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1
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Batisani K. The role of mRNA vaccines in infectious diseases: a new era of immunization. Trop Dis Travel Med Vaccines 2025; 11:12. [PMID: 40369626 PMCID: PMC12079950 DOI: 10.1186/s40794-025-00246-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 01/24/2025] [Indexed: 05/16/2025] Open
Abstract
The emergence of messenger RNA (mRNA) vaccines has marked a seminal shift in the field of immunization, heralding an era characterized by unprecedented speed and efficacy in the face of infectious diseases. The global crisis caused by the COVID-19 pandemic catalyzed the rapid development and deployment of two leading mRNA vaccines, Comirnaty and SpikeVax, showcasing not only the technological promise of mRNA, but also its transformative potential in public health strategies. This study seeks to provide an in-depth exploration of the foundational elements of mRNA vaccine technology, elucidate its unique advantages over traditional vaccine platforms, analyze the existing challenges that public health officials face, and envision future applications that extend far beyond current expectations. Through this exploration, we advocate for the integration of mRNA technology into existing public health frameworks to enhance global health security and adaptability in the face of emerging infectious threats.
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Affiliation(s)
- Kesaobaka Batisani
- School of Medicine and Health Sciences, University of Lusaka, Lusaka, Zambia.
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2
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Gulati GK, Simpson AC, MacMillen Z, Krieger K, Sharma S, Erasmus JH, Reed SG, Davie JW, Avril M, Khandhar AP. Preclinical development of lyophilized self-replicating RNA vaccines for COVID-19 and malaria with improved long-term thermostability. J Control Release 2025; 377:81-92. [PMID: 39547422 DOI: 10.1016/j.jconrel.2024.11.023] [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: 06/18/2024] [Revised: 10/02/2024] [Accepted: 11/10/2024] [Indexed: 11/17/2024]
Abstract
Messenger RNA (mRNA) vaccines against COVID-19 have demonstrated high efficacy and rapid deployment capability to target emerging infectious diseases. However, the need for ultra-low temperature storage made the distribution of LNP/mRNA vaccines to regions with limited resources impractical. This study explores the use of lyophilization to enhance the stability of self-replicating mRNA (repRNA) vaccines, allowing for their storage at non-freezing temperatures such as 2-8 °C or room temperature (25 °C). We lyophilized repRNA molecules complexed to a novel cationic emulsion delivery system, LION™, with different sugar-based lyoprotectants to identify candidates that provided the best vaccine integrity and effectiveness after being thermally stressed. For screening, we used repRNA encoding the reporter protein secreted embryonic alkaline phosphatase (SEAP) and for proof-of-concept, we used repRNA vaccines encoding SARS-CoV-2 full-length spike (WA-1 isolate) or full-length surface protein circumsporozoite (CS) of Plasmodium yoelii (Py). We found that lyophilization of LION/repRNA with sucrose provided the best colloidal stability, preserved in vitro expression, and induced equivalent antigen-specific antibody responses in mice compared to freshly prepared liquid LION/repRNA. Furthermore, lyophilized vaccines were stable for at least one week at 25 °C and at least one year at 2-8 °C. The cumulative analysis of stability-determining physicochemical data, in vitro potency, and in vivo immunogenicity in mice enabled the selection of a lead lyophilized composition containing 10 % w/v sucrose as the lyoprotectant. The data presented here provide a foundation for the clinical evaluation of next-generation thermostable repRNA vaccines that will enable more equitable vaccine access globally.
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Affiliation(s)
- Gaurav K Gulati
- HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA.
| | | | - Zachary MacMillen
- MalarVx, Inc, 1551 Eastlake Ave E, Suite 100, Seattle, WA 98102, USA
| | - Kyle Krieger
- HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA
| | - Shibbu Sharma
- HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA
| | - Jesse H Erasmus
- HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA
| | - Steven G Reed
- HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA
| | - James W Davie
- MalarVx, Inc, 1551 Eastlake Ave E, Suite 100, Seattle, WA 98102, USA
| | - Marion Avril
- MalarVx, Inc, 1551 Eastlake Ave E, Suite 100, Seattle, WA 98102, USA
| | - Amit P Khandhar
- HDT Bio, 1150 Eastlake Ave E Suite 200A, Seattle, WA 98109, USA.
