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Wong YC, Hang Ho DH, Zhou R, Zhang R, Woo KF, Cheng WY, Wang T, Du Y, Polly Pang KP, Tai WK, Jin X, Chen Z, Ngai Hung IF. An open-label study on the safety and immunogenicity of a PD-1-enhanced DNA vaccine used as a T cell booster for COVID-19. EBioMedicine 2025; 115:105699. [PMID: 40245494 DOI: 10.1016/j.ebiom.2025.105699] [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: 09/27/2024] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Inducing T cell responses by vaccines among elderly has been a long-standing challenge. There is a need for effective COVID-19 vaccines to boost waning immunity against emerging SARS-CoV-2 variants, especially for the elderly. This study investigated the safety and immunogenicity of a PD-1-enhanced COVID-19 DNA vaccine (ICCOV™), as a booster vaccine in healthy adults (aged 18-59 years) and elderly (aged 60-75 years). METHODS This open-label, non-randomised Phase 2 study enrolled healthy participants aged 18-75 years who had previously been vaccinated with Sinovac CoronaVac, Pfizer-bioNTech Comirnaty vaccines, or both. Participants were stratified into four cohorts according to age, primary vaccination, and COVID-19 infection history, namely Adult-CoronaVac, Adult-Comirnaty, Adult-Mixed, and Elderly-Mixed cohorts. Participants were administered with a single dose of 2 mg ICCOV intramuscularly followed by electroporation using the proprietary TERESA-EPT-I device. Participants were followed up for 60 days. The primary endpoint was T cell immunogenicity within 28 days post-ICCOV vaccination. The secondary endpoints were safety, T cell and antibody responses within 60 days post-vaccination (ClinicalTrials.govNCT05904054). FINDINGS The study was conducted at Gleneagles Hospital Hong Kong between 30 June and 30 November 2023. In total, 31 participants were enrolled across the Adult-Comirnaty (n = 4), Adult-Mixed (n = 15), and Elderly-Mixed (n = 12) cohorts. All enrolled participants completed the study and were included in safety and immunogenicity analyses. Among these participants, 2 from the Adult-Comirnaty cohort, 9 from the Adult-Mixed cohort, and 4 from the Elderly-Mixed cohort reported a total of 31 adverse events, all in grade 1-2. Pain at the administration site was the most frequently reported (38·7%). The proportion of participants demonstrating an increase of SARS-CoV-2-specific ELISpot T cell responses within 28 days post ICCOV vaccination was 100% (4/4), 80% (12/15), and 75% (9/12) in Adult-Comirnaty, Adult-Mixed, and Elderly-Mixed cohorts, respectively. Single ICCOV vaccination elicited SARS-CoV-2-specific, polyfunctional CD8+ and CD4+ T cells against both ancestral and Omicron strains in all cohorts. The magnitude of responses was not inferior in the elderly, compared to adults. No elevation of antibody responses was detected. INTERPRETATION Single PD-1-enhanced ICCOV booster DNA vaccination did not show major safety concerns. The ICCOV booster elicited cross-reactive T cell responses to multiple SARS-CoV-2 strains, including in the elderly. This report demonstrates the T-cell boosting immunogenicity of ICCOV in the susceptible elderly population. FUNDING Clinical Translational Catalyst, Hong Kong Science & Technology Parks Corporation.
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Affiliation(s)
- Yik Chun Wong
- AIDS Institute, Department of Microbiology and Pandemic Research Alliance Unit, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region of the People's Republic of China; Immuno Cure Holding (HK) Limited, Hong Kong Science Park, Hong Kong Special Administrative Region of the People's Republic of China
| | - Derek Hoi Hang Ho
- Immuno Cure Holding (HK) Limited, Hong Kong Science Park, Hong Kong Special Administrative Region of the People's Republic of China
| | - Runhong Zhou
- AIDS Institute, Department of Microbiology and Pandemic Research Alliance Unit, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region of the People's Republic of China
| | - Ruiqi Zhang
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of the People's Republic of China
| | - Kin Fai Woo
- AIDS Institute, Department of Microbiology and Pandemic Research Alliance Unit, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region of the People's Republic of China; Immuno Cure Holding (HK) Limited, Hong Kong Science Park, Hong Kong Special Administrative Region of the People's Republic of China
| | - Wing Yin Cheng
- Immuno Cure Holding (HK) Limited, Hong Kong Science Park, Hong Kong Special Administrative Region of the People's Republic of China
| | - Ting Wang
- Immuno Cure Holding (HK) Limited, Hong Kong Science Park, Hong Kong Special Administrative Region of the People's Republic of China
| | - Yanhua Du
- Immuno Cure Holding (HK) Limited, Hong Kong Science Park, Hong Kong Special Administrative Region of the People's Republic of China
| | - Ka Po Polly Pang
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of the People's Republic of China
| | - Wai Ki Tai
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of the People's Republic of China
| | - Xia Jin
- Immuno Cure Holding (HK) Limited, Hong Kong Science Park, Hong Kong Special Administrative Region of the People's Republic of China.
| | - Zhiwei Chen
- AIDS Institute, Department of Microbiology and Pandemic Research Alliance Unit, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region of the People's Republic of China; State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region of the People's Republic of China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region of the People's Republic of China.
| | - Ivan Fan Ngai Hung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region of the People's Republic of China.
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Bois A, Grandela C, Gallant J, Mummery C, Menasché P. Revitalizing the heart: strategies and tools for cardiomyocyte regeneration post-myocardial infarction. NPJ Regen Med 2025; 10:6. [PMID: 39843488 PMCID: PMC11754855 DOI: 10.1038/s41536-025-00394-2] [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: 04/26/2024] [Accepted: 01/13/2025] [Indexed: 01/24/2025] Open
Abstract
Myocardial infarction (MI) causes the loss of millions of cardiomyocytes, and current treatments do not address this root issue. New therapies focus on stimulating cardiomyocyte division in the adult heart, inspired by the regenerative capacities of lower vertebrates and neonatal mice. This review explores strategies for heart regeneration, offers insights into cardiomyocyte proliferation, evaluates in vivo models, and discusses integrating in vitro human cardiac models to advance cardiac regeneration research.
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Affiliation(s)
- Axelle Bois
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
- Department of Cardiovascular Surgery, Université Paris Cité, INSERM U970, PARCC Hôpital Européen Georges Pompidou, 75015, Paris, France
| | - Catarina Grandela
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - James Gallant
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Christine Mummery
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
| | - Philippe Menasché
- Department of Cardiovascular Surgery, Université Paris Cité, INSERM U970, PARCC Hôpital Européen Georges Pompidou, 75015, Paris, France
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Almansour I, Jermy BR. Nucleic acid vaccine candidates encapsulated with mesoporous silica nanoparticles against MERS-CoV. Hum Vaccin Immunother 2024; 20:2346390. [PMID: 38691025 PMCID: PMC11067998 DOI: 10.1080/21645515.2024.2346390] [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: 01/02/2024] [Accepted: 04/19/2024] [Indexed: 05/03/2024] Open
Abstract
Middle East respiratory coronavirus (MERS-CoV) is a newly emergent, highly pathogenic coronavirus that is associated with 34% mortality rate. MERS-CoV remains listed as priority pathogen by the WHO. Since its discovery in 2012 and despite the efforts to develop coronaviruses vaccines to fight against SARS-CoV-2, there are currently no MERS-CoV vaccine that has been approved. Therefore, there is high demand to continue on the development of prophylactic vaccines against MERS-CoV. Current advancements in vaccine developments can be adapted for the development of improved MERS-CoV vaccines candidates. Nucleic acid-based vaccines, including pDNA and mRNA, are relatively new class of vaccine platforms. In this work, we developed pDNA and mRNA vaccine candidates expressing S.FL gene of MERS-CoV. Further, we synthesized a silane functionalized hierarchical aluminosilicate to encapsulate each vaccine candidates. We tested the nucleic acid vaccine candidates in mice and evaluated humoral antibodies response. Interestingly, we determined that the non-encapsulated, codon optimized S.FL pDNA vaccine candidate elicited the highest level of antibody responses against S.FL and S1 of MERS-CoV. Encapsulation of mRNA with nanoporous aluminosilicate increased the humoral antibody responses, whereas encapsulation of pDNA did not. These findings suggests that MERS-CoV S.FL pDNA vaccine candidate induced the highest level of humoral responses. This study will enhance further optimization of nanosilica as potential carrier for mRNA vaccines. In conclusion, this study suggests MERS-CoV pDNA vaccine candidate as a suitable vaccine platform for further pivotal preclinical testings.
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Affiliation(s)
- Iman Almansour
- Nucleic Acid Vaccine Laboratory, Department of Epidemic Diseases Research, Institute for Research and Medical Consultations IRMC, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - B. Rabindran Jermy
- Department of Nanomedicine Research, Institute for Research and Medical Consultations IRMC, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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Berger S, Zeyn Y, Wagner E, Bros M. New insights for the development of efficient DNA vaccines. Microb Biotechnol 2024; 17:e70053. [PMID: 39545748 PMCID: PMC11565620 DOI: 10.1111/1751-7915.70053] [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: 04/25/2024] [Accepted: 10/29/2024] [Indexed: 11/17/2024] Open
Abstract
Despite the great potential of DNA vaccines for a broad range of applications, ranging from prevention of infections, over treatment of autoimmune and allergic diseases to cancer immunotherapies, the implementation of such therapies for clinical treatment is far behind the expectations up to now. The main reason is the poor immunogenicity of DNA vaccines in humans. Consequently, the improvement of the performance of DNA vaccines in vivo is required. This mini-review provides an overview of the current state of DNA vaccines and the various strategies to enhance the immunogenic potential of DNA vaccines, including (i) the optimization of the DNA construct itself regarding size, nuclear transfer and transcriptional regulation; (ii) the use of appropriate adjuvants; and (iii) improved delivery, for example, by careful choice of the administration route, physical methods such as electroporation and nanomaterials that may allow cell type-specific targeting. Moreover, combining nanoformulated DNA vaccines with other immunotherapies and prime-boost strategies may help to enhance success of treatment.
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Affiliation(s)
- Simone Berger
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for NanoScienceLudwig‐Maximilians‐Universität (LMU) MunichMunichGermany
| | - Yanira Zeyn
- Department of DermatologyUniversity Medical Center of the Johannes Gutenberg University (JGU) MainzMainzGermany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of Pharmacy, Center for NanoScienceLudwig‐Maximilians‐Universität (LMU) MunichMunichGermany
| | - Matthias Bros
- Department of DermatologyUniversity Medical Center of the Johannes Gutenberg University (JGU) MainzMainzGermany
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5
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Garcia-Atutxa I, Mondragon-Teran P, Huerta-Saquero A, Villanueva-Flores F. Advancements in monkeypox vaccines development: a critical review of emerging technologies. Front Immunol 2024; 15:1456060. [PMID: 39464881 PMCID: PMC11502315 DOI: 10.3389/fimmu.2024.1456060] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/20/2024] [Indexed: 10/29/2024] Open
Abstract
Monkeypox (mpox) is a zoonotic illness caused by the monkeypox virus (MPXV), with higher health concerns among people who are pregnant, children, and persons who are immunocompromised, including people with untreated and advanced HIV disease. Significant progress has been made in developing vaccines against mpox, yet critical challenges and limitations persist in ensuring their effectiveness, safety, and accessibility. The pertinence of this review is highlighted by the World Health Organization's declaration of a global health emergency on August 14, 2024, due to the recent mpox outbreak, underscoring the critical necessity for effective vaccine solutions in the face of a rapidly evolving virus. Here, we comprehensively analyze various vaccine platforms utilized in mpox prevention, including attenuated and non-replicating virus vaccines, viral vector-based vaccines, recombinant protein vaccines, and DNA and mRNA vaccines. We evaluate the advantages and limitations of each platform, highlighting the urgent need for ongoing research and innovation to enhance vaccine efficacy and safety. Recent advancements, such as incorporating immunostimulatory sequences, improved delivery systems, and developing polyvalent vaccines, are explored for their potential to offer broader protection against diverse orthopoxvirus strains. This work underscores the need to optimize currently available vaccines and investigate novel vaccination strategies to address future public health emergencies effectively. By focusing on these advanced methodologies, we aim to contribute to the development of robust and adaptable vaccine solutions for mpox and other related viral threats.
