batch mode, the continuous mode of operation had a 2.55-fold increase in space-time yield and a reduction in the processing time by half. The integrated continuous manufacturing process provides a reference for the efficient production of other viral vectored vaccines.
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Affiliation(s)
- Zeyu Yang
- Viral Vectors and Vaccines Bioprocessing Group, Department of Bioengineering, McGill University, Montreal, QC H3A 0G4, Canada
| | | | - Julia Puppin Chaves Fulber
- Viral Vectors and Vaccines Bioprocessing Group, Department of Bioengineering, McGill University, Montreal, QC H3A 0G4, Canada
| | - Michelle Yen Tran
- Viral Vectors and Vaccines Bioprocessing Group, Department of Bioengineering, McGill University, Montreal, QC H3A 0G4, Canada
| | - Omar Farnós
- Viral Vectors and Vaccines Bioprocessing Group, Department of Bioengineering, McGill University, Montreal, QC H3A 0G4, Canada
| | - Amine A Kamen
- Viral Vectors and Vaccines Bioprocessing Group, Department of Bioengineering, McGill University, Montreal, QC H3A 0G4, Canada
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20
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Wang S, Liang B, Wang W, Li L, Feng N, Zhao Y, Wang T, Yan F, Yang S, Xia X. Viral vectored vaccines: design, development, preventive and therapeutic applications in human diseases. Signal Transduct Target Ther 2023; 8:149. [PMID: 37029123 PMCID: PMC10081433 DOI: 10.1038/s41392-023-01408-5] [Citation(s) in RCA: 70] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 04/09/2023] Open
Abstract
Human diseases, particularly infectious diseases and cancers, pose unprecedented challenges to public health security and the global economy. The development and distribution of novel prophylactic and therapeutic vaccines are the prioritized countermeasures of human disease. Among all vaccine platforms, viral vector vaccines offer distinguished advantages and represent prominent choices for pathogens that have hampered control efforts based on conventional vaccine approaches. Currently, viral vector vaccines remain one of the best strategies for induction of robust humoral and cellular immunity against human diseases. Numerous viruses of different families and origins, including vesicular stomatitis virus, rabies virus, parainfluenza virus, measles virus, Newcastle disease virus, influenza virus, adenovirus and poxvirus, are deemed to be prominent viral vectors that differ in structural characteristics, design strategy, antigen presentation capability, immunogenicity and protective efficacy. This review summarized the overall profile of the design strategies, progress in advance and steps taken to address barriers to the deployment of these viral vector vaccines, simultaneously highlighting their potential for mucosal delivery, therapeutic application in cancer as well as other key aspects concerning the rational application of these viral vector vaccines. Appropriate and accurate technological advances in viral vector vaccines would consolidate their position as a leading approach to accelerate breakthroughs in novel vaccines and facilitate a rapid response to public health emergencies.
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Affiliation(s)
- Shen Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Bo Liang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Weiqi Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ling Li
- China National Research Center for Exotic Animal Diseases, China Animal Health and Epidemiology Center, Qingdao, China
| | - Na Feng
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Yongkun Zhao
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Tiecheng Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Feihu Yan
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
| | - Songtao Yang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
| | - Xianzhu Xia
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
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21
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Wang B, Li J, Wu S, Wang Y, Chen Y, Zhai Y, Song X, Zhao Z, Zhang Z, Zhang J, Yu R, Hou L, Chen W. A seroepidemiological survey of adenovirus type 7 circulation among healthy adults in China and in Sierra Leone, West Africa. Front Public Health 2023; 11:1095343. [PMID: 36815162 PMCID: PMC9940762 DOI: 10.3389/fpubh.2023.1095343] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/18/2023] [Indexed: 02/09/2023] Open
Abstract
Adenovirus type 7 (HAdV7) is one of the most pathogenic human adenoviruses (HAdVs) and can cause severe illness and even death, particularly in people with weakened immune systems. Many countries worldwide have experienced epidemics of this highly contagious pathogen, including China and Sierra Leone; however, studies describing the seroprevalence of anti-HAdV7 neutralizing antibodies (nAbs) are still lacking. Herein, we established an efficient neutralization assay based on a recombinant luciferase-expressing HAdV7 virus (HAd7-Luc) to monitor historical HAdV7 infections and predict outbreak distributions. Among the 2,350 serum samples collected from eight sites in China and Sierra Leone in this cross-sectional serological survey, the overall proportion of anti-HAdV7-seropositive individuals was nearly 60%, with higher seroprevalence rates in Sierra Leone than in China. Regionally, HAdV7 nAb titers were higher in China than in Sierra Leone and showed a geographic variation across different regions. Regardless of the location, the seropositive rate of HAdV7 nAb was lower than that of HAdV5 nAb, as was the nAb titer. The prevalence rates of antibodies against HAdV7 and HAdV5 were both related to age but not to sex. In addition, serologic cross-reactions were rarely observed among people infected with HAdV7 and HAdV5. These results indicate a humoral immune response acquired through endemic HAdV7 infection and enrich the understanding of not only the epidemiological prevention and control of HAdV7 but also the clinical application of HAdV7-based vaccines or gene therapy tools.
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Affiliation(s)
- Busen Wang
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Jianhua Li
- Zhejiang Provincial Center of Disease Control and Prevention, Hangzhou, China
| | - Shipo Wu
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Yudong Wang
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Yi Chen
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Yanfang Zhai
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Xiaohong Song
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Zhenghao Zhao
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Zhe Zhang
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Jinlong Zhang
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Rui Yu
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China
| | - Lihua Hou
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China,*Correspondence: Lihua Hou ✉
| | - Wei Chen
- Vaccine and Antibody Engineering Laboratory, Beijing Institute of Biotechnology, Beijing, China,Wei Chen ✉
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22
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Cho H, Binder J, Weeratna R, Dermyer M, Dai S, Boccia A, Li W, Li S, Jooss K, Merson J, Hollingsworth RE. Preclinical development of a vaccine-based immunotherapy regimen (VBIR) that induces potent and durable T cell responses to tumor-associated self-antigens. Cancer Immunol Immunother 2023; 72:287-300. [PMID: 35829790 PMCID: PMC10992523 DOI: 10.1007/s00262-022-03245-x] [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: 12/23/2021] [Accepted: 06/16/2022] [Indexed: 01/26/2023]
Abstract
The development of therapeutic cancer vaccines remains an active area, although previous approaches have yielded disappointing results. We have built on lessons from previous cancer vaccine approaches and immune checkpoint inhibitor research to develop VBIR, a vaccine-based immunotherapy regimen. Assessment of various technologies led to selection of a heterologous vaccine using chimpanzee adenovirus (AdC68) for priming followed by boosts with electroporation of DNA plasmid to deliver T cell antigens to the immune system. We found that priming with AdC68 rapidly activates and expands antigen-specific T cells and does not encounter pre-existing immunity as occurs with the use of a human adenovirus vaccine. The AdC68 vector does, however, induce new anti-virus immune responses, limiting its use for boosting. To circumvent this, boosting with DNA encoding the same antigens can be done repetitively to augment and maintain vaccine responses. Using mouse and monkey models, we found that the activation of both CD4 and CD8 T cells was amplified by combination with anti-CTLA-4 and anti-PD-1 antibodies. These antibodies were administered subcutaneously to target their distribution to vaccination sites and to reduce systemic exposure which may improve their safety. VBIR can break tolerance and activate T cells recognizing tumor-associated self-antigens. This activation lasts more than a year after completing treatment in monkeys, and inhibits tumor growth to a greater degree than is observed using the individual components in mouse cancer models. These results have encouraged the testing of this combination regimen in cancer patients with the aim of increasing responses beyond current therapies.