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3
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Lokras AG, Bobak TR, Baghel SS, Sebastiani F, Foged C. Advances in the design and delivery of RNA vaccines for infectious diseases. Adv Drug Deliv Rev 2024; 213:115419. [PMID: 39111358 DOI: 10.1016/j.addr.2024.115419] [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: 03/01/2024] [Revised: 07/19/2024] [Accepted: 07/30/2024] [Indexed: 08/23/2024]
Abstract
RNA medicines represent a paradigm shift in treatment and prevention of critical diseases of global significance, e.g., infectious diseases. The highly successful messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were developed at record speed during the coronavirus disease 2019 pandemic. A consequence of this is exceptionally shortened vaccine development times, which in combination with adaptability makes the RNA vaccine technology highly attractive against infectious diseases and for pandemic preparedness. Here, we review state of the art in the design and delivery of RNA vaccines for infectious diseases based on different RNA modalities, including linear mRNA, self-amplifying RNA, trans-amplifying RNA, and circular RNA. We provide an overview of the clinical pipeline of RNA vaccines for infectious diseases, and present analytical procedures, which are paramount for characterizing quality attributes and guaranteeing their quality, and we discuss future perspectives for using RNA vaccines to combat pathogens beyond SARS-CoV-2.
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Affiliation(s)
- Abhijeet Girish Lokras
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Thomas Rønnemoes Bobak
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Saahil Sandeep Baghel
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
| | - Federica Sebastiani
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark; Division of Physical Chemistry, Department of Chemistry, Lund University, 22100, Lund, Sweden
| | - Camilla Foged
- Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
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4
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Kitandwe PK, Rogers P, Hu K, Nayebare O, Blakney AK, McKay PF, Kaleebu P, Shattock RJ. A Lipid Nanoparticle-Formulated Self-Amplifying RNA Rift Valley Fever Vaccine Induces a Robust Humoral Immune Response in Mice. Vaccines (Basel) 2024; 12:1088. [PMID: 39460255 PMCID: PMC11511412 DOI: 10.3390/vaccines12101088] [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: 07/26/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 10/28/2024] Open
Abstract
Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that causes high fetal and neonatal mortality rates in ruminants and sometimes severe to fatal complications like encephalitis and hemorrhagic fever in humans. There is no licensed RVF vaccine for human use while approved livestock vaccines have suboptimal safety or efficacy. We designed self-amplifying RNA (saRNA) RVF vaccines and assessed their humoral immunogenicity in mice. Plasmid DNA encoding the Rift Valley fever virus (RVFV) medium (M) segment consensus sequence (WT consensus) and its derivatives mutated to enhance cell membrane expression of the viral surface glycoproteins n (Gn) and c (Gc) were assessed for in vitro expression. The WT consensus and best-expressing derivative (furin-T2A) were cloned into a Venezuelan equine encephalitis virus (VEEV) plasmid DNA replicon and in vitro transcribed into saRNA. The saRNA was formulated in lipid nanoparticles and its humoral immunogenicity in BALB/c mice was assessed. High quantities of dose-dependent RVFV Gn IgG antibodies were detected in the serum of all mice immunized with either WT consensus or furin-T2A saRNA RVF vaccines. Significant RVFV pseudovirus-neutralizing activity was induced in mice immunized with 1 µg or 10 µg of the WT consensus saRNA vaccine. The WT consensus saRNA RVF vaccine warrants further development.
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Affiliation(s)
- Paul K. Kitandwe
- MRC/UVRI & LSHTM Uganda Research Unit, Plot 51-59 Nakiwogo Road, Entebbe P.O. Box 49, Uganda; (O.N.); (P.K.)
| | - Paul Rogers
- Department of Infectious Diseases, Imperial College London, Norfolk Place, London W2 1PG, UK; (P.R.); (K.H.); (A.K.B.); (P.F.M.); (R.J.S.)
| | - Kai Hu
- Department of Infectious Diseases, Imperial College London, Norfolk Place, London W2 1PG, UK; (P.R.); (K.H.); (A.K.B.); (P.F.M.); (R.J.S.)
| | - Owen Nayebare
- MRC/UVRI & LSHTM Uganda Research Unit, Plot 51-59 Nakiwogo Road, Entebbe P.O. Box 49, Uganda; (O.N.); (P.K.)
| | - Anna K. Blakney
- Department of Infectious Diseases, Imperial College London, Norfolk Place, London W2 1PG, UK; (P.R.); (K.H.); (A.K.B.); (P.F.M.); (R.J.S.)
| | - Paul F. McKay
- Department of Infectious Diseases, Imperial College London, Norfolk Place, London W2 1PG, UK; (P.R.); (K.H.); (A.K.B.); (P.F.M.); (R.J.S.)
| | - Pontiano Kaleebu
- MRC/UVRI & LSHTM Uganda Research Unit, Plot 51-59 Nakiwogo Road, Entebbe P.O. Box 49, Uganda; (O.N.); (P.K.)