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Affiliation(s)
- Igor Garcia-Atutxa
- Computer Science Department, Universidad Católica de Murcia (UCAM), Murcia, Spain
| | - Paul Mondragon-Teran
- Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada (CICATA) Unidad Morelos del Instituto Politécnico Nacional (IPN), Xochitepec, Morelos, Mexico
| | - Alejandro Huerta-Saquero
- Departamento de Bionanotecnología, Centro de Nanociencias y Nanotecnología, Universidad Nacional Autónoma de México (UNAM), Ensenada, Mexico
| | - Francisca Villanueva-Flores
- Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada (CICATA) Unidad Morelos del Instituto Politécnico Nacional (IPN), Xochitepec, Morelos, Mexico
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Chi WY, Hu Y, Huang HC, Kuo HH, Lin SH, Kuo CTJ, Tao J, Fan D, Huang YM, Wu AA, Hung CF, Wu TC. Molecular targets and strategies in the development of nucleic acid cancer vaccines: from shared to personalized antigens. J Biomed Sci 2024; 31:94. [PMID: 39379923 PMCID: PMC11463125 DOI: 10.1186/s12929-024-01082-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 09/01/2024] [Indexed: 10/10/2024] Open
Abstract
Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.
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Affiliation(s)
- Wei-Yu Chi
- Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Medicine, New York, NY, USA
| | - Yingying Hu
- Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hsin-Che Huang
- Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hui-Hsuan Kuo
- Pharmacology PhD Program, Weill Cornell Medicine, New York, NY, USA
| | - Shu-Hong Lin
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston and MD Anderson Cancer Center, Houston, TX, USA
| | - Chun-Tien Jimmy Kuo
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Julia Tao
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Darrell Fan
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Yi-Min Huang
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Annie A Wu
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
| | - Chien-Fu Hung
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Obstetrics and Gynecology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - T-C Wu
- Department of Pathology, Johns Hopkins School of Medicine, 1550 Orleans St, CRB II Room 309, Baltimore, MD, 21287, USA.
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Department of Obstetrics and Gynecology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
- Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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Abdul-Rahman T, Lizano-Jubert I, Bliss ZSB, Garg N, Meale E, Roy P, Crino SA, Deepak BL, Miteu GD, Wireko AA, Qadeer A, Condurat A, Tanasa AD, Pyrpyris N, Sikora K, Horbas V, Sood A, Gupta R, Lavie CJ. RNA in cardiovascular disease: A new frontier of personalized medicine. Prog Cardiovasc Dis 2024; 85:93-102. [PMID: 38253161 DOI: 10.1016/j.pcad.2024.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 01/14/2024] [Indexed: 01/24/2024]
Abstract
Personalized medicine has witnessed remarkable progress with the emergence of RNA therapy, offering new possibilities for the treatment of various diseases, and in particular in the context of cardiovascular disease (CVD). The ability to target the human genome through RNA manipulation offers great potential not only in the treatment of cardiac pathologies but also in their diagnosis and prevention, notably in cases of hyperlipidemia and myocardial infarctions. While only a few RNA-based treatments have entered clinical trials or obtained approval from the US Food and Drug Administration, the growing body of research on this subject is promising. However, the development of RNA therapies faces several challenges that must be overcome. These include the efficient delivery of drugs into cells, the potential for immunogenic responses, and safety. Resolving these obstacles is crucial to advance the development of RNA therapies. This review explores the newest developments in medical studies, treatment plans, and results related to RNA therapies for heart disease. Furthermore, it discusses the exciting possibilities and difficulties in this innovative area of research.
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Affiliation(s)
| | | | | | - Neil Garg
- Rowan-Virtua School of osteopathic medicine, Stratford, NJ, USA
| | - Emily Meale
- Rowan-Virtua School of osteopathic medicine, Stratford, NJ, USA
| | - Poulami Roy
- Department of Medicine, North Bengal Medical College and Hospital, Siliguri, India
| | | | | | - Goshen David Miteu
- School of Biosciences, University of Nottingham, Nottingham, England, United Kingdom
| | | | - Abdul Qadeer
- Hospital Internal Medicine Department, Scottsdale Campus, Mayo Clinic, AZ, USA
| | | | | | - Nikolaos Pyrpyris
- First Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | | | | | - Aayushi Sood
- Department of Medicine, The Wright Center for Graduate Medical Education, Scranton, PA, USA
| | - Rahul Gupta
- Lehigh Valley Heart and Vascular Institute, Lehigh Valley Health Network, Allentown, PA, USA.
| | - Carl J Lavie
- Department of Cardiology, Ochsner Clinic Foundation, New Orleans, LA, United States; The University of Queensland Medical School, Ochsner Clinical School, New Orleans, LA, United States
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Marie C, Scherman D. Antibiotic-Free Gene Vectors: A 25-Year Journey to Clinical Trials. Genes (Basel) 2024; 15:261. [PMID: 38540320 PMCID: PMC10970329 DOI: 10.3390/genes15030261] [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: 01/02/2024] [Revised: 02/07/2024] [Accepted: 02/15/2024] [Indexed: 06/15/2024] Open
Abstract
Until very recently, the major use, for gene therapy, specifically of linear or circular DNA, such as plasmids, was as ancillary products for viral vectors' production or as a genetic template for mRNA production. Thanks to targeted and more efficient physical or chemical delivery techniques and to the refinement of their structure, non-viral plasmid DNA are now under intensive consideration as pharmaceutical drugs. Plasmids traditionally carry an antibiotic resistance gene for providing the selection pressure necessary for maintenance in a bacterial host. Nearly a dozen different antibiotic-free gene vectors have now been developed and are currently assessed in preclinical assays and phase I/II clinical trials. Their reduced size leads to increased transfection efficiency and prolonged transgene expression. In addition, associating non-viral gene vectors and DNA transposons, which mediate transgene integration into the host genome, circumvents plasmid dilution in dividing eukaryotic cells which generate a loss of the therapeutic gene. Combining these novel molecular tools allowed a significantly higher yield of genetically engineered T and Natural Killer cells for adoptive immunotherapies due to a reduced cytotoxicity and increased transposition rate. This review describes the main progresses accomplished for safer, more efficient and cost-effective gene and cell therapies using non-viral approaches and antibiotic-free gene vectors.
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Affiliation(s)
- Corinne Marie
- Université Paris Cité, CNRS, Inserm, UTCBS, 75006 Paris, France;
- Chimie ParisTech, Université PSL, 75005 Paris, France
| | - Daniel Scherman
- Université Paris Cité, CNRS, Inserm, UTCBS, 75006 Paris, France;
- Fondation Maladies Rares, 75014 Paris, France
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Francis JE, Skakic I, Majumdar D, Taki AC, Shukla R, Walduck A, Smooker PM. Solid Lipid Nanoparticles Delivering a DNA Vaccine Encoding Helicobacter pylori Urease A Subunit: Immune Analyses before and after a Mouse Model of Infection. Int J Mol Sci 2024; 25:1076. [PMID: 38256149 PMCID: PMC10816323 DOI: 10.3390/ijms25021076] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/08/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
In this study, novel solid lipid particles containing the adjuvant lipid monophosphoryl lipid A (termed 'SLN-A') were synthesised. The SLN-A particles were able to efficiently bind and form complexes with a DNA vaccine encoding the urease alpha subunit of Helicobacter pylori. The resultant nanoparticles were termed lipoplex-A. In a mouse model of H. pylori infection, the lipoplex-A nanoparticles were used to immunise mice, and the resultant immune responses were analysed. It was found that the lipoplex-A vaccine was able to induce high levels of antigen-specific antibodies and an influx of gastric CD4+ T cells in vaccinated mice. In particular, a prime with lipoplex-A and a boost with soluble UreA protein induced significantly high levels of the IgG1 antibody, whereas two doses of lipoplex-A induced high levels of the IgG2c antibody. In this study, lipoplex-A vaccination did not lead to a significant reduction in H. pylori colonisation in a challenge model; however, these results point to the utility of the system for delivering DNA vaccine-encoded antigens to induce immune responses and suggest the ability to tailor those responses.
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Affiliation(s)
- Jasmine E. Francis
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Ivana Skakic
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Debolina Majumdar
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Aya C. Taki
- Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, VIC 3010, Australia;
| | - Ravi Shukla
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Anna Walduck
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
| | - Peter M. Smooker
- School of Science, RMIT University, 264 Plenty Road, Bundoora, VIC 3083, Australia; (J.E.F.); (I.S.); (D.M.); (R.S.); (A.W.)
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Kozak M, Hu J. DNA Vaccines: Their Formulations, Engineering and Delivery. Vaccines (Basel) 2024; 12:71. [PMID: 38250884 PMCID: PMC10820593 DOI: 10.3390/vaccines12010071] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/02/2024] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
The concept of DNA vaccination was introduced in the early 1990s. Since then, advancements in the augmentation of the immunogenicity of DNA vaccines have brought this technology to the market, especially in veterinary medicine, to prevent many diseases. Along with the successful COVID mRNA vaccines, the first DNA vaccine for human use, the Indian ZyCovD vaccine against SARS-CoV-2, was approved in 2021. In the current review, we first give an overview of the DNA vaccine focusing on the science, including adjuvants and delivery methods. We then cover some of the emerging science in the field of DNA vaccines, notably efforts to optimize delivery systems, better engineer delivery apparatuses, identify optimal delivery sites, personalize cancer immunotherapy through DNA vaccination, enhance adjuvant science through gene adjuvants, enhance off-target and heritable immunity through epigenetic modification, and predict epitopes with bioinformatic approaches. We also discuss the major limitations of DNA vaccines and we aim to address many theoretical concerns.
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Affiliation(s)
- Michael Kozak
- The Jake Gittlen Laboratories for Cancer Research, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
- The Department of Pathology and Laboratory Medicine, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Jiafen Hu
- The Jake Gittlen Laboratories for Cancer Research, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
- The Department of Pathology and Laboratory Medicine, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
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11
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Karpov DS, Sosnovtseva AO, Pylina SV, Bastrich AN, Petrova DA, Kovalev MA, Shuvalova AI, Eremkina AK, Mokrysheva NG. Challenges of CRISPR/Cas-Based Cell Therapy for Type 1 Diabetes: How Not to Engineer a "Trojan Horse". Int J Mol Sci 2023; 24:17320. [PMID: 38139149 PMCID: PMC10743607 DOI: 10.3390/ijms242417320] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of insulin-producing β-cells in the pancreas by cytotoxic T-cells. To date, there are no drugs that can prevent the development of T1D. Insulin replacement therapy is the standard care for patients with T1D. This treatment is life-saving, but is expensive, can lead to acute and long-term complications, and results in reduced overall life expectancy. This has stimulated the research and development of alternative treatments for T1D. In this review, we consider potential therapies for T1D using cellular regenerative medicine approaches with a focus on CRISPR/Cas-engineered cellular products. However, CRISPR/Cas as a genome editing tool has several drawbacks that should be considered for safe and efficient cell engineering. In addition, cellular engineering approaches themselves pose a hidden threat. The purpose of this review is to critically discuss novel strategies for the treatment of T1D using genome editing technology. A well-designed approach to β-cell derivation using CRISPR/Cas-based genome editing technology will significantly reduce the risk of incorrectly engineered cell products that could behave as a "Trojan horse".