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Affiliation(s)
- Helen Cho
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
- Samyang Holdings Corporation, 295 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, Korea
| | - Joe Binder
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
| | - Risini Weeratna
- Pfizer Vaccines and Immunotherapeutics, 340 Terry Fox Drive, Suite 200, Ottawa, ON, Canada
- National Research Council of Canada, Ottawa, ON, Canada
| | - Michael Dermyer
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
| | - Stanley Dai
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
- Nektar Therapeutics, 455 Mission Bay Boulevard, South San Francisco, CA, 94158, USA
| | - Antionio Boccia
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
| | - Wei Li
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
| | - Shangjin Li
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
| | - Karin Jooss
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
- Gritstone Oncology Inc., 5858 Horton Street, Suite 210, Emeryville, CA, USA
| | - James Merson
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA
- Johnson & Johnson, 5000 Shoreline Ct., South San Francisco, CA, USA
| | - Robert E Hollingsworth
- Pfizer Cancer Vaccines and Immunotherapeutics, 10777 Science Center Drive, San Diego, CA, USA.
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23
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A Renaissance for Oncolytic Adenoviruses? Viruses 2023; 15:v15020358. [PMID: 36851572 PMCID: PMC9964350 DOI: 10.3390/v15020358] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/18/2023] [Accepted: 01/22/2023] [Indexed: 01/28/2023] Open
Abstract
In the 1990s, adenovirus became one of the first virus types to be genetically engineered to selectively destroy cancer cells. In the intervening years, the field of "oncolytic viruses" has slowly progressed and culminated in 2015 with the FDA approval of Talimogene laherparepvec, a genetically engineered herpesvirus, for the treatment of metastatic melanoma. Despite the slower progress in translating oncolytic adenovirus to the clinic, interest in the virus remains strong. Among all the clinical trials currently using viral oncolytic agents, the largest proportion of these are using recombinant adenovirus. Many trials are currently underway to use oncolytic virus in combination with immune checkpoint inhibitors (ICIs), and early results using oncolytic adenovirus in this manner are starting to show promise. Many of the existing strategies to engineer adenoviruses were designed to enhance selective tumor cell replication without much regard to interactions with the immune system. Adenovirus possesses a wide range of viral factors to attenuate both innate anti-viral pathways and immune cell killing. In this review, we summarize the strategies of oncolytic adenoviruses currently in clinical trials, and speculate how the mutational backgrounds of these viruses may impact upon the efficacy of these agents in oncolytic and immunotherapy. Despite decades of research on human adenoviruses, the interactions that these viruses have with the immune system remains one of the most understudied aspects of the virus and needs to be improved to rationally design the next generation of engineered viruses.
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24
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Nilson R, Krutzke L, Wienen F, Rojewski M, Zeplin PH, Funk W, Schrezenmeier H, Kochanek S, Kritzinger A. Evaluation of Human Mesenchymal Stromal Cells as Carriers for the Delivery of Oncolytic HAdV-5 to Head and Neck Squamous Cell Carcinomas. Viruses 2023; 15:218. [PMID: 36680258 PMCID: PMC9864513 DOI: 10.3390/v15010218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Human multipotent mesenchymal stromal cells (hMSCs) are of significant therapeutic interest due to their ability to deliver oncolytic adenoviruses to tumors. This approach is also investigated for targeting head and neck squamous cell carcinomas (HNSCCs). HAdV-5-HexPos3, a recently reported capsid-modified vector based on human adenovirus type 5 (HAdV-5), showed strongly improved infection of both hMSCs and the HNSCC cell line UM-SCC-11B. Given that, we generated life cycle-unmodified and -modified replication-competent HAdV-5-HexPos3 vector variants and analyzed their replication within bone marrow- and adipose tissue-derived hMSCs. Efficient replication was detected for both life cycle-unmodified and -modified vectors. Moreover, we analyzed the migration of vector-carrying hMSCs toward different HNSCCs. Although migration of hMSCs to HNSCC cell lines was confirmed in vitro, no homing of hMSCs to HNSCC xenografts was observed in vivo in mice and in ovo in a chorioallantoic membrane model. Taken together, our data suggest that HAdV-5-HexPos3 is a potent candidate for hMSC-based oncolytic therapy of HNSCCs. However, it also emphasizes the importance of generating optimized in vivo models for the evaluation of hMSC as carrier cells.
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Affiliation(s)
- Robin Nilson
- Department of Gene Therapy, University Medical Center Ulm, 89081 Ulm, Germany
| | - Lea Krutzke
- Department of Gene Therapy, University Medical Center Ulm, 89081 Ulm, Germany
| | - Frederik Wienen
- Department of Gene Therapy, University Medical Center Ulm, 89081 Ulm, Germany
| | - Markus Rojewski
- Institute for Transfusion Medicine, University Medical Center Ulm, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service, 89081 Ulm, Germany
| | - Philip Helge Zeplin
- Schlosspark Klinik Ludwigsburg, Privatklinik für Plastische und Ästhetische Chirurgie, 71638 Ludwigsburg, Germany
| | | | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Medical Center Ulm, 89081 Ulm, Germany
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service, 89081 Ulm, Germany
| | - Stefan Kochanek
- Department of Gene Therapy, University Medical Center Ulm, 89081 Ulm, Germany
| | - Astrid Kritzinger
- Department of Gene Therapy, University Medical Center Ulm, 89081 Ulm, Germany
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25
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Wienen F, Nilson R, Allmendinger E, Graumann D, Fiedler E, Bosse-Doenecke E, Kochanek S, Krutzke L. Affilin-based retargeting of adenoviral vectors to the epidermal growth factor receptor. BIOMATERIALS ADVANCES 2023; 144:213208. [PMID: 36442453 DOI: 10.1016/j.bioadv.2022.213208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Treatment of head and neck squamous cell carcinomas (HNSCC) by oncolytic adenoviral vectors holds promise as an efficient anti-cancer therapy. The epidermal growth factor receptor (EGFR) represents an attractive target receptor since it is frequently overexpressed in many types of HNSCC. METHODS To achieve EGFR-specific targeting by human adenovirus type 5 (HAdV-5) based vectors, the EGFR affinity ligand Affilin was covalently attached in a position specific manner either to the fiber or the hexon protein of the vector capsid. In vitro and in vivo studies investigated EGFR-specific cancer cell transduction, susceptibility to natural sequestration mechanisms, pharmacokinetics and biodistribution profiles of Affilin-decorated vectors. RESULTS Affilin-decorated vectors showed strongly enhanced and EGFR-specific cancer cell transduction in vitro and less susceptibility to known sequestration mechanisms of HAdV-5 particles. However, in vivo neither systemic nor intratumoral vector administration resulted in an improved transduction of EGFR-positive tumors. Comprehensive analyses indicated hampered EGFR-targeting by Affilin-decorated vectors was caused by rapid vector particle consumption due to binding to the murine EGFR, insufficient tumor vascularization and poor target accessibility for Affilin in the solid tumor caused by a pronounced tumor stroma. CONCLUSION In vitro studies yielded proof-of-concept results demonstrating that covalent attachment of a receptor-specific Affilin to the adenoviral capsid provides an effective and versatile tool to address cancer-specific target receptors by adenoviral vectors. Regarding EGFR as the vector target, off-target tissue transduction and low receptor accessibility within the tumor tissue prevented efficient tumor transduction by Affilin-decorated vectors, rendering EGFR a difficult-to-target receptor for adenoviral vectors.
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Affiliation(s)
- Frederik Wienen
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Germany
| | - Robin Nilson
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Germany
| | - Ellen Allmendinger
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Germany
| | - David Graumann
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Germany
| | - Erik Fiedler
- Navigo Proteins GmbH, Heinrich-Damerow-Str. 1, 06120 Halle, Germany
| | | | - Stefan Kochanek
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Germany
| | - Lea Krutzke
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Germany.