- Uganda Virus Research Institute, Plot 51-59, Nakiwogo Road, Entebbe P.O. Box 49, Uganda
| | - Robin J. Shattock
- Department of Infectious Diseases, Imperial College London, Norfolk Place, London W2 1PG, UK; (P.R.); (K.H.); (A.K.B.); (P.F.M.); (R.J.S.)
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5
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Sha CM, Wang J, Dokholyan NV. Predicting 3D RNA structure from the nucleotide sequence using Euclidean neural networks. Biophys J 2024; 123:2671-2681. [PMID: 37838833 PMCID: PMC11393712 DOI: 10.1016/j.bpj.2023.10.011] [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: 08/07/2023] [Revised: 09/19/2023] [Accepted: 10/12/2023] [Indexed: 10/16/2023] Open
Abstract
Fast and accurate 3D RNA structure prediction remains a major challenge in structural biology, mostly due to the size and flexibility of RNA molecules, as well as the lack of diverse experimentally determined structures of RNA molecules. Unlike DNA structure, RNA structure is far less constrained by basepair hydrogen bonding, resulting in an explosion of potential stable states. Here, we propose a convolutional neural network that predicts all pairwise distances between residues in an RNA, using a recently described smooth parametrization of Euclidean distance matrices. We achieve high-accuracy predictions on RNAs up to 100 nt in length in fractions of a second, a factor of 107 faster than existing molecular dynamics-based methods. We also convert our coarse-grained machine learning output into an all-atom model using discrete molecular dynamics with constraints. Our proposed computational pipeline predicts all-atom RNA models solely from the nucleotide sequence. However, this method suffers from the same limitation as nucleic acid molecular dynamics: the scarcity of available RNA crystal structures for training.
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Affiliation(s)
- Congzhou M Sha
- Department of Engineering Science and Mechanics, Penn State University, State College, Pennsylvania; Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania
| | - Jian Wang
- Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania
| | - Nikolay V Dokholyan
- Department of Engineering Science and Mechanics, Penn State University, State College, Pennsylvania; Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania; Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, Pennsylvania; Department of Chemistry, Penn State University, State College, Pennsylvania; Department of Biomedical Engineering, Penn State University, State College, Pennsylvania.
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6
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Mahroum N, Habra M, Alrifaai MA, Shoenfeld Y. Antiphospholipid syndrome in the era of COVID-19 - Two sides of a coin. Autoimmun Rev 2024; 23:103543. [PMID: 38604461 DOI: 10.1016/j.autrev.2024.103543] [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: 01/31/2024] [Revised: 04/08/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
In addition to the respiratory symptoms associated with COVID-19, the disease has consistently been linked to many autoimmune diseases such as systemic lupus erythematous and antiphospholipid syndrome (APS). APS in particular was of paramount significance due to its devastating clinical sequela. In fact, the hypercoagulable state seen in patients with acute COVID-19 and the critical role of anticoagulant treatment in affected individuals shed light on the possible relatedness between APS and COVID-19. Moreover, the role of autoimmunity in the assumed association is not less important especially with the accumulated data available regarding the autoimmunity-triggering effect of SARS-CoV-2 infection. This is furtherly strengthened at the time patients with COVID-19 manifested antiphospholipid antibodies of different types following infection. Additionally, the severe form of the APS spectrum, catastrophic APS (CAPS), was shown to have overlapping characteristics with severe COVID-19 such as cytokine storm and multi-organ failure. Interestingly, COVID vaccine-induced autoimmune phenomena described in the medical literature have pointed to an association with APS. Whether the antiphospholipid antibodies were present or de novo, COVID vaccine-induced vascular thrombosis in certain individuals necessitates further investigations regarding the possible mechanisms involved. In our current paper, we aimed to focus on the associations mentioned, their implications, importance, and consequences.