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Affiliation(s)
- Dmitry S. Karpov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Anastasiia O. Sosnovtseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Svetlana V. Pylina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Asya N. Bastrich
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Darya A. Petrova
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Maxim A. Kovalev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Anastasija I. Shuvalova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (D.S.K.); (A.O.S.); (M.A.K.); (A.I.S.)
| | - Anna K. Eremkina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
| | - Natalia G. Mokrysheva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.N.B.); (D.A.P.); (A.K.E.)
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12
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Pagliari S, Dema B, Sanchez-Martinez A, Montalvo Zurbia-Flores G, Rollier CS. DNA Vaccines: History, Molecular Mechanisms and Future Perspectives. J Mol Biol 2023; 435:168297. [PMID: 37797831 DOI: 10.1016/j.jmb.2023.168297] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/07/2023]
Abstract
The history of DNA vaccine began as early as the 1960s with the discovery that naked DNA can transfect mammalian cells in vivo. In 1992, the evidence that such transfection could lead to the generation of antigen-specific antibody responses was obtained and supported the development of this technology as a novel vaccine platform. The technology then attracted immense interest and high hopes in vaccinology, as evidence of high immunogenicity and protection against virulent challenges accumulated from several animal models for several diseases. In particular, the capacity to induce T-cell responses was unprecedented in non-live vaccines. However, the technology suffered its major knock when the success in animals failed to translate to humans, where DNA vaccine candidates were shown to be safe but remained poorly immunogenic, or not associated with clinical benefit. Thanks to a thorough exploration of the molecular mechanisms of action of these vaccines, an impressive range of approaches have been and are currently being explored to overcome this major challenge. Despite limited success so far in humans as compared with later genetic vaccine technologies such as viral vectors and mRNA, DNA vaccines are not yet optimised for human use and may still realise their potential.
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Affiliation(s)
- Sthefany Pagliari
- School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK; Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Barbara Dema
- Pandemic Science Institute, Institute of Developmental and Regenerative Medicine (IDRM), University of Oxford, Oxford, UK
| | | | | | - Christine S Rollier
- School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
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13
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Skolnik JM, Morrow MP. Vaccines for HPV-associated diseases. Mol Aspects Med 2023; 94:101224. [PMID: 37931422 DOI: 10.1016/j.mam.2023.101224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/19/2023] [Accepted: 10/24/2023] [Indexed: 11/08/2023]
Abstract
Human papillomavirus (HPV) infection represents a significant global health concern owing to its role in the etiology of conditions ranging from benign low-grade lesions to cancers of the cervix, head and neck, anus, vagina, vulva, and penis. Prophylactic vaccination programs, primarily targeting adolescent girls, have achieved dramatic reductions in rates of HPV infection and cervical cancer in recent years. However, there is a clear demand for a strategy to manage the needs of the many people who are already living with persistent HPV infection and/or HPV-associated conditions. Unlike prophylactic vaccines, which act to prevent HPV infection, therapeutic vaccination presents an opportunity to induce cellular immunity against established HPV infections and lesions and prevent progression to cancer. Several HPV vaccines are undergoing clinical development, using a range of platforms. Peptide- or protein-based vaccines, vector-based vaccines, whole-cell vaccines, and nucleic acid vaccines each offer relative merits and limitations for the delivery of HPV antigens and the subsequent generation of targeted immune responses. There has been particular interest in DNA-based vaccines, which elicit both cellular and humoral immune responses to provide long-lasting immunity. DNA vaccines offer several practical advantages over other vaccine platforms, including the potential for rapid and scalable manufacturing, targeting of many different antigens, and potential for repeat boosting. Furthermore, unlike vectored approaches, DNA vaccines are thermostable over extended time periods, which may enable shipping and storage. Several delivery strategies are available to address the main challenge of DNA vaccines, namely their relatively low transfection efficiency. We review the latest clinical data supporting the development of DNA vaccines and reflect on this exciting prospect in the management of HPV-related disease.
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14
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Comes JDG, Pijlman GP, Hick TAH. Rise of the RNA machines - self-amplification in mRNA vaccine design. Trends Biotechnol 2023; 41:1417-1429. [PMID: 37328401 PMCID: PMC10266560 DOI: 10.1016/j.tibtech.2023.05.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 06/18/2023]
Abstract
mRNA vaccines have won the race for early COVID-19 vaccine approval, yet improvements are necessary to retain this leading role in combating infectious diseases. A next generation of self-amplifying mRNAs, also known as replicons, form an ideal vaccine platform. Replicons induce potent humoral and cellular responses with few adverse effects upon a minimal, single-dose immunization. Delivery of replicons is achieved with virus-like replicon particles (VRPs), or in nonviral vehicles such as liposomes or lipid nanoparticles. Here, we discuss innovative advances, including multivalent, mucosal, and therapeutic replicon vaccines, and highlight novelties in replicon design. As soon as essential safety evaluations have been resolved, this promising vaccine concept can transform into a widely applied clinical platform technology taking center stage in pandemic preparedness.
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Affiliation(s)
- Jerome D G Comes
- Wageningen University and Research, Laboratory of Virology, Droevendaalsesteeg 1, 6708PB, Wageningen, The Netherlands
| | - Gorben P Pijlman
- Wageningen University and Research, Laboratory of Virology, Droevendaalsesteeg 1, 6708PB, Wageningen, The Netherlands.
| | - Tessy A H Hick
- Wageningen University and Research, Laboratory of Virology, Droevendaalsesteeg 1, 6708PB, Wageningen, The Netherlands
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15
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Zhang W, Pfeifle A, Lansdell C, Frahm G, Cecillon J, Tamming L, Gravel C, Gao J, Thulasi Raman SN, Wang L, Sauve S, Rosu-Myles M, Li X, Johnston MJW. The Expression Kinetics and Immunogenicity of Lipid Nanoparticles Delivering Plasmid DNA and mRNA in Mice. Vaccines (Basel) 2023; 11:1580. [PMID: 37896985 PMCID: PMC10610642 DOI: 10.3390/vaccines11101580] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/05/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
In recent years, lipid nanoparticles (LNPs) have emerged as a revolutionary technology for vaccine delivery. LNPs serve as an integral component of mRNA vaccines by protecting and transporting the mRNA payload into host cells. Despite their prominence in mRNA vaccines, there remains a notable gap in our understanding of the potential application of LNPs for the delivery of DNA vaccines. In this study, we sought to investigate the suitability of leading LNP formulations for the delivery of plasmid DNA (pDNA). In addition, we aimed to explore key differences in the properties of popular LNP formulations when delivering either mRNA or DNA. To address these questions, we compared three leading LNP formulations encapsulating mRNA- or pDNA-encoding firefly luciferase based on potency, expression kinetics, biodistribution, and immunogenicity. Following intramuscular injection in mice, we determined that RNA-LNPs formulated with either SM-102 or ALC-0315 lipids were the most potent (all p-values < 0.01) and immunogenic (all p-values < 0.05), while DNA-LNPs formulated with SM-102 or ALC-0315 demonstrated the longest duration of signal. Additionally, all LNP formulations were found to induce expression in the liver that was proportional to the signal at the injection site (SM102: r = 0.8787, p < 0.0001; ALC0315: r = 0.9012, p < 0.0001; KC2: r = 0.9343, p < 0.0001). Overall, this study provides important insights into the differences between leading LNP formulations and their applicability to DNA- and RNA-based vaccinations.
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Affiliation(s)
- Wanyue Zhang
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Annabelle Pfeifle
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Casey Lansdell
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
| | - Grant Frahm
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
| | - Jonathon Cecillon
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Levi Tamming
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Caroline Gravel
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
| | - Jun Gao
- Centre for Vaccines, Clinical Trials and Biostatistics, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada
| | - Sathya N. Thulasi Raman
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Simon Sauve
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
| | - Michael Rosu-Myles
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Xuguang Li
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada;
| | - Michael J. W. Johnston
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON K1A 0K9, Canada; (W.Z.); (A.P.)
- Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada
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16
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Baghban R, Ghasemian A, Mahmoodi S. Nucleic acid-based vaccine platforms against the coronavirus disease 19 (COVID-19). Arch Microbiol 2023; 205:150. [PMID: 36995507 PMCID: PMC10062302 DOI: 10.1007/s00203-023-03480-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 03/11/2023] [Accepted: 03/11/2023] [Indexed: 03/31/2023]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has infected 673,010,496 patients and caused the death of 6,854,959 cases globally until today. Enormous efforts have been made to develop fundamentally different COVID-19 vaccine platforms. Nucleic acid-based vaccines consisting of mRNA and DNA vaccines (third-generation vaccines) have been promising in terms of rapid and convenient production and efficient provocation of immune responses against the COVID-19. Several DNA-based (ZyCoV-D, INO-4800, AG0302-COVID19, and GX-19N) and mRNA-based (BNT162b2, mRNA-1273, and ARCoV) approved vaccine platforms have been utilized for the COVID-19 prevention. mRNA vaccines are at the forefront of all platforms for COVID-19 prevention. However, these vaccines have lower stability, while DNA vaccines are needed with higher doses to stimulate the immune responses. Intracellular delivery of nucleic acid-based vaccines and their adverse events needs further research. Considering re-emergence of the COVID-19 variants of concern, vaccine reassessment and the development of polyvalent vaccines, or pan-coronavirus strategies, is essential for effective infection prevention.
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Affiliation(s)
- Roghayyeh Baghban
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolmajid Ghasemian
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Shirin Mahmoodi
- Department of Medical Biotechnology, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran.
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17
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Improved DNA Vaccine Delivery with Needle-Free Injection Systems. Vaccines (Basel) 2023; 11:vaccines11020280. [PMID: 36851159 PMCID: PMC9964240 DOI: 10.3390/vaccines11020280] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
DNA vaccines have inherent advantages compared to other vaccine types, including safety, rapid design and construction, ease and speed to manufacture, and thermostability. However, a major drawback of candidate DNA vaccines delivered by needle and syringe is the poor immunogenicity associated with inefficient cellular uptake of the DNA. This uptake is essential because the target vaccine antigen is produced within cells and then presented to the immune system. Multiple techniques have been employed to boost the immunogenicity and protective efficacy of DNA vaccines, including physical delivery methods, molecular and traditional adjuvants, and genetic sequence enhancements. Needle-free injection systems (NFIS) are an attractive alternative due to the induction of potent immunogenicity, enhanced protective efficacy, and elimination of needles. These advantages led to a milestone achievement in the field with the approval for Restricted Use in Emergency Situation of a DNA vaccine against COVID-19, delivered exclusively with NFIS. In this review, we discuss physical delivery methods for DNA vaccines with an emphasis on commercially available NFIS and their resulting safety, immunogenic effectiveness, and protective efficacy. As is discussed, prophylactic DNA vaccines delivered by NFIS tend to induce non-inferior immunogenicity to electroporation and enhanced responses compared to needle and syringe.
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18
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Mone K, Lasrado N, Sur M, Reddy J. Vaccines against Group B Coxsackieviruses and Their Importance. Vaccines (Basel) 2023; 11:vaccines11020274. [PMID: 36851152 PMCID: PMC9961666 DOI: 10.3390/vaccines11020274] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
The group B coxsackieviruses (CVBs) exist in six serotypes (CVB1 to CVB6). Disease associations have been reported for most serotypes, and multiple serotypes can cause similar diseases. For example, CVB1, CVB3, and CVB5 are generally implicated in the causation of myocarditis, whereas CVB1 and CVB4 could accelerate the development of type 1 diabetes (T1D). Yet, no vaccines against these viruses are currently available. In this review, we have analyzed the attributes of experimentally tested vaccines and discussed their merits and demerits or limitations, as well as their impact in preventing infections, most importantly myocarditis and T1D.