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26
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Klann PJ, Wang X, Elfert A, Zhang W, Köhler C, Güttsches AK, Jacobsen F, Weyen U, Roos A, Ehrke-Schulz E, Ehrhardt A, Vorgerd M, Bayer W. Seroprevalence of Binding and Neutralizing Antibodies against 39 Human Adenovirus Types in Patients with Neuromuscular Disorders. Viruses 2022; 15:79. [PMID: 36680119 PMCID: PMC9866721 DOI: 10.3390/v15010079] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/22/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
High pre-existing antibodies against viral vectors reduce their functionality and may lead to adverse complications. To circumvent this problem in future gene therapy approaches, we tested the seroprevalence of a large range of human adenovirus types in patients with neuromuscular disorders (NMDs) to find appropriate viral vector candidates for gene replacement therapy for NMDs. Binding and neutralizing antibodies against 39 human adenovirus types were tested in the sera of 133 patients with NMDs and 76 healthy controls aged 17-92 years. The influence of age, sex, and NMDs on antibody levels was analyzed. The seroprevalence of different adenoviruses in the cohort varied widely. The highest levels of binding antibodies were detected against HAdV-D27, -C1, -D24, -D70, -B14, -C6, -D13, -B34, and -E4, whereas the lowest reactivity was detected against HAdV-F41, -A31, -B11, -D75, -D8, -D65, -D26, -D80, and -D17. The highest neutralizing reactivity was observed against HAdV-B3, -C2, -E4, -C1, -G52, -C5, and -F41, whereas the lowest neutralizing reactivity was observed against HAdV-D74, -B34, -D73, -B37, -D48, -D13, -D75, -D8, -B35, and -B16. We detected no influence of sex and only minor differences between different age groups. Importantly, there were no significant differences between healthy controls and patients with NMDs. Our data show that patients with NMDs have very similar levels of binding and neutralizing antibodies against HAdV compared to healthy individuals, and we identified HAdV-A31, -B16, -B34, -B35, -D8, -D37, -D48, -D73, -D74, -D75, and -D80 as promising candidates for future vector development due to their low binding and neutralizing antibody prevalence.
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Affiliation(s)
- Patrick Julian Klann
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany
- Heimer Institute for Muscle Research, Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany
| | - Xiaoyan Wang
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany
| | - Anna Elfert
- Heimer Institute for Muscle Research, Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany
| | - Wenli Zhang
- Virology and Microbiology, Center for Medical Education and Research, Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Cornelia Köhler
- Clinics for Pediatrics and Adolescent Medicine, University Hospital Sankt Josef, Ruhr-University Bochum, 44791 Bochum, Germany
| | - Anne-Katrin Güttsches
- Heimer Institute for Muscle Research, Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany
| | - Frank Jacobsen
- Heimer Institute for Muscle Research, Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany
| | - Ute Weyen
- Heimer Institute for Muscle Research, Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany
| | - Andreas Roos
- Heimer Institute for Muscle Research, Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany
| | - Eric Ehrke-Schulz
- Virology and Microbiology, Center for Medical Education and Research, Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Anja Ehrhardt
- Virology and Microbiology, Center for Medical Education and Research, Department of Human Medicine, Faculty of Health, Witten/Herdecke University, 58453 Witten, Germany
| | - Matthias Vorgerd
- Heimer Institute for Muscle Research, Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789 Bochum, Germany
| | - Wibke Bayer
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany
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27
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Effects of pre-existing anti-adenovirus antibodies on transgene expression levels and therapeutic efficacies of arming oncolytic adenovirus. Sci Rep 2022; 12:21560. [PMID: 36513733 PMCID: PMC9747716 DOI: 10.1038/s41598-022-26030-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 12/08/2022] [Indexed: 12/15/2022] Open
Abstract
Oncolytic adenoviruses (OAds), most of which are based on species C human adenovirus serotype 5 (Ad5) (OAd5), have recently received much attention as potential anticancer agents. High seroprevalence of anti-Ad5 neutralizing antibodies is a major hurdle for Ad5-based gene therapy. However, the impacts of anti-Ad5 neutralizing antibodies on OAd5-mediated transgene expression in the tumor and antitumor effects remain to be fully elucidated. In this study, we examined the impact of anti-Ad5 neutralizing antibodies on the OAd5-mediated antitumor effects and OAd5-mediated transgene expression. The luciferase expression of OAd-tAIB-Luc, which contains the cytomegalovirus promoter-driven luciferase gene, was inhibited in human cultured cells in the presence of human serum. Although the inhibitory effects of human serum possessing the low anti-Ad5 neutralizing antibody titers were overcome by long-term infection, the in vitro tumor cell lysis activities of OAd-tAIB-Luc were entirely attenuated by human serum containing the high titers of anti-Ad5 neutralizing antibodies. OAd-tAIB-Luc-mediated luciferase expression in the subcutaneous tumors 3 days after administration and tumor growth suppression levels following intratumoral administration were significantly lower in mice possessing the high titers of anti-Ad5 neutralizing antibodies, compared to those in control mice. These results suggested that pre-existing anti-Ad5 antibodies attenuated both transgene expression and potential antitumor effects of OAd5 following intratumoral administration.
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28
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Huang L, Liu MQ, Wan CQ, Cheng NN, Su YB, Zheng YP, Peng XL, Yu JM, Fu YH, He JS. The protective immunity induced by intranasally inoculated serotype 63 chimpanzee adenovirus vector expressing human respiratory syncytial virus prefusion fusion glycoprotein in BALB/c mice. Front Microbiol 2022; 13:1041338. [PMID: 36466668 PMCID: PMC9716990 DOI: 10.3389/fmicb.2022.1041338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 10/21/2022] [Indexed: 12/23/2023] Open
Abstract
Human respiratory syncytial virus (RSV) is a ubiquitous pediatric pathogen causing serious lower respiratory tract disease worldwide. No licensed vaccine is currently available. In this work, the coding gene for mDS-Dav1, the full-length and prefusion conformation RSV fusion glycoprotein (F), was designed by introducing the stabilized prefusion F (preF) mutations from DS-Cav1 into the encoding gene of wild-type RSV (wtRSV) F protein. The recombinant adenovirus encoding mDS-Cav1, rChAd63-mDS-Cav1, was constructed based on serotype 63 chimpanzee adenovirus vector and characterized in vitro. After immunizing mice via intranasal route, the rChAd63-mDS-Cav1 induced enhanced neutralizing antibody and F-specific CD8+ T cell responses as well as good immune protection against RSV challenge with the absence of enhanced RSV disease (ERD) in BALB/c mice. The results indicate that rChAd63-mDS-Cav1 is a promising mucosal vaccine candidate against RSV infection and warrants further development.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yuan-Hui Fu
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, China
| | - Jin-Sheng He
- College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, China
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29
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Analysis of the Prevalence of Binding and Neutralizing Antibodies against 39 Human Adenovirus Types in Student Cohorts Reveals Low-Prevalence Types and a Decline in Binding Antibody Levels during the SARS-CoV-2 Pandemic. J Virol 2022; 96:e0113322. [DOI: 10.1128/jvi.01133-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Vectors based on human adenoviruses (HAdVs) are important for the development of novel immunizations, oncolytic therapies, and gene therapies. The use of HAdV-based vaccines against Ebola virus, the rapid adaptation of the vector technology for vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their very good efficacy have shown the great potential of HAdV-based vaccines.