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Affiliation(s)
- Naim Mahroum
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
| | - Mona Habra
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | | | - Yehuda Shoenfeld
- Zabludowicz Center for autoimmune diseases, Sheba Medical Center, Ramat-Gan, Israel; Reichman University, Herzliya, Israel
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7
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Kulkarni NA, Nanjappa SG. Advances in Dendritic-Cell-Based Vaccines against Respiratory Fungal Infections. Vaccines (Basel) 2024; 12:981. [PMID: 39340013 PMCID: PMC11435842 DOI: 10.3390/vaccines12090981] [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: 07/24/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Ever since the discovery of dendritic cells by Ralph Steinman and Zanvil Cohn in 1973, it is increasingly evident that dendritic cells are integral for adaptive immune responses, and there is an undeniable focus on them for vaccines development. Fungal infections, often thought to be innocuous, are becoming significant threats due to an increased immunocompromised or immune-suppressed population and climate change. Further, the recent COVID-19 pandemic unraveled the wrath of fungal infections and devastating outcomes. Invasive fungal infections cause significant case fatality rates ranging from 20% to 90%. Regrettably, no licensed fungal vaccines exist, and there is an urgent need for preventive and therapeutic purposes. In this review, we discuss the ontogeny, subsets, tissue distribution, and functions of lung dendritic cells. In the latter part, we summarize and discuss the studies on the DC-based vaccines against pulmonary fungal infections. Finally, we highlight some emerging potential avenues that can be incorporated for DC-based vaccines against fungal infections.
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Affiliation(s)
| | - Som G. Nanjappa
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61802, USA
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8
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Opsomer L, Jana S, Mertens I, Cui X, Hoogenboom R, Sanders NN. Efficient in vitro and in vivo transfection of self-amplifying mRNA with linear poly(propylenimine) and poly(ethylenimine-propylenimine) random copolymers as non-viral carriers. J Mater Chem B 2024; 12:3927-3946. [PMID: 38563779 DOI: 10.1039/d3tb03003b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Messenger RNA (mRNA) based vaccines have been introduced worldwide to combat the Covid-19 pandemic. These vaccines consist of non-amplifying mRNA formulated in lipid nanoparticles (LNPs). Consequently, LNPs are considered benchmark non-viral carriers for nucleic acid delivery. However, the formulation and manufacturing of these mRNA-LNP nanoparticles are expensive and time-consuming. Therefore, we used self-amplifying mRNA (saRNA) and synthesized novel polymers as alternative non-viral carrier platform to LNPs, which enable a simple, rapid, one-pot formulation of saRNA-polyplexes. Our novel polymer-based carrier platform consists of randomly concatenated ethylenimine and propylenimine comonomers, resulting in linear, poly(ethylenimine-ran-propylenimine) (L-PEIx-ran-PPIy) copolymers with controllable degrees of polymerization. Here we demonstrate in multiple cell lines, that our saRNA-polyplexes show comparable to higher in vitro saRNA transfection efficiencies and higher cell viabilities compared to formulations with Lipofectamine MessengerMAX™ (LFMM), a commercial, lipid-based carrier considered to be the in vitro gold standard carrier. This is especially true for our in vitro best performing saRNA-polyplexes with N/P 5, which are characterised with a size below 100 nm, a positive zeta potential, a near 100% encapsulation efficiency, a high retention capacity and the ability to protect the saRNA from degradation mediated by RNase A. Furthermore, an ex vivo hemolysis assay with pig red blood cells demonstrated that the saRNA-polyplexes exhibit negligible hemolytic activity. Finally, a bioluminescence-based in vivo study was performed over a 35-day period, and showed that the polymers result in a higher and prolonged bioluminescent signal compared to naked saRNA and L-PEI based polyplexes. Moreover, the polymers show different expression profiles compared to those of LNPs, with one of our new polymers (L-PPI250) demonstrating a higher sustained expression for at least 35 days after injection.
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Affiliation(s)
- Lisa Opsomer
- Laboratory of Gene Therapy, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, B-9820 Merelbeke, Belgium.
| | - Somdeb Jana
- Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, 9000 Ghent, Belgium.
| | - Ine Mertens
- Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, 9000 Ghent, Belgium.
| | - Xiaole Cui
- Laboratory of Gene Therapy, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, B-9820 Merelbeke, Belgium.
| | - Richard Hoogenboom
- Supramolecular Chemistry Group, Centre of Macromolecular Chemistry (CMaC), Department of Organic and Macromolecular Chemistry, Ghent University, 9000 Ghent, Belgium.
| | - Niek N Sanders
- Laboratory of Gene Therapy, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, B-9820 Merelbeke, Belgium.