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Affiliation(s)
- Kiruthiga Mone
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Ninaad Lasrado
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Meghna Sur
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Jay Reddy
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
- Correspondence: ; Tel.: +1-(402)-472-8541
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19
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Hossaini Alhashemi S, Ahmadi F, Dehshahri A. Lessons learned from COVID-19 pandemic: Vaccine platform is a key player. Process Biochem 2023; 124:269-279. [PMID: 36514356 PMCID: PMC9731819 DOI: 10.1016/j.procbio.2022.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/15/2022] [Accepted: 12/02/2022] [Indexed: 12/13/2022]
Abstract
The SARS-CoV-2 outbreak and emergence of COVID-19 resulted in the development of different vaccines based on various platforms to combat the disease. While the conventional platforms of inactivated/live attenuated, subunit proteins and virus-like particles (VLPs) have provided efficient and safe vaccines, novel platforms of viral vector- and nucleic acid-based vaccines opened up new horizons for vaccine development. The emergence of COVID-19 pandemic showed that the availability of platforms with high possibility of quick translation from bench to bedside is a prerequisite step in vaccine development in pandemics. Moreover, parallel development of different platforms as well as considering the shipping, storage condition, distribution infrastructure and route of administration are key players for successful and robust response. This review highlights the lessons learned from the current COVID-19 pandemic in terms of vaccine development to provide quick response to future outbreaks of infectious diseases and the importance of vaccine platform in its storage condition and shipping. Finally, the potential application of current COVID-19 vaccine platforms in the treatment of non-infectious diseases has been discussed.
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Affiliation(s)
| | - Fatemeh Ahmadi
- Department of Pharmaceutics, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran,Correspondence to: School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Dehshahri
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran,Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran,Correspondence to: School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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20
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Cagigi A, Douradinha B. Have mRNA vaccines sentenced DNA vaccines to death? Expert Rev Vaccines 2023; 22:1154-1167. [PMID: 37941101 DOI: 10.1080/14760584.2023.2282065] [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: 09/01/2023] [Accepted: 11/07/2023] [Indexed: 11/10/2023]
Abstract
INTRODUCTION After receiving emergency approval during the COVID-19 pandemic, mRNA vaccines have taken center stage in the quest to enhance future vaccination strategies for both infectious diseases and cancer. Indeed, they have significantly overshadowed another facet of genetic vaccination, specifically DNA vaccines. Nevertheless, it is important to acknowledge that both types of genetic vaccines have distinct advantages and disadvantages that set them apart from each other. AREAS COVERED In this work, we delve extensively into the history of genetic vaccines, their mechanisms of action, their strengths, and limitations, and ultimately highlight ongoing research in key areas for potential enhancement of both DNA and mRNA vaccines. EXPERT OPINION Here, we assess the significance of the primary benefits and drawbacks associated with DNA and mRNA vaccination. We challenge the current lines of thought by highlighting that the existing drawbacks of DNA vaccination could potentially be more straightforward to address compared to those linked with mRNA vaccination. In our view, this suggests that DNA vaccines should remain viable contenders in the pursuit of the future of vaccination.
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Affiliation(s)
- Alberto Cagigi
- Nykode Therapeutics ASA, Oslo Science Park, Oslo, Norway
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21
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Liu MA. DNA and mRNA Vaccines for Chronic Viral Infections and Cancer: Rationale, Mechanisms, and Progress. Cancers (Basel) 2022; 14:cancers14235874. [PMID: 36497356 PMCID: PMC9740312 DOI: 10.3390/cancers14235874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/30/2022] Open
Abstract
Interest in the capabilities of nucleic acid vaccines, (DNA and mRNA vaccines) for both prophylactic and therapeutic uses have greatly increased following the successful deployment of two mRNA and, on a more limited scale, one DNA vaccine for COVID-19. In addition to targeting other pathogens for prophylactic vaccines, efforts are also being made towards using them for therapies for chronic infections and cancer. An examination of past and current successes for such therapies using other technologies with an emphasis on the immunological mechanisms will be provided followed by an assessment of the relevant characteristics of DNA and mRNA vaccines to predict their utility for therapies for chronic viral infections and cancer. Efforts and progress for these targets will be described.
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Affiliation(s)
- Margaret A. Liu
- ProTherImmune, 3656 Happy Valley Road, Lafayette, CA 94549, USA; ; Tel.: +1-925-299-2959
- Department of Medicine at Solna, Karolinska Institutet, 17177 Stockholm, Sweden
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22
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Martínez-Puente DH, Pérez-Trujillo JJ, Zavala-Flores LM, García-García A, Villanueva-Olivo A, Rodríguez-Rocha H, Valdés J, Saucedo-Cárdenas O, Montes de Oca-Luna R, Loera-Arias MDJ. Plasmid DNA for Therapeutic Applications in Cancer. Pharmaceutics 2022; 14:pharmaceutics14091861. [PMID: 36145609 PMCID: PMC9503848 DOI: 10.3390/pharmaceutics14091861] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/30/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Recently, the interest in using nucleic acids for therapeutic applications has been increasing. DNA molecules can be manipulated to express a gene of interest for gene therapy applications or vaccine development. Plasmid DNA can be developed to treat different diseases, such as infections and cancer. In most cancers, the immune system is limited or suppressed, allowing cancer cells to grow. DNA vaccination has demonstrated its capacity to stimulate the immune system to fight against cancer cells. Furthermore, plasmids for cancer gene therapy can direct the expression of proteins with different functions, such as enzymes, toxins, and cytotoxic or proapoptotic proteins, to directly kill cancer cells. The progress and promising results reported in animal models in recent years have led to interesting clinical results. These DNA strategies are expected to be approved for cancer treatment in the near future. This review discusses the main strategies, challenges, and future perspectives of using plasmid DNA for cancer treatment.
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Affiliation(s)
| | - José Juan Pérez-Trujillo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Laura Mireya Zavala-Flores
- Department of Molecular Genetics, Northeast Biomedical Research Center (CIBIN) of IMSS, Nuevo Leon Delegation, Monterrey 64720, Mexico
| | - Aracely García-García
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Arnulfo Villanueva-Olivo
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Humberto Rodríguez-Rocha
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Jesús Valdés
- Departamento de Bioquímica, CINVESTAV-México, Av. IPN 2508, Colonia San Pedro Zacatenco, Mexico City 07360, Mexico
| | - Odila Saucedo-Cárdenas
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
| | - Roberto Montes de Oca-Luna
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
- Correspondence: (R.M.d.O.-L.); (M.d.J.L.-A.); Tel.: +52-81-8329-4195 (R.M.d.O.-L. & M.d.J.L.-A.)
| | - María de Jesús Loera-Arias
- Histology Department, Faculty of Medicine, Universidad Autonoma de Nuevo Leon (UANL), Monterrey 64460, Mexico
- Correspondence: (R.M.d.O.-L.); (M.d.J.L.-A.); Tel.: +52-81-8329-4195 (R.M.d.O.-L. & M.d.J.L.-A.)
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Mokhtary P, Pourhashem Z, Mehrizi AA, Sala C, Rappuoli R. Recent Progress in the Discovery and Development of Monoclonal Antibodies against Viral Infections. Biomedicines 2022; 10:biomedicines10081861. [PMID: 36009408 PMCID: PMC9405509 DOI: 10.3390/biomedicines10081861] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/21/2022] [Accepted: 07/29/2022] [Indexed: 01/09/2023] Open
Abstract
Monoclonal antibodies (mAbs), the new revolutionary class of medications, are fast becoming tools against various diseases thanks to a unique structure and function that allow them to bind highly specific targets or receptors. These specialized proteins can be produced in large quantities via the hybridoma technique introduced in 1975 or by means of modern technologies. Additional methods have been developed to generate mAbs with new biological properties such as humanized, chimeric, or murine. The inclusion of mAbs in therapeutic regimens is a major medical advance and will hopefully lead to significant improvements in infectious disease management. Since the first therapeutic mAb, muromonab-CD3, was approved by the U.S. Food and Drug Administration (FDA) in 1986, the list of approved mAbs and their clinical indications and applications have been proliferating. New technologies have been developed to modify the structure of mAbs, thereby increasing efficacy and improving delivery routes. Gene delivery technologies, such as non-viral synthetic plasmid DNA and messenger RNA vectors (DMabs or mRNA-encoded mAbs), built to express tailored mAb genes, might help overcome some of the challenges of mAb therapy, including production restrictions, cold-chain storage, transportation requirements, and expensive manufacturing and distribution processes. This paper reviews some of the recent developments in mAb discovery against viral infections and illustrates how mAbs can help to combat viral diseases and outbreaks.
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Affiliation(s)
- Pardis Mokhtary
- Monoclonal Antibody Discovery Laboratory, Fondazione Toscana Life Sciences, 53100 Siena, Italy;
- Department of Biochemistry and Molecular Biology, University of Siena, 53100 Siena, Italy
| | - Zeinab Pourhashem
- Student Research Committee, Pasteur Institute of Iran, Tehran 1316943551, Iran;
- Malaria and Vector Research Group, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran;
| | - Akram Abouei Mehrizi
- Malaria and Vector Research Group, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran;
| | - Claudia Sala
- Monoclonal Antibody Discovery Laboratory, Fondazione Toscana Life Sciences, 53100 Siena, Italy;
- Correspondence: (C.S.); (R.R.)
| | - Rino Rappuoli
- Monoclonal Antibody Discovery Laboratory, Fondazione Toscana Life Sciences, 53100 Siena, Italy;
- Correspondence: (C.S.); (R.R.)
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Conforti A, Salvatori E, Lione L, Compagnone M, Pinto E, Shorrock C, Hayward JA, Sun Y, Liang BM, Palombo F, Viscount B, Aurisicchio L. Linear DNA amplicons as a novel cancer vaccine strategy. J Exp Clin Cancer Res 2022; 41:195. [PMID: 35668533 PMCID: PMC9169303 DOI: 10.1186/s13046-022-02402-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/20/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND DNA-based vaccines represent a simple, safe and promising strategy for harnessing the immune system to fight infectious diseases as well as various forms of cancer and thus are considered an important tool in the cancer immunotherapy toolbox. Nonetheless, the manufacture of plasmid DNA vaccines has several drawbacks, including long lead times and the need to remove impurities from bacterial cultures. Here we report the development of polymerase chain reaction (PCR)-produced amplicon expression vectors as DNA vaccines and their in vivo application to elicit antigen-specific immune responses in animal cancer models. METHODS Plasmid DNA and amplicon expression was assessed both in vitro, by Hela cells transfection, and in vivo, by evaluating luciferase expression in wild-type mice through optical imaging. Immunogenicity induced by DNA amplicons was assessed by vaccinating wild-type mice against a tumor-associated antigen, whereas the antitumoral effect of DNA amplicons was evaluated in a murine cancer model in combination with immune-checkpoint inhibitors (ICIs). RESULTS Amplicons encoding tumor-associated-antigens, such as telomerase reverse transcriptase or neoantigens expressed by murine tumor cell lines, were able to elicit antigen-specific immune responses and proved to significantly impact tumor growth when administered in combination with ICIs. CONCLUSIONS These results strongly support the further exploration of the use of PCR-based amplicons as an innovative immunotherapeutic approach to cancer treatment.