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30
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Solis-Andrade KI, Gonzalez-Ortega O, Govea-Alonso DO, Comas-Garcia M, Rosales-Mendoza S. Production and Purification of LTB-RBD: A Potential Antigen for Mucosal Vaccine Development against SARS-CoV-2. Vaccines (Basel) 2022; 10:vaccines10101759. [PMID: 36298624 PMCID: PMC9609574 DOI: 10.3390/vaccines10101759] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/27/2022] [Accepted: 10/17/2022] [Indexed: 11/16/2022] Open
Abstract
Most of the current SARS-CoV-2 vaccines are based on parenteral immunization targeting the S protein. Although protective, such vaccines could be optimized by inducing effective immune responses (neutralizing IgA responses) at the mucosal surfaces, allowing them to block the virus at the earliest stage of the infectious cycle. Herein a recombinant chimeric antigen called LTB-RBD is described, which comprises the B subunit of the heat-labile enterotoxin from E. coli and a segment of the RBD from SARS-CoV-2 (aa 439-504, carrying B and T cell epitopes) from the Wuhan sequence and the variant of concern (VOC)—delta. Since LTB is a mucosal adjuvant, targeting the GM1 receptor at the surface and facilitating antigen translocation to the submucosa, this candidate will help in designing mucosal vaccines (i.e., oral or intranasal formulations). LTB-RBD was produced in E. coli and purified to homogeneity by IMAC and IMAC-anionic exchange chromatography. The yields in terms of pure LTB-RBD were 1.2 mg per liter of culture for the Wuhan sequence and 3.5 mg per liter for the delta variant. The E. coli-made LTB-RBD induced seric IgG responses and IgA responses in the mouth and feces of mice when subcutaneously administered and intestinal and mouth IgA responses when administered nasally. The expression and purification protocols developed for LTB-RBD constitute a robust system to produce vaccine candidates against SARS-CoV-2 and its variants, offering a low-cost production system with no tags and with ease of adaptation to new variants. The E. coli-made LTB-RBD will be the basis for developing mucosal vaccine candidates capable of inducing sterilizing immunity against SARS-CoV-2.
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Affiliation(s)
- Karla I. Solis-Andrade
- Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Dr. Manuel Nava 6, San Luis Potosí 78210, Mexico
- Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, Av. Sierra Leona 550, Lomas 2ª. Sección, San Luis Potosí 78210, Mexico
| | - Omar Gonzalez-Ortega
- Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Dr. Manuel Nava 6, San Luis Potosí 78210, Mexico
- Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, Av. Sierra Leona 550, Lomas 2ª. Sección, San Luis Potosí 78210, Mexico
| | - Dania O. Govea-Alonso
- Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Dr. Manuel Nava 6, San Luis Potosí 78210, Mexico
- Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, Av. Sierra Leona 550, Lomas 2ª. Sección, San Luis Potosí 78210, Mexico
| | - Mauricio Comas-Garcia
- Sección de Microscopía de Alta Resolución, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, Av. Sierra Leona 550, Lomas 2ª. Sección, San Luis Potosí 78210, Mexico
- Sección de Genómica Médica, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, Av. Sierra Leona 550, Lomas 2ª. Sección, San Luis Potosí 78210, Mexico
- Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, Av. Parque Chapultepec 1570, San Luis Potosí 78210, Mexico
| | - Sergio Rosales-Mendoza
- Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, Av. Dr. Manuel Nava 6, San Luis Potosí 78210, Mexico
- Sección de Biotecnología, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, Av. Sierra Leona 550, Lomas 2ª. Sección, San Luis Potosí 78210, Mexico
- Correspondence: ; Tel./Fax: +52-444-826-2440
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Tsilingiris D, Vallianou NG, Karampela I, Muscogiuri G, Dalamaga M. Use of adenovirus type-5 vector vaccines in COVID-19: potential implications for metabolic health? Minerva Endocrinol (Torino) 2022; 47:264-269. [PMID: 35621112 DOI: 10.23736/s2724-6507.22.03797-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Propedeutic Internal Medicine, School of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece -
| | - Natalia G Vallianou
- First Department of Internal Medicine, Evangelismos General Hospital, Athens, Greece
| | - Irene Karampela
- Second Department of Critical Care, Medical School, Attikon General University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Giovanna Muscogiuri
- Unit of Endocrinology, Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy.,Unit of Endocrinology, Department of Clinical Medicine and Surgery, School of Medicine, Centro Italiano per la Cura e il Benessere del Patiente con Obesità (CIBO), University of Naples Federico II, Naples, Italy
| | - Maria Dalamaga
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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32
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Spunde K, Korotkaja K, Zajakina A. Recombinant Viral Vectors for Therapeutic Programming of Tumour Microenvironment: Advantages and Limitations. Biomedicines 2022; 10:2142. [PMID: 36140243 PMCID: PMC9495732 DOI: 10.3390/biomedicines10092142] [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: 08/01/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/30/2022] Open
Abstract
Viral vectors have been widely investigated as tools for cancer immunotherapy. Although many preclinical studies demonstrate significant virus-mediated tumour inhibition in synergy with immune checkpoint molecules and other drugs, the clinical success of viral vector applications in cancer therapy currently is limited. A number of challenges have to be solved to translate promising vectors to clinics. One of the key elements of successful virus-based cancer immunotherapy is the understanding of the tumour immune state and the development of vectors to modify the immunosuppressive tumour microenvironment (TME). Tumour-associated immune cells, as the main component of TME, support tumour progression through multiple pathways inducing resistance to treatment and promoting cancer cell escape mechanisms. In this review, we consider DNA and RNA virus vectors delivering immunomodulatory genes (cytokines, chemokines, co-stimulatory molecules, antibodies, etc.) and discuss how these viruses break an immunosuppressive cell development and switch TME to an immune-responsive "hot" state. We highlight the advantages and limitations of virus vectors for targeted therapeutic programming of tumour immune cell populations and tumour stroma, and propose future steps to establish viral vectors as a standard, efficient, safe, and non-toxic cancer immunotherapy approach that can complement other promising treatment strategies, e.g., checkpoint inhibitors, CAR-T, and advanced chemotherapeutics.
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Affiliation(s)
| | | | - Anna Zajakina
- Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Ratsupites Str. 1, k.1, LV-1067 Riga, Latvia
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33
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Yang M, Olaoba OT, Zhang C, Kimchi ET, Staveley-O’Carroll KF, Li G. Cancer Immunotherapy and Delivery System: An Update. Pharmaceutics 2022; 14:1630. [PMID: 36015256 PMCID: PMC9413869 DOI: 10.3390/pharmaceutics14081630] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/26/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023] Open
Abstract
With an understanding of immunity in the tumor microenvironment, immunotherapy turns out to be a powerful tool in the clinic to treat many cancers. The strategies applied in cancer immunotherapy mainly include blockade of immune checkpoints, adoptive transfer of engineered cells, such as T cells, natural killer cells, and macrophages, cytokine therapy, cancer vaccines, and oncolytic virotherapy. Many factors, such as product price, off-target side effects, immunosuppressive tumor microenvironment, and cancer cell heterogeneity, affect the treatment efficacy of immunotherapies against cancers. In addition, some treatments, such as chimeric antigen receptor (CAR) T cell therapy, are more effective in treating patients with lymphoma, leukemia, and multiple myeloma rather than solid tumors. To improve the efficacy of targeted immunotherapy and reduce off-target effects, delivery systems for immunotherapies have been developed in past decades using tools such as nanoparticles, hydrogel matrix, and implantable scaffolds. This review first summarizes the currently common immunotherapies and their limitations. It then synopsizes the relative delivery systems that can be applied to improve treatment efficacy and minimize side effects. The challenges, frontiers, and prospects for applying these delivery systems in cancer immunotherapy are also discussed. Finally, the application of these approaches in clinical trials is reviewed.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Olamide Tosin Olaoba
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA
- Department of Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO 65212, USA
| | - Chunye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, USA
| | - Eric T. Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
- Department of Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO 65212, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
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Watson-Levings RS, Palmer GD, Levings PP, Dacanay EA, Evans CH, Ghivizzani SC. Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation. Front Bioeng Biotechnol 2022; 10:901317. [PMID: 35837555 PMCID: PMC9274665 DOI: 10.3389/fbioe.2022.901317] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
In orthopaedics, gene-based treatment approaches are being investigated for an array of common -yet medically challenging- pathologic conditions of the skeletal connective tissues and structures (bone, cartilage, ligament, tendon, joints, intervertebral discs etc.). As the skeletal system protects the vital organs and provides weight-bearing structural support, the various tissues are principally composed of dense extracellular matrix (ECM), often with minimal cellularity and vasculature. Due to their functional roles, composition, and distribution throughout the body the skeletal tissues are prone to traumatic injury, and/or structural failure from chronic inflammation and matrix degradation. Due to a mixture of environment and endogenous factors repair processes are often slow and fail to restore the native quality of the ECM and its function. In other cases, large-scale lesions from severe trauma or tumor surgery, exceed the body’s healing and regenerative capacity. Although a wide range of exogenous gene products (proteins and RNAs) have the potential to enhance tissue repair/regeneration and inhibit degenerative disease their clinical use is hindered by the absence of practical methods for safe, effective delivery. Cumulatively, a large body of evidence demonstrates the capacity to transfer coding sequences for biologic agents to cells in the skeletal tissues to achieve prolonged delivery at functional levels to augment local repair or inhibit pathologic processes. With an eye toward clinical translation, we discuss the research progress in the primary injury and disease targets in orthopaedic gene therapy. Technical considerations important to the exploration and pre-clinical development are presented, with an emphasis on vector technologies and delivery strategies whose capacity to generate and sustain functional transgene expression in vivo is well-established.