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Affiliation(s)
- Antonella Conforti
- Takis, Via Castel Romano 100, 00128 Rome, Italy
- Evvivax, Via Castel Romano 100, 00128 Rome, Italy
| | | | - Lucia Lione
- Takis, Via Castel Romano 100, 00128 Rome, Italy
| | | | | | - Clay Shorrock
- Applied DNA Sciences, 50 Health Sciences Drive, Stony Brook, NY 11790 USA
| | - James A. Hayward
- Applied DNA Sciences, 50 Health Sciences Drive, Stony Brook, NY 11790 USA
| | - Yuhua Sun
- Applied DNA Sciences, 50 Health Sciences Drive, Stony Brook, NY 11790 USA
| | - Ben Minghwa Liang
- Applied DNA Sciences, 50 Health Sciences Drive, Stony Brook, NY 11790 USA
| | - Fabio Palombo
- Takis, Via Castel Romano 100, 00128 Rome, Italy
- Neomatrix, Via Castel Romano 100, 00128 Rome, Italy
| | - Brian Viscount
- Applied DNA Sciences, 50 Health Sciences Drive, Stony Brook, NY 11790 USA
| | - Luigi Aurisicchio
- Takis, Via Castel Romano 100, 00128 Rome, Italy
- Evvivax, Via Castel Romano 100, 00128 Rome, Italy
- Neomatrix, Via Castel Romano 100, 00128 Rome, Italy
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25
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Chuang ST, Conklin B, Stein JB, Pan G, Lee KB. Nanotechnology-enabled immunoengineering approaches to advance therapeutic applications. NANO CONVERGENCE 2022; 9:19. [PMID: 35482149 PMCID: PMC9047473 DOI: 10.1186/s40580-022-00310-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/12/2022] [Indexed: 05/24/2023]
Abstract
Immunotherapy has reached clinical success in the last decade, with the emergence of new and effective treatments such as checkpoint blockade therapy and CAR T-cell therapy that have drastically improved patient outcomes. Still, these therapies can be improved to limit off-target effects, mitigate systemic toxicities, and increase overall efficacies. Nanoscale engineering offers strategies that enable researchers to attain these goals through the manipulation of immune cell functions, such as enhancing immunity against cancers and pathogens, controlling the site of immune response, and promoting tolerance via the delivery of small molecule drugs or biologics. By tuning the properties of the nanomaterials, such as size, shape, charge, and surface chemistry, different types of immune cells can be targeted and engineered, such as dendritic cells for immunization, or T cells for promoting adaptive immunity. Researchers have come to better understand the critical role the immune system plays in the progression of pathologies besides cancer, and developing nanoengineering approaches that seek to harness the potential of immune cell activities can lead to favorable outcomes for the treatment of injuries and diseases.
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Affiliation(s)
- Skylar T Chuang
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Brandon Conklin
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Joshua B Stein
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - George Pan
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Ki-Bum Lee
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
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26
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Gierlikowski W, Gierlikowska B. MicroRNAs as Regulators of Phagocytosis. Cells 2022; 11:cells11091380. [PMID: 35563685 PMCID: PMC9106007 DOI: 10.3390/cells11091380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/11/2022] [Accepted: 04/17/2022] [Indexed: 12/10/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression and thus act as important regulators of cellular phenotype and function. As their expression may be dysregulated in numerous diseases, they are of interest as biomarkers. What is more, attempts of modulation of some microRNAs for therapeutic reasons have been undertaken. In this review, we discuss the current knowledge regarding the influence of microRNAs on phagocytosis, which may be exerted on different levels, such as through macrophages polarization, phagosome maturation, reactive oxygen species production and cytokines synthesis. This phenomenon plays an important role in numerous pathological conditions.
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Affiliation(s)
- Wojciech Gierlikowski
- Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
- Correspondence:
| | - Barbara Gierlikowska
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Żwirki i Wigury 63a, 02-091 Warsaw, Poland;
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27
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Tamming LA, Duque D, Tran A, Zhang W, Pfeifle A, Laryea E, Wu J, Raman SNT, Gravel C, Russell MS, Hashem AM, Alsulaiman RM, Alhabbab RY, Gao J, Safronetz D, Cao J, Wang L, Chen W, Johnston MJW, Sauve S, Rosu-Myles M, Li X. DNA Based Vaccine Expressing SARS-CoV-2 Spike-CD40L Fusion Protein Confers Protection Against Challenge in a Syrian Hamster Model. Front Immunol 2022; 12:785349. [PMID: 35095861 PMCID: PMC8789660 DOI: 10.3389/fimmu.2021.785349] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/10/2021] [Indexed: 12/03/2022] Open
Abstract
SARS-CoV-2 infections present a tremendous threat to public health. Safe and efficacious vaccines are the most effective means in preventing the infections. A variety of vaccines have demonstrated excellent efficacy and safety around the globe. Yet, development of alternative forms of vaccines remains beneficial, particularly those with simpler production processes, less stringent storage conditions, and the capability of being used in heterologous prime/boost regimens which have shown improved efficacy against many diseases. Here we reported a novel DNA vaccine comprised of the SARS-CoV-2 spike protein fused with CD40 ligand (CD40L) serving as both a targeting ligand and molecular adjuvant. A single intramuscular injection in Syrian hamsters induced significant neutralizing antibodies 3-weeks after vaccination, with a boost substantially improving immune responses. Moreover, the vaccine also reduced weight loss and suppressed viral replication in the lungs and nasal turbinates of challenged animals. Finally, the incorporation of CD40L into the DNA vaccine was shown to reduce lung pathology more effectively than the DNA vaccine devoid of CD40L. These results collectively indicate that this DNA vaccine candidate could be further explored because of its efficacy and known safety profile.
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Affiliation(s)
- Levi A. Tamming
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Diana Duque
- Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, ON, Canada
| | - Anh Tran
- Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, ON, Canada
| | - Wanyue Zhang
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Annabelle Pfeifle
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Emmanuel Laryea
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Jianguo Wu
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
| | - Sathya N. Thulasi Raman
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
| | - Caroline Gravel
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
| | - Marsha S. Russell
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
| | - Anwar M. Hashem
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Reem M. Alsulaiman
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Rowa Y. Alhabbab
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jun Gao
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
| | - David Safronetz
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Jingxin Cao
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Wangxue Chen
- Human Health Therapeutics Research Center, National Research Council of Canada, Ottawa, ON, Canada
| | - Michael J. W. Johnston
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
- Department of Chemistry, Carleton University, Ottawa, ON, Canada
| | - Simon Sauve
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
| | - Michael Rosu-Myles
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Xuguang Li
- Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada and World Health Organization Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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28
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Naik R, Peden K. Regulatory Considerations on the Development of mRNA Vaccines. Curr Top Microbiol Immunol 2022; 440:187-205. [PMID: 32638114 DOI: 10.1007/82_2020_220] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Developing traditional viral vaccines for infectious diseases usually takes years, as these are usually produced either by chemical inactivation of the virus or attenuation of the pathogen, processes that can take considerable time to validate and also require the live pathogen. With the advent of nucleic-acid vaccines (DNA and mRNA), the time to vaccine design and production is considerably shortened, since once the platform has been established, all that is required is the sequence of the antigen gene, its synthesis and insertion into an appropriate expression vector; importantly, no infectious virus is required. mRNA vaccines have some advantages over DNA vaccines, such as expression in non-dividing cells and the absence of the perceived risk of integration into host genome. Also, generally lower doses are required to induce the immune response. Based on experience in recent clinical trials, mRNA-based vaccines are a promising novel platform that might be useful for the development of vaccines against emerging pandemic infectious diseases. This chapter discusses some of the specific issues that mRNA vaccines raise with respect to production, quality, safety and efficacy, and how they have been addressed so as to allow their evaluation in clinical trials.
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Affiliation(s)
- Ramachandra Naik
- Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 71, Room 3045, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
| | - Keith Peden
- Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 52/72, Room 1220, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
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29
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Shafaati M, Saidijam M, Soleimani M, Hazrati F, Mirzaei R, Amirheidari B, Tanzadehpanah H, Karampoor S, Kazemi S, Yavari B, Mahaki H, Safaei M, Rahbarizadeh F, Samadi P, Ahmadyousefi Y. A brief review on DNA vaccines in the era of COVID-19. Future Virol 2021; 17:10.2217/fvl-2021-0170. [PMID: 34858516 PMCID: PMC8629371 DOI: 10.2217/fvl-2021-0170] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 11/05/2021] [Indexed: 02/08/2023]
Abstract
This article provides a brief overview of DNA vaccines. First, the basic DNA vaccine design strategies are described, then specific issues related to the industrial production of DNA vaccines are discussed, including the production and purification of DNA products such as plasmid DNA, minicircle DNA, minimalistic, immunologically defined gene expression (MIDGE) and Doggybone™. The use of adjuvants to enhance the immunogenicity of DNA vaccines is then discussed. In addition, different delivery routes and several physical and chemical methods to increase the efficacy of DNA delivery into cells are explained. Recent preclinical and clinical trials of DNA vaccines for COVID-19 are then summarized. Lastly, the advantages and obstacles of DNA vaccines are discussed.
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Affiliation(s)
- Maryam Shafaati
- Department of Microbiology, Faculty of Sciences, Jahrom Branch, Islamic Azad University, Jahrom, Iran
| | - Massoud Saidijam
- Department of Medical Biotechnology, School of Advanced Medical Sciences & Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Meysam Soleimani
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fereshte Hazrati
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Bagher Amirheidari
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
- Extremophile and Productive Microorganisms Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamid Tanzadehpanah
- Department of Medical Biotechnology, School of Advanced Medical Sciences & Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sajad Karampoor
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sima Kazemi
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Bahram Yavari
- Department of Medical Biotechnology, School of Advanced Medical Sciences & Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hanie Mahaki
- Vascular & Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Safaei
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Fatemeh Rahbarizadeh
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pouria Samadi
- Department of Medical Biotechnology, School of Advanced Medical Sciences & Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Yaghoub Ahmadyousefi
- Department of Medical Biotechnology, School of Advanced Medical Sciences & Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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30
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Insights into COVID-19 Vaccine Development Based on Immunogenic Structural Proteins of SARS-CoV-2, Host Immune Responses, and Herd Immunity. Cells 2021; 10:cells10112949. [PMID: 34831172 PMCID: PMC8616290 DOI: 10.3390/cells10112949] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/05/2021] [Accepted: 10/18/2021] [Indexed: 01/18/2023] Open
Abstract
The first quarter of the 21st century has remarkably been characterized by a multitude of challenges confronting human society as a whole in terms of several outbreaks of infectious viral diseases, such as the 2003 severe acute respiratory syndrome (SARS), China; the 2009 influenza H1N1, Mexico; the 2012 Middle East respiratory syndrome (MERS), Saudi Arabia; and the ongoing coronavirus disease 19 (COVID-19), China. COVID-19, caused by SARS-CoV-2, reportedly broke out in December 2019, Wuhan, the capital of China’s Hubei province, and continues unabated, leading to considerable devastation and death worldwide. The most common target organ of SARS-CoV-2 is the lungs, especially the bronchial and alveolar epithelial cells, culminating in acute respiratory distress syndrome (ARDS) in severe patients. Nevertheless, other tissues and organs are also known to be critically affected following infection, thereby complicating the overall aetiology and prognosis. Excluding H1N1, the SARS-CoV (also referred as SARS-CoV-1), MERS, and SARS-CoV-2 are collectively referred to as coronaviruses, and taxonomically placed under the realm Riboviria, order Nidovirales, suborder Cornidovirineae, family Coronaviridae, subfamily Orthocoronavirinae, genus Betacoronavirus, and subgenus Sarbecovirus. As of 23 September 2021, the ongoing SARS-CoV-2 pandemic has globally resulted in around 229 million and 4.7 million reported infections and deaths, respectively, apart from causing huge psychosomatic debilitation, academic loss, and deep economic recession. Such an unprecedented pandemic has compelled researchers, especially epidemiologists and immunologists, to search for SARS-CoV-2-associated potential immunogenic molecules to develop a vaccine as an immediate prophylactic measure. Amongst multiple structural and non-structural proteins, the homotrimeric spike (S) glycoprotein has been empirically found as the most suitable candidate for vaccine development owing to its immense immunogenic potential, which makes it capable of eliciting both humoral and cell-mediated immune responses. As a consequence, it has become possible to design appropriate, safe, and effective vaccines, apart from related therapeutic agents, to reduce both morbidity and mortality. As of 23 September 2021, four vaccines, namely, Comirnaty, COVID-19 vaccine Janssen, Spikevax, and Vaxzevria, have received the European Medicines Agency’s (EMA) approval, and around thirty are under the phase three clinical trial with emergency authorization by the vaccine-developing country-specific National Regulatory Authority (NRA). In addition, 100–150 vaccines are under various phases of pre-clinical and clinical trials. The mainstay of global vaccination is to introduce herd immunity, which would protect the majority of the population, including immunocompromised individuals, from infection and disease. Here, we primarily discuss category-wise vaccine development, their respective advantages and disadvantages, associated efficiency and potential safety aspects, antigenicity of SARS-CoV-2 structural proteins and immune responses to them along with the emergence of SARS-CoV-2 VOC, and the urgent need of achieving herd immunity to contain the pandemic.