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Affiliation(s)
- Rachael S. Watson-Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Glyn D. Palmer
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Padraic P. Levings
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - E. Anthony Dacanay
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christopher H. Evans
- Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MI, United States
| | - Steven C. Ghivizzani
- Department of Orthopaedic Surgery and Sports Medicine, University of Florida College of Medicine, Gainesville, FL, United States
- *Correspondence: Steven C. Ghivizzani,
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35
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Green-Tripp G, Nattress C, Halldén G. Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses. Front Mol Biosci 2022; 9:901392. [PMID: 35813830 PMCID: PMC9263221 DOI: 10.3389/fmolb.2022.901392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/24/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer (BC) is the most common cancer globally, accounting for 685,000 deaths in 2020. Triple-negative breast cancers (TNBC) lack oestrogen (ER) and progesterone (PR) hormone receptor expression and HER2 overexpression. TNBC represent 10–15% of all BC with high incidence in women under 50-years old that have BRCA mutations, and have a dismal prognosis. African American and Hispanic women are at higher risk partly due to the common occurrence of BRCA mutations. The standard treatment for TNBC includes surgery, radiotherapy, and chemotherapy although, resistance to all standard-of-care therapies eventually develops. It is crucial to identify and develop more efficacious therapeutics with different mechanisms of action to improve on survival in these women. Recent findings with oncolytic adenoviruses (OAds) may generate a new strategy to improve on the outcomes for women afflicted by TNBC and other types of BC. OAds are genetically engineered to selectively lyse, eliminate and recruit the host antitumour immune responses, leaving normal cells unharmed. The most common modifications are deletions in the early gene products including the E1B55 KDa protein, specific regions of the E1A protein, or insertion of tumour-specific promoters. Clinical trials using OAds for various adenocarcinomas have not yet been sufficiently evaluated in BC patients. Preclinical studies demonstrated efficacy in BC cell lines, including TNBC cells, with promising novel adenoviral mutants. Here we review the results reported for the most promising OAds in preclinical studies and clinical trials administered alone and in combination with current standard of care or with novel therapeutics. Combinations of OAds with small molecule drugs targeting the epidermal growth factor receptor (EGFR), androgen receptor (AR), and DNA damage repair by the novel PARP inhibitors are currently under investigation with reported enhanced efficacy. The combination of the PARP-inhibitor Olaparib with OAds showed an impressive anti-tumour effect. The most promising findings to date are with OAds in combination with antibodies towards the immune checkpoints or expression of cytokines from the viral backbone. Although safety and efficacy have been demonstrated in numerous clinical trials and preclinical studies with cancer-selective OAds, further developments are needed to eliminate metastatic lesions, increase immune activation and intratumoural viral spread. We discuss shortcomings of the OAds and potential solutions for improving on patient outcomes.
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Affiliation(s)
- Gabriela Green-Tripp
- Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Callum Nattress
- Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
- Cell Communication Lab, Department of Oncology, University College London Cancer Institute, London, United Kingdom
| | - Gunnel Halldén
- Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
- *Correspondence: Gunnel Halldén,
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36
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Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective. Pharmaceutics 2022; 14:pharmaceutics14061287. [PMID: 35745859 PMCID: PMC9231068 DOI: 10.3390/pharmaceutics14061287] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/09/2022] [Accepted: 06/15/2022] [Indexed: 02/06/2023] Open
Abstract
Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack of natural history information, the limits of currently available preclinical models, and the wide range of phenotypic presentations seen in MD patients have all hampered the development of effective therapies. The growing number of pre-clinical and clinical trials over the last decade has shown that gene therapy is a viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism and efficient delivery, transgene expression, and immunotoxicity. This manuscript offers a comprehensive overview of the state of the art of gene therapy in MD, addressing the main challenges, the most feasible solutions, and the future perspectives of the field.
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37
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Nilson R, Lübbers O, Schmidt CQ, Rojewski M, Zeplin PH, Funk W, Schrezenmeier H, Kritzinger A, Kochanek S, Krutzke L. Hexon modification of human adenovirus type 5 vectors enables efficient transduction of human multipotent mesenchymal stromal cells. Mol Ther Methods Clin Dev 2022; 25:96-110. [PMID: 35402633 PMCID: PMC8956844 DOI: 10.1016/j.omtm.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/04/2022] [Indexed: 11/29/2022]
Abstract
In adenovirus type 5 (HAdV-5)-derived viral vectors, the fiber protein has been the preferred locale for modifications to alter the natural viral tropism. Hexon, the most abundant capsid protein, has rarely been used for retargeting purposes, likely because the insertion of larger targeting peptides into Hexon often interferes with the assembly of the viral capsid. We previously observed that positively charged molecules enhance the transduction of human multipotent mesenchymal stromal cells (hMSCs)—a cell type of significant interest for clinical development but inefficiently transduced by unmodified HAdV-5-based vectors. As efficient HAdV-5-mediated gene transfer would greatly increase the therapeutic potential of hMSCs, we tested the hypothesis that introducing positively charged amino acids into Hexon might enhance the transduction of hMSCs, enabling efficient expression of selected transgenes. From the constructs that could be rescued as functional virions, one (HAdV-5-HexPos3) showed striking transduction of hMSCs with up to 500-fold increased efficiency. Evaluation of the underlying mechanism identified heparan sulfate proteoglycans (HSPGs) to be essential for virus uptake by the cells. The ease and efficiency of transduction of hMSCs with this vector will facilitate the development of genetically modified hMSCs as therapeutic vehicles in different disciplines, including oncology or regenerative medicine.