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Verdecia M, Kokai-Kun JF, Kibbey M, Acharya S, Venema J, Atouf F. COVID-19 vaccine platforms: Delivering on a promise? Hum Vaccin Immunother 2021; 17:2873-2893. [PMID: 34033528 PMCID: PMC8381795 DOI: 10.1080/21645515.2021.1911204] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/24/2021] [Indexed: 12/13/2022] Open
Abstract
The emergence of the novel SARS-CoV-2 and COVID-19 has brought into sharp focus the need for a vaccine to prevent this disease. Vaccines have saved millions of lives since their introduction to the public over 200 years ago. The potential for vaccination reached new heights in the mid-20th century with the development of technologies that expanded the ability to create novel vaccines. Since then, there has been continued technological advancement in vaccine development. The resulting platforms provide the promise for solutions for many infectious diseases, including those that have been with us for decades as well as those just now emerging. Each vaccine platform represents a different technology with a unique set of advantages and challenges, especially when considering manufacturing. Therefore, it is essential to understand each platform as a separate product and process with its specific quality considerations. This review outlines the relevant platforms for developing a vaccine for SARS-CoV-2 and discusses the advantages and disadvantages of each.
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Affiliation(s)
- Mark Verdecia
- United States Pharmacopeial Convention, Rockville, MD, USA
| | | | - Maura Kibbey
- United States Pharmacopeial Convention, Rockville, MD, USA
| | - Sarita Acharya
- United States Pharmacopeial Convention, Rockville, MD, USA
| | - Jaap Venema
- United States Pharmacopeial Convention, Rockville, MD, USA
| | - Fouad Atouf
- United States Pharmacopeial Convention, Rockville, MD, USA
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32
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Chen X, Chen J, Zhuo BY, Yang X, Luo MB. Simulation study for the pulling translocation of a polymer globule. Polym J 2021. [DOI: 10.1038/s41428-021-00502-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Characterization of integration frequency and insertion sites of adenovirus DNA into mouse liver genomic DNA following intravenous injection. Gene Ther 2021; 29:322-332. [PMID: 34404916 DOI: 10.1038/s41434-021-00278-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/30/2021] [Accepted: 07/06/2021] [Indexed: 11/08/2022]
Abstract
While generally referred to as "non-integrating" vectors, adenovirus vectors have the potential to integrate into host DNA via random, illegitimate (nonhomologous) recombination. The present study provides a quantitative assessment of the potential integration frequency of adenovirus 5 (Ad5)-based vectors following intravenous injection in mice, a common route of administration in gene therapy applications particularly for transgene expression in liver. We examined the uptake level and persistence in liver of first generation (FG) and helper-dependent (HD) Ad5 vectors containing the mouse leptin transgene. As expected, the persistence of the HD vector was markedly higher than that of the FG vector. For both vectors, the majority of the vector DNA remained extrachromosomal and predominantly in the form of episomal monomers. However, using a quantitative gel-purification-based integration assay, a portion of the detectable vector was found to be associated with high molecular weight (HMW) genomic DNA, indicating potential integration with a frequency of up to ~44 and 7000 integration events per μg cellular genomic DNA (or ~0.0003 and 0.05 integrations per cell, respectively) for the FG and HD Ad5 vectors, respectively, following intravenous injection of 1 × 1011 virus particles. To confirm integration occurred (versus residual episomal vector DNA co-purifying with genomic DNA), we characterized nine independent integration events using Repeat-Anchored Integration Capture (RAIC) PCR. Sequencing of the insertion sites suggests that both of the vectors integrate randomly, but within short segments of homology between the vector breakpoint and the insertion site. Eight of the nine integrations were in intergenic DNA and one was within an intron. These findings represent the first quantitative assessment and characterization of Ad5 vector integration following intravenous administration in vivo in wild-type mice.
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Löffler P. Review: Vaccine Myth-Buster - Cleaning Up With Prejudices and Dangerous Misinformation. Front Immunol 2021; 12:663280. [PMID: 34177902 PMCID: PMC8222972 DOI: 10.3389/fimmu.2021.663280] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/24/2021] [Indexed: 12/19/2022] Open
Abstract
Although vaccines have already saved and will continue to save millions of lives, they are under attack. Vaccine safety is the main target of criticism. The rapid distribution of false information, or even conspiracy theories on the internet has tremendously favored vaccine hesitancy. The World Health Organization (WHO) named vaccine hesitancy one of the top ten threats to global health in 2019. Parents and patients have several concerns about vaccine safety, of which the ubiquitous anxieties include inactivating agents, adjuvants, preservatives, or new technologies such as genetic vaccines. In general, increasing doubts concerning side effects have been observed, which may lead to an increasing mistrust of scientific results and thus, the scientific method. Hence, this review targets five topics concerning vaccines and reviews current scientific publications in order to summarize the available information refuting conspiracy theories and myths about vaccination. The topics have been selected based on the author's personal perception of the most frequently occurring safety controversies: the inactivation agent formaldehyde, the adjuvant aluminum, the preservative mercury, the mistakenly-drawn correlation between vaccines and autism and genetic vaccines. The scientific literature shows that vaccine safety is constantly studied. Furthermore, the literature does not support the allegations that vaccines may cause a serious threat to general human life. The author suggests that more researchers explaining their research ideas, methods and results publicly could strengthen the general confidence in science. In general, vaccines present one of the safest and most cost-effective medications and none of the targeted topics raised serious health concerns.
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Affiliation(s)
- Paul Löffler
- Institute for Environmental Sciences, University of Koblenz-Landau, Landau, Germany
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Nano-Microparticle Platforms in Developing Next-Generation Vaccines. Vaccines (Basel) 2021; 9:vaccines9060606. [PMID: 34198865 PMCID: PMC8228777 DOI: 10.3390/vaccines9060606] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/03/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022] Open
Abstract
The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.
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Abstract
PURPOSE OF REVIEW The development of mRNA vaccines against coronavirus disease 2019 has brought worldwide attention to the transformative potential of RNA-based therapeutics. The latter is essentially biological software that can be rapidly designed and generated, with an extensive catalog of applications. This review aims to highlight the mechanisms of action by which RNA-based drugs can affect specific gene targets and how RNA drugs can be employed to treat cardiovascular disease, with the focus on the therapeutics being evaluated in clinical trials. The recent advances in nanotechnology aiding the translation of such therapies into the clinic are also discussed. RECENT FINDINGS There is a growing body of studies demonstrating utility of RNA for targeting previously 'undruggable' pathways involved in development and progression of cardiovascular disease. Some challenges in RNA delivery have been overcome thanks to nanotechnology. There are several RNA-based drugs to treat hypercholesterolemia and myocardial infarction which are currently in clinical trials. SUMMARY RNA therapeutics is a rapidly emerging field of biotherapeutics based upon a powerful and versatile platform with a nearly unlimited capacity to address unmet clinical needs. These therapeutics are destined to change the standard of care for many diseases, including cardiovascular disease.
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Affiliation(s)
- Christian Boada
- RNA Therapeutics Program, Department of Cardiovascular Sciences, Houston Methodist Academic Institute, TX
- Texas A&M School of Medicine, College Station, TX
| | - Roman Sukhovershin
- RNA Therapeutics Program, Department of Cardiovascular Sciences, Houston Methodist Academic Institute, TX
| | | | - John P. Cooke
- RNA Therapeutics Program, Department of Cardiovascular Sciences, Houston Methodist Academic Institute, TX
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Damase TR, Sukhovershin R, Boada C, Taraballi F, Pettigrew RI, Cooke JP. The Limitless Future of RNA Therapeutics. Front Bioeng Biotechnol 2021; 9:628137. [PMID: 33816449 PMCID: PMC8012680 DOI: 10.3389/fbioe.2021.628137] [Citation(s) in RCA: 337] [Impact Index Per Article: 84.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/15/2021] [Indexed: 12/19/2022] Open
Abstract
Recent advances in the generation, purification and cellular delivery of RNA have enabled development of RNA-based therapeutics for a broad array of applications. RNA therapeutics comprise a rapidly expanding category of drugs that will change the standard of care for many diseases and actualize personalized medicine. These drugs are cost effective, relatively simple to manufacture, and can target previously undruggable pathways. It is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized RNA constructs. In this review we discuss general concepts of different classes of RNA-based therapeutics, including antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and messenger RNA. Furthermore, we provide an overview of the RNA-based therapies that are currently being evaluated in clinical trials or have already received regulatory approval. The challenges and advantages associated with use of RNA-based drugs are also discussed along with various approaches for RNA delivery. In addition, we introduce a new concept of hospital-based RNA therapeutics and share our experience with establishing such a platform at Houston Methodist Hospital.
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Affiliation(s)
- Tulsi Ram Damase
- RNA Therapeutics Program, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Roman Sukhovershin
- RNA Therapeutics Program, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Christian Boada
- Colleges of Medicine, Engineering, Texas A&M University and Houston Methodist Hospital, Houston, TX, United States
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, United States
- Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX, United States
| | - Roderic I. Pettigrew
- Colleges of Medicine, Engineering, Texas A&M University and Houston Methodist Hospital, Houston, TX, United States
| | - John P. Cooke
- RNA Therapeutics Program, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
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Transfected DNA is targeted by STING-mediated restriction. Biochem Biophys Res Commun 2021; 549:207-213. [PMID: 33684697 DOI: 10.1016/j.bbrc.2021.02.109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 02/23/2021] [Indexed: 11/20/2022]
Abstract
DNA transfection is routinely used for delivering expression of gene of interest to target cells. Transfected DNA has been known to activate cellular DNA sensor(s) and innate immune responses, but the effects of such responses on transfected DNA are not fully understood. STING (stimulator of interferon genes) is an important adaptor protein in cellular innate immune response to various DNA and RNA stimuli and upon activation induces significant type I interferon responses. In this work, we characterized the effects of STING on gene expression driven by transfected double-stranded DNA. We observed that gene expression from transfected DNA was repressed in the presence of overexpressed STING, but increased if endogenous STING was knocked down through RNA interference. Endogenous chromosomal genes and chromosome-integrated exogenous genes were not affected by such STING-mediated restriction, which did not depend on DNA circularity or linearity, promoter used, or bacterial sequences in transfected DNA. Mechanistically, STING-mediated repression of transfected DNA correlates with reduced mRNA levels, and partially involves the induction of interferon β production by STING. Collectively, these data indicate that episomal double-stranded DNA is targeted by STING-mediated cell defense.