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Affiliation(s)
- Robin Nilson
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Olivia Lübbers
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Christoph Q Schmidt
- Department of Applied Immunology and Immunopharmacology, University Medical Center Ulm, Ulm, Germany
| | - Markus Rojewski
- Institute for Transfusion Medicine, University Medical Center Ulm, Ulm, Germany.,Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service, Ulm, Germany
| | - Philip Helge Zeplin
- Schlosspark Klinik Ludwigsburg, Privatklinik für Plastische und Ästhetische Chirurgie, Ludwigsburg, Germany
| | | | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Medical Center Ulm, Ulm, Germany.,Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service, Ulm, Germany
| | - Astrid Kritzinger
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Stefan Kochanek
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
| | - Lea Krutzke
- Department of Gene Therapy, University of Ulm, Helmholtzstraße 8/1, 89081 Ulm, Baden-Württemberg, Germany
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38
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Jt S, M H, Wam B, Ac B, Sa N. Adenoviral vectors for cardiovascular gene therapy applications: a clinical and industry perspective. J Mol Med (Berl) 2022; 100:875-901. [PMID: 35606652 PMCID: PMC9126699 DOI: 10.1007/s00109-022-02208-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 04/29/2022] [Accepted: 05/10/2022] [Indexed: 11/29/2022]
Abstract
Abstract Despite the development of novel pharmacological treatments, cardiovascular disease morbidity and mortality remain high indicating an unmet clinical need. Viral gene therapy enables targeted delivery of therapeutic transgenes and represents an attractive platform for tackling acquired and inherited cardiovascular diseases in the future. Current cardiovascular gene therapy trials in humans mainly focus on improving cardiac angiogenesis and function. Encouragingly, local delivery of therapeutic transgenes utilising first-generation human adenovirus serotype (HAd)-5 is safe in the short term and has shown some efficacy in drug refractory angina pectoris and heart failure with reduced ejection fraction. Despite this success, systemic delivery of therapeutic HAd-5 vectors targeting cardiovascular tissues and internal organs is limited by negligible gene transfer to target cells, elimination by the immune system, liver sequestration, off-target effects, and episomal degradation. To circumvent these barriers, cardiovascular gene therapy research has focused on determining the safety and efficacy of rare alternative serotypes and/or genetically engineered adenoviral capsid protein-modified vectors following local or systemic delivery. Pre-clinical studies have identified several vectors including HAd-11, HAd-35, and HAd-20–42-42 as promising platforms for local and systemic targeting of vascular endothelial and smooth muscle cells. In the past, clinical gene therapy trials were often restricted by limited scale-up capabilities of gene therapy medicinal products (GTMPs) and lack of regulatory guidance. However, significant improvement of industrial GTMP scale-up and purification, development of novel producer cell lines, and issuing of GTMP regulatory guidance by national regulatory health agencies have addressed many of these challenges, creating a more robust framework for future adenoviral-based cardiovascular gene therapy. In addition, this has enabled the mass roll out of adenovirus vector-based COVID-19 vaccines. Key messages
First-generation HAd-5 vectors are widely used in cardiovascular gene therapy. HAd-5-based gene therapy was shown to lead to cardiac angiogenesis and improved function. Novel HAd vectors may represent promising transgene carriers for systemic delivery. Novel methods allow industrial scale-up of rare/genetically altered Ad serotypes. National regulatory health agencies have issued guidance on GMP for GTMPs.
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Affiliation(s)
- Schwartze Jt
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
| | - Havenga M
- Batavia Biosciences B.V., Bioscience Park Leiden, Zernikedreef 16, 2333, CL, Leiden, The Netherlands
| | - Bakker Wam
- Batavia Biosciences B.V., Bioscience Park Leiden, Zernikedreef 16, 2333, CL, Leiden, The Netherlands
| | - Bradshaw Ac
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Nicklin Sa
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
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Majhen D. Human adenovirus type 26 basic biology and its usage as vaccine vector. Rev Med Virol 2022; 32:e2338. [PMID: 35278248 DOI: 10.1002/rmv.2338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 11/10/2022]
Abstract
Due to their nature, adenoviruses have been recognised as promising candidates for vaccine vector development. Since they mimic natural infection, recombinant adenovirus vectors have been proven as ideal shuttles to deliver foreign transgenes aiming at inducing both humoral and cellular immune response. In addition, a potent adjuvant effect can be exerted due to the adenovirus inherent stimulation of various elements of innate and adaptive immunity. Due to its low seroprevalence in humans as well as induction of favourable immune response to inserted transgene, human adenovirus type 26 (HAdV-D26) has been recognised as a promising platform for vaccine vector development and is studied in number of completed or ongoing clinical studies. Very recently HAdV-D26 based Ebola and Covid-19 vaccines were approved for medical use. In this review, current state of the art regarding HAdV-D26 basic biology and its usage as vaccine vector will be discussed.
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Affiliation(s)
- Dragomira Majhen
- Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
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40
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Middle East Respiratory Syndrome coronavirus vaccine development: updating clinical studies using platform technologies. J Microbiol 2022; 60:238-246. [PMID: 35089585 PMCID: PMC8795722 DOI: 10.1007/s12275-022-1547-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/12/2021] [Accepted: 12/15/2021] [Indexed: 12/25/2022]
Abstract
Middle East Respiratory Syndrome coronavirus (MERS-CoV), a contagious zoonotic virus, causes severe respiratory infection with a case fatality rate of approximately 35% in humans. Intermittent sporadic cases in communities and healthcare facility outbreaks have continued to occur since its first identification in 2012. The World Health Organization has declared MERS-CoV a priority pathogen for worldwide research and vaccine development due to its epidemic potential and the insufficient countermeasures available. The Coalition for Epidemic Preparedness Innovations is supporting vaccine development against emerging diseases, including MERS-CoV, based on platform technologies using DNA, mRNA, viral vector, and protein subunit vaccines. In this paper, we review the usefulness and structure of a spike glycoprotein as a MERS-CoV vaccine candidate molecule, and provide an update on the status of MERS-CoV vaccine development. Vaccine candidates based on both DNA and viral vectors coding MERS-CoV spike gene have completed early phase clinical trials. A harmonized approach is required to assess the immunogenicity of various candidate vaccine platforms. Platform technologies accelerated COVID-19 vaccine development and can also be applied to developing vaccines against other emerging viral diseases.
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41
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The Application of Polycaprolactone Scaffolds with Poly(ε-caprolactone)–Poly(ethylene glycol)–Poly(ε-caprolactone) Loaded on Kidney Cell Culture. MATERIALS 2022; 15:ma15041591. [PMID: 35208131 PMCID: PMC8880131 DOI: 10.3390/ma15041591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 02/04/2023]
Abstract
Human embryonic kidney cells are the host of adenovirus type-5 (Ad5) amplification. An Ad5-vector-based COVID-19 vaccine has been proven to be tolerated and immunogenic in healthy adults. Therefore, a rationally designed scaffold for culturing human embryonic kidney cells is useful for further studying its mechanism of action. Herein, a three-dimensional layered reticulated polycaprolactone (PCL) scaffold coated with poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCEC) was developed to proliferate human embryonic kidney cells and to be used to amplify the Ad5 vector. The results indicate that PCEC improves the hydrophilicity and the cell culture ability of PCL cell culture scaffolds, resulting in a three times higher cell proliferation ratio of human embryonic kidney cells compared with those grown on bare PCL cell culture scaffolds. Meanwhile, the cytotoxicity test results showed that the scaffold material is noncytotoxic. This work provides an effective and scalable method for the in-depth study of adenoviruses.
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Humoral and Cellular Responses to COVID-19 Vaccines in SARS-CoV-2 Infection-Naïve and -Recovered Korean Individuals. Vaccines (Basel) 2022; 10:vaccines10020332. [PMID: 35214791 PMCID: PMC8878120 DOI: 10.3390/vaccines10020332] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 11/17/2022] Open
Abstract
In the face of a global COVID-19 vaccine shortage, an efficient vaccination strategy is required. Therefore, the immunogenicity of single or double COVID-19 vaccination doses (ChAdOX1, BNT162b2, or mRNA-1273) of SARS-CoV-2-recovered individuals was compared to that of unvaccinated individuals with SARS-CoV-2 infection at least one year post-convalescence. Moreover, the immunogenicity of SARS-CoV-2-naïve individuals vaccinated with a complete schedule of Ad26.CoV2.S, ChAdOX1, BNT162b2, mRNA-1273, or ChAdOX1/BNT162b2 vaccines was evaluated. Anti-SARS-CoV-2 S1 IgG antibody (S1-IgG), pseudotyped virus-neutralizing antibody titer (pVNT50), and IFN-γ ELISpot counts were measured. Humoral immune responses were significantly higher in vaccinated than in unvaccinated recovered individuals, with a 43-fold increase in the mean pVNT50 values. However, there was no significant difference in the pVNT50 and IFN-γ ELISpot values between the single- and double-dose regimens. In SARS-CoV-2-naïve individuals, antibody responses varied according to the vaccine type: BNT162b2 and mRNA-1273 induced similar levels of S1-IgG to those observed in vaccinated, convalescent individuals; in contrast, pVNT50 was much lower in SARS-CoV-2-naïve vaccinees than in vaccinated recovered individuals. Therefore, a single dose of ChAdOX1, BNT162b2, or mRNA-1273 vaccines would be a good alternative for recovered individuals instead of a double-dose regimen.
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Ex Vivo and In Vivo CD46 Receptor Utilization by Species D Human Adenovirus Serotype 26 (HAdV26). J Virol 2022; 96:e0082621. [PMID: 34787457 PMCID: PMC8826919 DOI: 10.1128/jvi.00826-21] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.
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Adenovirus-α-defensin complexes induce NLRP3-associated maturation of human phagocytes via TLR4 engagement. J Virol 2022; 96:e0185021. [PMID: 35080426 DOI: 10.1128/jvi.01850-21] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Intramuscular delivery of human adenovirus (HAdV)-based vaccines leads to rapid recruitment of neutrophils, which then release antimicrobial peptides/proteins (AMPs). How these AMPs influence vaccine efficacy over the subsequent 24 h is poorly understood. In this study, we asked if human neutrophil protein 1 (HNP-1), an α-defensin that influences the direct and indirect innate immune responses to a range of pathogens, impacts the response of human phagocytes to three HAdV species/types (HAdV-C5, -D26, -B35). We show that HNP-1 binds to the capsids, redirects HAdV-C5, -D26, -B35 to Toll-like receptor 4 (TLR4), which leads to internalization, an NLRP3-mediated inflammasome response, and IL-1β release. Surprisingly, IL-1β release was not associated with notable disruption of plasma membrane integrity. These data further our understanding of HAdV vaccine immunogenicity and may provide pathways to extend the efficacy. Importance This study examines the interactions between danger-associated molecular patterns and human adenoviruses and its impact on vaccines. HAdVs and HNP-1 can interact, these interactions will modify the response of antigen-presenting cells., which will influence vaccine efficacy.
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Tate SJ, Van de Sande L, Ceelen WP, Torkington J, Parker AL. The Feasibility of Pressurised Intraperitoneal Aerosolised Virotherapy (PIPAV) to Administer Oncolytic Adenoviruses. Pharmaceutics 2021; 13:2043. [PMID: 34959325 PMCID: PMC8708803 DOI: 10.3390/pharmaceutics13122043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/07/2021] [Accepted: 11/25/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The prognosis of patients with peritoneal metastases is poor. Treatment options are limited because systemically delivered chemotherapy is not usually effective in this type of disease. Pressurised intraperitoneal aerosolised chemotherapy (PIPAC) is a recently developed alternative technology for delivering intraperitoneal chemotherapy, potentially enhancing treatment efficacy. Here, we assess the feasibility of pressurised intraperitoneal aerosolised virotherapy (PIPAV) to deliver a different class of anticancer agents, oncolytic adenoviruses, in vitro and in vivo. METHODS Adenoviral vectors expressing reporter genes green fluorescence protein (Ad5.GFP) or firefly luciferase (Ad5.Luc) were subject to pressurised aerosolisation. The ability of the virus to survive PIPAV was assessed in vitro and in vivo by monitoring reporter gene activity. Wistar rats subjected to PIPAV were assessed for any adverse procedure related events. RESULTS In vitro transduction assays demonstrated that Ad5 retained viability following pressurised aerosolisation and could transduce permissive cells equally effectively as non-aerosolised control vector. PIPAV was well tolerated in rats, although minimal transduction was observed following intraperitoneal administration. CONCLUSIONS PIPAV appears viable and well tolerated, though in vivo efficacy requires further optimisation.
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Affiliation(s)
- Sophia J. Tate
- Division of Cancer and Genetics, Cardiff University, Cardiff CF14 4XN, UK;
| | - Leen Van de Sande
- Department of Human Structure and Repair, Ghent University, B-9000 Ghent, Belgium; (L.V.d.S.); (W.P.C.)
| | - Wim P. Ceelen
- Department of Human Structure and Repair, Ghent University, B-9000 Ghent, Belgium; (L.V.d.S.); (W.P.C.)
| | - Jared Torkington
- Department of General Surgery, University Hospital of Wales, Cardiff CF14 4XW, UK;
| | - Alan L. Parker
- Division of Cancer and Genetics, Cardiff University, Cardiff CF14 4XN, UK;
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Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials. PLoS Pathog 2021; 17:e1010016. [PMID: 34843602 PMCID: PMC8659322 DOI: 10.1371/journal.ppat.1010016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 12/09/2021] [Accepted: 10/07/2021] [Indexed: 01/07/2023] Open
Abstract
Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies. Trial registration: ClinicalTrials.gov NCT00801697, NCT00961883, NCT02207920, NCT00125970, NCT02852005).
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Wang Y, Zhang Z, Shang L, Gao H, Du X, Li F, Gao Y, Qi G, Guo W, Qu Z, Dong T. Immunological Study of Reconstructed Common Ancestral Sequence of Adenovirus Hexon Protein. Front Microbiol 2021; 12:717047. [PMID: 34777273 PMCID: PMC8578728 DOI: 10.3389/fmicb.2021.717047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 10/08/2021] [Indexed: 11/16/2022] Open
Abstract
Aim: To reconstruct the ancestral sequence of human adenoviral hexon protein by combining sequence variations and structural information. And to provide a candidate hexon protein for developing new adenoviral vector capable of escaping the pre-existing immunity in healthy populations. Methods: The sequences of 74 adenovirus-type strains were used to predict the ancestral sequence of human adenovirus hexon protein using FastML and MEGA software. The three-dimensional structure model was built using homology modeling methods. The immunological features of ancestral loop 1 and loop 2 regions of sequences were tested using protein segments expressed in a prokaryotic expression system and polypeptides synthesized with human serum samples. Results: The tower region of the hexon protein had the highest sequence variability, while the neck and base regions remained constant among different types. The modern strains successfully predicted the common ancestral sequence of the human adenovirus hexon. The positive sera against neutralizing epitopes on the common ancestor of adenoviral hexon were relatively rare among healthy adults. Conclusion: The existing strains inferred the common ancestor of human adenoviruses, with epitopes never observed in the current human strains. The predicted common ancestor hexon is a good prospect in the improvement of adenovirus vectors.