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Pushparajah D, Jimenez S, Wong S, Alattas H, Nafissi N, Slavcev RA. Advances in gene-based vaccine platforms to address the COVID-19 pandemic. Adv Drug Deliv Rev 2021; 170:113-141. [PMID: 33422546 PMCID: PMC7789827 DOI: 10.1016/j.addr.2021.01.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/23/2020] [Accepted: 01/01/2021] [Indexed: 01/07/2023]
Abstract
The novel betacoronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spread across the globe at an unprecedented rate since its first emergence in Wuhan City, China in December 2019. Scientific communities around the world have been rigorously working to develop a potent vaccine to combat COVID-19 (coronavirus disease 2019), employing conventional and novel vaccine strategies. Gene-based vaccine platforms based on viral vectors, DNA, and RNA, have shown promising results encompassing both humoral and cell-mediated immune responses in previous studies, supporting their implementation for COVID-19 vaccine development. In fact, the U.S. Food and Drug Administration (FDA) recently authorized the emergency use of two RNA-based COVID-19 vaccines. We review current gene-based vaccine candidates proceeding through clinical trials, including their antigenic targets, delivery vehicles, and route of administration. Important features of previous gene-based vaccine developments against other infectious diseases are discussed in guiding the design and development of effective vaccines against COVID-19 and future derivatives.
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Affiliation(s)
- Deborah Pushparajah
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada
| | - Salma Jimenez
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada; Theraphage, 151 Charles St W Suite # 199, Kitchener, ON, N2G 1H6, Canada
| | - Shirley Wong
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada
| | - Hibah Alattas
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada
| | - Nafiseh Nafissi
- Mediphage Bioceuticals, 661 University Avenue, Suite 1300, Toronto, ON, M5G 0B7, Canada
| | - Roderick A Slavcev
- School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener N2G 1C5, Canada; Mediphage Bioceuticals, 661 University Avenue, Suite 1300, Toronto, ON, M5G 0B7, Canada; Theraphage, 151 Charles St W Suite # 199, Kitchener, ON, N2G 1H6, Canada.
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Fomsgaard A, Liu MA. The Key Role of Nucleic Acid Vaccines for One Health. Viruses 2021; 13:258. [PMID: 33567520 PMCID: PMC7916035 DOI: 10.3390/v13020258] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/02/2021] [Accepted: 02/05/2021] [Indexed: 01/07/2023] Open
Abstract
The ongoing SARS-CoV-2 pandemic has highlighted both the importance of One Health, i.e., the interactions and transmission of pathogens between animals and humans, and the potential power of gene-based vaccines, specifically nucleic acid vaccines. This review will highlight key aspects of the development of plasmid DNA Nucleic Acid (NA) vaccines, which have been licensed for several veterinary uses, and tested for a number of human diseases, and will explain how an understanding of their immunological and real-world attributes are important for their efficacy, and how they helped pave the way for mRNA vaccines. The review highlights how combining efforts for vaccine development for both animals and humans is crucial for advancing new technologies and for combatting emerging diseases.
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Affiliation(s)
- Anders Fomsgaard
- Department of Virology and Microbiological Special Diagnostic, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen, Denmark
| | - Margaret A. Liu
- ProTherImmune, 3656 Happy Valley Road, Lafayette, CA 94549, USA
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Liu CH, Huang HY, Tu YF, Lai WY, Wang CL, Sun JR, Chien Y, Lin TW, Lin YY, Chien CS, Huang CH, Chen YM, Huang PI, Wang FD, Yang YP. Highlight of severe acute respiratory syndrome coronavirus-2 vaccine development against COVID-19 pandemic. J Chin Med Assoc 2021; 84:9-13. [PMID: 33186212 DOI: 10.1097/jcma.0000000000000461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has brought an unprecedented impact upon the global economy and public health. Although the SARS-CoV-2 virology has been gradually investigated, measures to combat this new threat in public health are still absent. To date, no certificated drug or vaccine has been developed for the treatment or prevention of coronavirus disease Extensive researches and international coordination has been conducted to rapidly develop novel vaccines against SARS-CoV-2 pandemic. Several major breakthroughs have been made through the identification of the genetic sequence and structural/non-structural proteins of SARS-CoV-2, which enabled the development of RNA-, DNA-based vaccines, subunit vaccines, and attenuated viral vaccines. In this review article, we present an overview of the recent advances of SARS-CoV-2 vaccines and the challenges that may be encountered in the development process, highlighting the advantages and disadvantages of these approaches that may help in effectively countering COVID-19.
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Affiliation(s)
- Cheng-Hsuan Liu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming Medical University, Taipei, Taiwan, ROC
| | - Hsuan-Yang Huang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yung-Fang Tu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming Medical University, Taipei, Taiwan, ROC
| | - Wei-Yi Lai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chia-Lin Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Jun-Ren Sun
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yueh Chien
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Tzu-Wei Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ying Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chian-Shiu Chien
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chih-Heng Huang
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yuh-Min Chen
- School of Medicine, National Yang-Ming Medical University, Taipei, Taiwan, ROC
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pin-I Huang
- School of Medicine, National Yang-Ming Medical University, Taipei, Taiwan, ROC
- Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fu-Der Wang
- School of Medicine, National Yang-Ming Medical University, Taipei, Taiwan, ROC
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming Medical University, Taipei, Taiwan, ROC
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Integrase-Defective Lentiviral Vectors for Delivery of Monoclonal Antibodies against Influenza. Viruses 2020; 12:v12121460. [PMID: 33348840 PMCID: PMC7767071 DOI: 10.3390/v12121460] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/07/2020] [Accepted: 12/14/2020] [Indexed: 12/21/2022] Open
Abstract
Delivering rapid protection against infectious agents to non-immune populations is a formidable public health challenge. Although passive immunotherapy is a fast and effective method of protection, large-scale production and administration of monoclonal antibodies (mAbs) is expensive and unpractical. Viral vector-mediated delivery of mAbs offers an attractive alternative to their direct injection. Integrase-defective lentiviral vectors (IDLV) are advantageous for this purpose due to the absence of pre-existing anti-vector immunity and the safety features of non-integration and non-replication. We engineered IDLV to produce the humanized mAb VN04-2 (IDLV-VN04-2), which is broadly neutralizing against H5 influenza A virus (IAV), and tested the vectors’ ability to produce antibodies and protect from IAV in vivo. We found that IDLV-transduced cells produced functional VN04-2 mAbs in a time- and dose-dependent fashion. These mAbs specifically bind the hemagglutinin (HA), but not the nucleoprotein (NP) of IAV. VN04-2 mAbs were detected in the serum of mice at different times after intranasal (i.n.) or intramuscular (i.m.) administration of IDLV-VN04-2. Administration of IDLV-VN04-2 by the i.n. route provided rapid protection against lethal IAV challenge, although the protection did not persist at later time points. Our data suggest that administration of mAb-expressing IDLV may represent an effective strategy for rapid protection against infectious diseases.
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McNee A, Smith TRF, Holzer B, Clark B, Bessell E, Guibinga G, Brown H, Schultheis K, Fisher P, Ramos S, Nunez A, Bernard M, Graham S, Martini V, Chrun T, Xiao Y, Kash JC, Taubenberger JK, Elliott S, Patel A, Beverley P, Rijal P, Weiner DB, Townsend A, Broderick KE, Tchilian E. Establishment of a Pig Influenza Challenge Model for Evaluation of Monoclonal Antibody Delivery Platforms. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 205:648-660. [PMID: 32591390 PMCID: PMC7372317 DOI: 10.4049/jimmunol.2000429] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/29/2020] [Indexed: 12/14/2022]
Abstract
mAbs are a possible adjunct to vaccination and drugs in treatment of influenza virus infection. However, questions remain whether small animal models accurately predict efficacy in humans. We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing mAbs. We show that a strongly neutralizing mAb (2-12C) against the hemagglutinin head administered prophylactically at 15 mg/kg reduced viral load and lung pathology after pandemic H1N1 influenza challenge. A lower dose of 1 mg/kg of 2-12C or a DNA plasmid-encoded version of 2-12C reduced pathology and viral load in the lungs but not viral shedding in nasal swabs. We propose that the pig influenza model will be useful for testing candidate mAbs and emerging delivery platforms prior to human trials.
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Affiliation(s)
- Adam McNee
- The Pirbright Institute, Pirbright GU24 0NF, United Kingdom
| | | | - Barbara Holzer
- The Pirbright Institute, Pirbright GU24 0NF, United Kingdom
| | - Becky Clark
- The Pirbright Institute, Pirbright GU24 0NF, United Kingdom
| | - Emily Bessell
- The Pirbright Institute, Pirbright GU24 0NF, United Kingdom
| | | | | | | | | | | | - Alejandro Nunez
- Animal and Plant Health Agency-Weybridge, New Haw, Addlestone KT15 3NB, United Kingdom
| | - Matthieu Bernard
- Animal and Plant Health Agency-Weybridge, New Haw, Addlestone KT15 3NB, United Kingdom
| | - Simon Graham
- The Pirbright Institute, Pirbright GU24 0NF, United Kingdom
| | | | - Tiphany Chrun
- The Pirbright Institute, Pirbright GU24 0NF, United Kingdom
| | - Yongli Xiao
- Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3203
| | - John C Kash
- Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3203
| | - Jeffery K Taubenberger
- Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3203
| | - Sarah Elliott
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19103
| | - Ami Patel
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19103
| | - Peter Beverley
- National Heart and Lung Institute, St Mary's Campus, Imperial College London, London W2 1PG, United Kingdom; and
| | - Pramila Rijal
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
| | - David B Weiner
- Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA 19103
| | - Alain Townsend
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom
| | | | - Elma Tchilian
- The Pirbright Institute, Pirbright GU24 0NF, United Kingdom;
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Barra F, Della Corte L, Noberasco G, Foreste V, Riemma G, Di Filippo C, Bifulco G, Orsi A, Icardi G, Ferrero S. Advances in therapeutic vaccines for treating human papillomavirus-related cervical intraepithelial neoplasia. J Obstet Gynaecol Res 2020; 46:989-1006. [PMID: 32390320 DOI: 10.1111/jog.14276] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 03/23/2020] [Accepted: 04/12/2020] [Indexed: 12/29/2022]
Abstract
AIM Human papillomavirus (HPV) is the etiologic agent of the majority of cervical intraepithelial lesions (CIN) and cervical cancers. While prophylactic HPV vaccines prevent infections from the main high-risk HPV types associated with cervical cancer, alternative nonsurgical and nonablative therapeutics to treat HPV infection and preinvasive HPV diseases have been experimentally investigated. Therapeutic vaccines are an emerging investigational strategy. This review aims to introduce the results of the main clinical trials on the use of therapeutic vaccines for treating HPV infection and -related CIN, reporting the ongoing studies on this field. METHODS Data research was conducted using MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library querying for all articles related to therapeutic vaccines for the treatment of HPV-related CIN. Selection criteria included randomized clinical trials, nonrandomized controlled studies and review articles. RESULTS Preliminary data are available on the evaluation of therapeutic vaccines for treating cervical HPV infections and CIN. Despite having in vitro demonstrated to obtain humoral and cytotoxic responses, therapeutic vaccines have not yet clinically demonstrated consistent success; moreover, each class of therapeutic vaccines has advantages and limitations. Early clinical data are available in the literature for these compounds, except for MVA E2, which reached the phase III clinical trial status, obtaining positive clinical outcomes. CONCLUSION Despite promising results, to date many obstacles are still present before hypothesize an introduction in the clinical practice within the next years. Further studies will draw a definitive conclusion on the role of therapeutic vaccines in this setting.