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Affiliation(s)
- Yingchen Wang
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China
| | - Zhe Zhang
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China
| | - Lei Shang
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China
| | - Hong Gao
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China
| | - Xiqiao Du
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China.,Harbin Center for Disease Control and Prevention, Harbin, China
| | - Falong Li
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China
| | - Ya Gao
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China
| | - Guiyun Qi
- The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Weiyuan Guo
- The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Zhangyi Qu
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China.,Department of Natural Focus Disease Control, Institute of Environment-Associated Disease, Sino-Russia Joint Medical Research Center, Harbin Medical University, Harbin, China
| | - Tuo Dong
- Department of Microbiology, Public Health College, Harbin Medical University, Harbin, China
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Geurink L, van Tricht E, van der Burg D, Scheppink G, Pajic B, Dudink J, Sänger-van de Griend C. Sixteen capillary electrophoresis applications for viral vaccine analysis. Electrophoresis 2021; 43:1068-1090. [PMID: 34739151 DOI: 10.1002/elps.202100269] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/14/2021] [Accepted: 10/25/2021] [Indexed: 12/14/2022]
Abstract
A broad range of CE applications from our organization is reviewed to give a flavor of the use of CE within the field of vaccine analyses. Applicability of CE for viral vaccine characterization, and release and stability testing of seasonal influenza virosomal vaccines, universal subunit influenza vaccines, Sabin inactivated polio vaccines (sIPV), and adenovirus vector vaccines were demonstrated. Diverse CZE, CE-SDS, CGE, and cIEF methods were developed, validated, and applied for virus, protein, posttranslational modifications, DNA, and excipient concentration determinations, as well as for the integrity and composition verifications, and identity testing (e.g., CZE for intact virus particles, CE-SDS application for hemagglutinin quantification and influenza strain identification, chloride or bromide determination in process samples). Results were supported by other methods such as RP-HPLC, dynamic light scattering (DLS), and zeta potential measurements. Overall, 16 CE methods are presented that were developed and applied, comprising six adenovirus methods, five viral protein methods, and methods for antibodies determination of glycans, host cell-DNA, excipient chloride, and process impurity bromide. These methods were applied to support in-process control, release, stability, process- and product characterization and development, and critical reagent testing. Thirteen methods were validated. Intact virus particles were analyzed at concentrations as low as 0.8 pmol/L. Overall, CE took viral vaccine testing beyond what was previously possible, improved process and product understanding, and, in total, safety, efficacy, and quality.
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Affiliation(s)
- Lars Geurink
- Janssen Vaccines and Prevention B.V., CN Leiden, The Netherlands.,Department of Medicinal Chemistry, Faculty of Pharmacy, Biomedical Centre, Uppsala University, Uppsala, Sweden
| | - Ewoud van Tricht
- Janssen Vaccines and Prevention B.V., CN Leiden, The Netherlands
| | | | - Gerard Scheppink
- Janssen Vaccines and Prevention B.V., CN Leiden, The Netherlands
| | - Bojana Pajic
- Janssen Vaccines and Prevention B.V., CN Leiden, The Netherlands
| | - Justin Dudink
- Janssen Vaccines and Prevention B.V., CN Leiden, The Netherlands
| | - Cari Sänger-van de Griend
- Janssen Vaccines and Prevention B.V., CN Leiden, The Netherlands.,Department of Medicinal Chemistry, Faculty of Pharmacy, Biomedical Centre, Uppsala University, Uppsala, Sweden.,Kantisto B.V., Baarn, The Netherlands
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Lanini S, Capone S, Antinori A, Milleri S, Nicastri E, Camerini R, Agrati C, Castilletti C, Mori F, Sacchi A, Matusali G, Gagliardini R, Ammendola V, Cimini E, Grazioli F, Scorzolini L, Napolitano F, Plazzi MM, Soriani M, De Luca A, Battella S, Sommella A, Contino AM, Barra F, Gentile M, Raggioli A, Shi Y, Girardi E, Maeurer M, Capobianchi MR, Vaia F, Piacentini M, Kroemer G, Vitelli A, Colloca S, Folgori A, Ippolito G, Ottou S, Vita S, Vergori A, D'Abramo A, Petrecchia A, Montaldo C, Scalise E, Grassi G, Casetti R, Bordoni V, Notari S, Colavita F, Meschi S, Lapa D, Bordi L, Murachelli S, Tambasco T, Grillo A, Masone E, Marchioni E, Bardhi D, Porzio O, Cocca F, Murachelli S, Turrini I, Malescio F, Ziviani L, Lawlor R, Poli F, Martire F, Zamboni D, Mazzaferri F. GRAd-COV2, a gorilla adenovirus-based candidate vaccine against COVID-19, is safe and immunogenic in younger and older adults. Sci Transl Med 2021; 14:eabj1996. [PMID: 34698501 DOI: 10.1126/scitranslmed.abj1996] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Simone Lanini
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | - Andrea Antinori
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | - Stefano Milleri
- Centro Ricerche Cliniche di Verona srl; 37134, Verona, Italy
| | - Emanuele Nicastri
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | - Chiara Agrati
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | - Concetta Castilletti
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | - Alessandra Sacchi
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | - Giulia Matusali
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | - Roberta Gagliardini
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | - Eleonora Cimini
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | - Laura Scorzolini
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | - Maria M Plazzi
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | - Aldo De Luca
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | | | | | | | | | | | | | - Yufang Shi
- First Affiliated Hospital of Soochow University; Suzhou, 215008, Jiangsu, China.,Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; 200061, Shanghai, China
| | - Enrico Girardi
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | - Markus Maeurer
- Division of Immunotherapy, ImmunoSurgery, Champalimaud Foundation; 1400-038, Lisboa, Portugal.,I Medical Clinic, University of Mainz; 55122, Mainz, Germany
| | - Maria R Capobianchi
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy.,Saint Camillus International University of Health Sciences, 00131, Rome, Italy
| | - Francesco Vaia
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
| | - Mauro Piacentini
- Department of Biology, University of Rome "Tor Vergata; 00133, Rome, Italy
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, 75006, Paris, France.,Metabolomics and Cell Biology Platforms, Institut Gustave Roussy; 94805, Villejuif, France.,Pôle de Biologie, Hôpital Européen Georges Pompidou; 75015, Paris, France.,Department of Women's and Children's Health, Karolinska University Hospital, 17164, Stockholm, Sweden
| | | | | | | | - Giuseppe Ippolito
- Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; 00149, Rome, Italy
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Szarka G, Balogh M, Tengölics ÁJ, Ganczer A, Völgyi B, Kovács-Öller T. The role of gap junctions in cell death and neuromodulation in the retina. Neural Regen Res 2021; 16:1911-1920. [PMID: 33642359 PMCID: PMC8343308 DOI: 10.4103/1673-5374.308069] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 10/14/2020] [Accepted: 01/11/2021] [Indexed: 12/26/2022] Open
Abstract
Vision altering diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, myopia, retinal vascular disease, traumatic brain injuries and others cripple many lives and are projected to continue to cause anguish in the foreseeable future. Gap junctions serve as an emerging target for neuromodulation and possible regeneration as they directly connect healthy and/or diseased cells, thereby playing a crucial role in pathophysiology. Since they are permeable for macromolecules, able to cross the cellular barriers, they show duality in illness as a cause and as a therapeutic target. In this review, we take recent advancements in gap junction neuromodulation (pharmacological blockade, gene therapy, electrical and light stimulation) into account, to show the gap junction's role in neuronal cell death and the possible routes of rescuing neuronal and glial cells in the retina succeeding illness or injury.
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Affiliation(s)
- Gergely Szarka
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Retinal Electrical Synapses Research Group, National Brain Research Program (NAP 2.0), Hungarian Academy of Sciences, Budapest, Hungary
- Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary
| | - Márton Balogh
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Retinal Electrical Synapses Research Group, National Brain Research Program (NAP 2.0), Hungarian Academy of Sciences, Budapest, Hungary
- Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary
| | - Ádám J. Tengölics
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Retinal Electrical Synapses Research Group, National Brain Research Program (NAP 2.0), Hungarian Academy of Sciences, Budapest, Hungary
- Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary
| | - Alma Ganczer
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Retinal Electrical Synapses Research Group, National Brain Research Program (NAP 2.0), Hungarian Academy of Sciences, Budapest, Hungary
- Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary
| | - Béla Völgyi
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Retinal Electrical Synapses Research Group, National Brain Research Program (NAP 2.0), Hungarian Academy of Sciences, Budapest, Hungary
- Department of Experimental Zoology and Neurobiology, University of Pécs, Pécs, Hungary
- Medical School, University of Pécs, Pécs, Hungary
| | - Tamás Kovács-Öller
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Retinal Electrical Synapses Research Group, National Brain Research Program (NAP 2.0), Hungarian Academy of Sciences, Budapest, Hungary
- Medical School, University of Pécs, Pécs, Hungary
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