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Affiliation(s)
- Fabio Barra
- Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Luigi Della Corte
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giovanni Noberasco
- Department of Health Sciences (DiSSal), University of Genoa, Genoa, Italy
| | - Virginia Foreste
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gaetano Riemma
- Department of Woman, Child and General and Specialized Surgery, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Claudia Di Filippo
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Giuseppe Bifulco
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Andrea Orsi
- Department of Health Sciences (DiSSal), University of Genoa, Genoa, Italy.,HygieneUnit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Giancarlo Icardi
- Department of Health Sciences (DiSSal), University of Genoa, Genoa, Italy.,HygieneUnit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Simone Ferrero
- Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
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Wassie T, Zeng F, Jiang X, Liu G, Kasimu H, Ling S, Girmay S. Effect of Kisspeptin-54 immunization on performance, carcass characteristics, meat quality and safety of Yiling goats. Meat Sci 2020; 166:108139. [PMID: 32289558 DOI: 10.1016/j.meatsci.2020.108139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 03/08/2020] [Accepted: 04/04/2020] [Indexed: 02/07/2023]
Abstract
This study aimed to evaluate the effects of kisspeptin-54 immunocastration vaccine on performance, carcass characteristics, meat quality, and safety of Yiling goats. Thirty buck goats were randomly assigned into three groups: PVAX-B2L-Kisspeptin-54-asd immunized (PBK-asd), control, and surgically castrated. PBK-asd immunization significantly stimulated serum anti-kisspeptin antibody production and reduced testosterone hormone compared with the control group (p < .05). Interestingly, PBK-asd plasmid did not integrate into the host genome and had no significant effect on growth hormone, body weight, and average daily gain (ADG). Conversely, surgical castration significantly reduced ADG and carcass weight compared to the control group. Furthermore, PBK-asd immunization did not affect carcass characteristics (dressing percentage, loin area, and fat thickness) and meat quality traits (pH, color, cooking loss, drip loss, and shearing force). These results indicate that the Kisspeptin-54 DNA vaccine is safe and has potential to be used as an alternative to surgical castration for goats without negatively affecting carcass and meat quality.
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Affiliation(s)
- Teketay Wassie
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Fanmei Zeng
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Xunping Jiang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, People's Republic of China; Laboratory of Sheep and Goat Genetics, Breeding and Reproduction, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, People's Republic of China.
| | - Guiqiong Liu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, People's Republic of China; Laboratory of Sheep and Goat Genetics, Breeding and Reproduction, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Hailati Kasimu
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Sun Ling
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
| | - Shishay Girmay
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, People's Republic of China
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Smalley Rumfield C, Roller N, Pellom ST, Schlom J, Jochems C. Therapeutic Vaccines for HPV-Associated Malignancies. Immunotargets Ther 2020; 9:167-200. [PMID: 33117742 PMCID: PMC7549137 DOI: 10.2147/itt.s273327] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/03/2020] [Indexed: 12/13/2022] Open
Abstract
Human papillomavirus (HPV)-related malignancies are responsible for almost all cases of cervical cancer in women, and over 50% of all cases of head and neck carcinoma. Worldwide, HPV-positive malignancies account for 4.5% of the global cancer burden, or over 600,000 cases per year. HPV infection is a pressing public health issue, as more than 80% of all individuals have been exposed to HPV by age 50, representing an important target for vaccine development to reduce the incidence of cancer and the economic cost of HPV-related health issues. The approval of Gardasil® as a prophylactic vaccine for high-risk HPV 16 and 18 and low-risk HPV6 and 11 for people aged 11-26 in 2006, and of Cervarix® in 2009, revolutionized the field and has since reduced HPV infection in young populations. Unfortunately, prophylactic vaccination does not induce immunity in those with established HPV infections or HPV-induced neoplasms, and there are currently no therapeutic HPV vaccines approved by the US Food and Drug Administration. This comprehensive review will detail the progress made in the development of therapeutic vaccines against high-risk HPV types, and potential combinations with other immunotherapeutic agents for more efficient and rational designs of combination treatments for HPV-associated malignancies.
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Affiliation(s)
- Claire Smalley Rumfield
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Nicholas Roller
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Samuel Troy Pellom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Correspondence: Jeffrey Schlom Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Room 8B09, Bethesda, MD20892, USATel +1 240-858-3463Fax +1 240-541-4558 Email
| | - Caroline Jochems
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Zhao X, Long J, Liang F, Liu N, Sun Y, Xi Y. Dynamic profiles, biodistribution and integration evaluation after intramuscular/intravenous delivery of a novel therapeutic DNA vaccine encoding chicken type II collagen for rheumatoid arthritis in vaccinated normal rodent. J Nanobiotechnology 2019; 17:94. [PMID: 31492169 PMCID: PMC6729025 DOI: 10.1186/s12951-019-0528-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 08/28/2019] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The persistence, biodistribution, and risk of integration into the host genome of any new therapeutic DNA vaccine must be established in preclinical studies. We previously developed the DNA vaccine pcDNA-CCOL2A1 encoding chicken type II collagen (CCII) for the treatment of rheumatoid arthritis (RA). In the present study, we characterized its dynamic profile, biodistribution, and potential for genomic DNA integration in normal vaccinated rodent. RESULTS A real-time quantitative PCR analysis (RT-qPCR) of animals administered a single dose of pcDNA-CCOL2A1 (300 μg/kg by intramuscular injection) showed that CCOL2A1 mRNA level in the blood peaked between 2 and 6 h post-immunization and then rapidly declined, and was undetectable between day 1-42. CCOL2A1 transcript was detected at the muscle injection site on days 3-14 post-immunization. Starting from day 14, the transcript was detected in the heart, liver, lung, and kidney but not in the spleen or thymus, and was expressed only in the lung on day 28. There was no CCOL2A1 mRNA present in the testes or ovaries at any time point. Non-invasive in vivo fluorescence imaging revealed CCII protein expression from 2 h up to day 10 and from 2 h up to day 35 after administration of pcDNA-CCOL2A1 via the intravenous and intramuscular routes, respectively; the protein had disappeared by day 42. Importantly, CCOL2A1 was not integrated into the host genome. CONCLUSIONS These results indicate that pcDNA-CCOL2A1 vaccine is rapidly cleared within a short period of time and is therefore safe, and merits further development as a therapeutic vaccine for RA treatment.
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Affiliation(s)
- Xiao Zhao
- Department of Immunology and National Center for Biomedicine Analysis, the Fifth Medical Center (formerly known as Beijing 307 Hospital), Chinese PLA General Hospital, No. 8, Dongda Ave, Fengtai District, Beijing, 100071, People's Republic of China
| | - Juan Long
- Department of Immunology and National Center for Biomedicine Analysis, the Fifth Medical Center (formerly known as Beijing 307 Hospital), Chinese PLA General Hospital, No. 8, Dongda Ave, Fengtai District, Beijing, 100071, People's Republic of China
| | - Fei Liang
- Department of Immunology and National Center for Biomedicine Analysis, the Fifth Medical Center (formerly known as Beijing 307 Hospital), Chinese PLA General Hospital, No. 8, Dongda Ave, Fengtai District, Beijing, 100071, People's Republic of China
| | - Nan Liu
- Department of Immunology and National Center for Biomedicine Analysis, the Fifth Medical Center (formerly known as Beijing 307 Hospital), Chinese PLA General Hospital, No. 8, Dongda Ave, Fengtai District, Beijing, 100071, People's Republic of China
| | - Yuying Sun
- Department of Immunology and National Center for Biomedicine Analysis, the Fifth Medical Center (formerly known as Beijing 307 Hospital), Chinese PLA General Hospital, No. 8, Dongda Ave, Fengtai District, Beijing, 100071, People's Republic of China
| | - Yongzhi Xi
- Department of Immunology and National Center for Biomedicine Analysis, the Fifth Medical Center (formerly known as Beijing 307 Hospital), Chinese PLA General Hospital, No. 8, Dongda Ave, Fengtai District, Beijing, 100071, People's Republic of China.
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Liu MA. A Comparison of Plasmid DNA and mRNA as Vaccine Technologies. Vaccines (Basel) 2019; 7:E37. [PMID: 31022829 PMCID: PMC6631684 DOI: 10.3390/vaccines7020037] [Citation(s) in RCA: 279] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 04/19/2019] [Accepted: 04/20/2019] [Indexed: 12/13/2022] Open
Abstract
This review provides a comparison of the theoretical issues and experimental findings for plasmid DNA and mRNA vaccine technologies. While both have been under development since the 1990s, in recent years, significant excitement has turned to mRNA despite the licensure of several veterinary DNA vaccines. Both have required efforts to increase their potency either via manipulating the plasmid DNA and the mRNA directly or through the addition of adjuvants or immunomodulators as well as delivery systems and formulations. The greater inherent inflammatory nature of the mRNA vaccines is discussed for both its potential immunological utility for vaccines and for the potential toxicity. The status of the clinical trials of mRNA vaccines is described along with a comparison to DNA vaccines, specifically the immunogenicity of both licensed veterinary DNA vaccines and select DNA vaccine candidates in human clinical trials.
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Affiliation(s)
- Margaret A Liu
- ProTherImmune, 3656 Happy Valley Road, Lafayette, CA 94549, USA.
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Van Hoecke L, Roose K. How mRNA therapeutics are entering the monoclonal antibody field. J Transl Med 2019; 17:54. [PMID: 30795778 PMCID: PMC6387507 DOI: 10.1186/s12967-019-1804-8] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/17/2019] [Indexed: 01/06/2023] Open
Abstract
In 1975, Milstein and Köhler revolutionized the medical world with the development of the hybridoma technique to produce monoclonal antibodies. Since then, monoclonal antibodies have entered almost every branch of biomedical research. Antibodies are now used as frontline therapeutics in highly divergent indications, ranging from autoimmune disease over allergic asthma to cancer. Wider accessibility and implementation of antibody-based therapeutics is however hindered by manufacturing challenges and high development costs inherent to protein-based drugs. For these reasons, alternative ways are being pursued to produce and deliver antibodies more cost-effectively without hampering safety. Over the past decade, messenger RNA (mRNA) based drugs have emerged as a highly appealing new class of biologics that can be used to encode any protein of interest directly in vivo. Whereas current clinical efforts to use mRNA as a drug are mainly situated at the level of prophylactic and therapeutic vaccination, three recent preclinical studies have addressed the feasibility of using mRNA to encode therapeutic antibodies directly in vivo. Here, we highlight the potential of mRNA-based approaches to solve several of the issues associated with antibodies produced and delivered in protein format. Nonetheless, we also identify key hurdles that mRNA-based approaches still need to take to fulfill this potential and ultimately replace the current protein antibody format.
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Affiliation(s)
- Lien Van Hoecke
- VIB Center for Medical Biotechnology, VIB, Ghent, Belgium. .,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
| | - Kenny Roose
- VIB Center for Medical Biotechnology, VIB, Ghent, Belgium.,Departement of Biochemistry and Microbiology, Ghent University, Ghent, Belgium
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Engineered mRNA-expressed antibodies prevent respiratory syncytial virus infection. Nat Commun 2018; 9:3999. [PMID: 30275522 PMCID: PMC6167369 DOI: 10.1038/s41467-018-06508-3] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 09/10/2018] [Indexed: 01/12/2023] Open
Abstract
The lung is a critical prophylaxis target for clinically important infectious agents, including human respiratory syncytial virus (RSV) and influenza. Here, we develop a modular, synthetic mRNA-based approach to express neutralizing antibodies directly in the lung via aerosol, to prevent RSV infections. First, we express palivizumab, which reduces RSV F copies by 90.8%. Second, we express engineered, membrane-anchored palivizumab, which prevents detectable infection in transfected cells, reducing in vitro titer and in vivo RSV F copies by 99.7% and 89.6%, respectively. Finally, we express an anchored or secreted high-affinity, anti-RSV F, camelid antibody (RSV aVHH and sVHH). We demonstrate that RSV aVHH, but not RSV sVHH, significantly inhibits RSV 7 days post transfection, and we show that RSV aVHH is present in the lung for at least 28 days. Overall, our data suggests that expressing membrane-anchored broadly neutralizing antibodies in the lungs could potentially be a promising pulmonary prophylaxis approach. Engineered neutralizing antibodies are potential therapeutics for numerous viruses, such as respiratory syncytial virus (RSV). Here, the authors develop an mRNA-based approach to express membrane-anchored neutralizing antibodies in the lung and demonstrate that it inhibits RSV infections in mice.
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