- Cancer Research Institute (CRIG), Ghent University, B-9000 Ghent, Belgium
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9
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Nawaz S, Janiad S, Fatima A, Saleem M, Fatima U, Ali A. Rapidly Evolving SARS-CoV-2: A Brief Review Regarding the Variants and their Effects on Vaccine Efficacies. Infect Disord Drug Targets 2024; 24:58-66. [PMID: 38178666 DOI: 10.2174/0118715265271109231129112515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/14/2023] [Accepted: 10/26/2023] [Indexed: 01/06/2024]
Abstract
Since the commencement of Corona Virus Disease 2019 (COVID-19) pandemic, which has resulted in millions of mortalities globally, the efforts to minimize the damages have equally been up to the task. One of those efforts includes the mass vaccine development initiative targeting the deadly Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). So far, vaccines have tremendously decreased the rate of transmission and infection in most parts of the world. However, the repeated resurgence of different types of mutated versions of the virus, also known as variants, has somehow created uncertainties about the efficacies of different types of vaccines. This review discusses some of the interesting SARS-CoV-2 features, including general structure, genomics, and mechanisms of variants development and their consequent immune escape. This review also focuses very briefly on antigenic drift, shift, and vaccine-developing platforms.
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Affiliation(s)
- Shahid Nawaz
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Sara Janiad
- Department of Microbiology and Molecular Genetics, The Women University Multan, Multan, Pakistan
| | - Aiman Fatima
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Maira Saleem
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Urooj Fatima
- Department of Microbiology and Molecular Genetics, The Women University Multan, Multan, Pakistan
| | - Asad Ali
- Institute of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
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10
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Adhikary S, Buttar HS, Tuli HS, Kaur G. Exploring the promise of COVID-19 vaccines: A review of preclinical studies. FEATURES, TRANSMISSION, DETECTION, AND CASE STUDIES IN COVID-19 2024:389-399. [DOI: 10.1016/b978-0-323-95646-8.00052-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Casmil IC, Huang C, Blakney AK. A duplex droplet digital PCR assay for absolute quantification and characterization of long self-amplifying RNA. Sci Rep 2023; 13:19050. [PMID: 37923834 PMCID: PMC10624827 DOI: 10.1038/s41598-023-46314-6] [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: 03/02/2023] [Accepted: 10/30/2023] [Indexed: 11/06/2023] Open
Abstract
Self-amplifying messenger ribonucleic acid (saRNA) provides extended expression of genes of interest by encoding an alphavirus-derived RNA replicase and thus is 2-3 times larger than conventional messenger RNA. However, quality assessment of long RNA transcripts is challenging using standard techniques. Here, we utilized a multiplex droplet digital polymerase chain reaction (ddPCR) assay to assess the quality of saRNA produced from an in vitro transcription reaction and the replication kinetics in human cell lines. Using the one-step reverse transcription ddPCR, we show that an in vitro transcription generates 50-60% full-length saRNA transcripts. However, we note that the two-step reverse transcription ddPCR assay results in a 20% decrease from results obtained using the one-step and confirmed using capillary gel electrophoresis. Additionally, we provided three formulas that differ in the level of stringency and assumptions made to calculate the fraction of intact saRNA. Using ddPCR, we also showed that subgenomic transcripts of saRNA were 19-to-108-fold higher than genomic transcripts at different hours post-transfection of mammalian cells in copies. Therefore, we demonstrate that multiplex ddPCR is well suited for quality assessment of long RNA and replication kinetics of saRNA based on absolute quantification.
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Affiliation(s)
- Irafasha C Casmil
- Michael Smith Laboratories, School of Biomedical Engineering, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Cynthia Huang
- Michael Smith Laboratories, School of Biomedical Engineering, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Anna K Blakney
- Michael Smith Laboratories, School of Biomedical Engineering, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
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12
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Abstract
RNA modification is manifested as chemically altered nucleotides, widely exists in diverse natural RNAs, and is closely related to RNA structure and function. Currently, mRNA-based vaccines have received great attention and rapid development as novel and mighty fighters against various diseases including cancer. The achievement of RNA vaccines in clinical application is largely attributed to some methodological innovations including the incorporation of modified nucleotides into the synthetic RNA. The selection of optimal RNA modifications aimed at reducing the instability and immunogenicity of RNA molecules is a very critical task to improve the efficacy and safety of mRNA vaccines. This review summarizes the functions of RNA modifications and their application in mRNA vaccines, highlights recent advances of mRNA vaccines in cancer immunotherapy, and provides perspectives for future development of mRNA vaccines in the context of personalized tumor therapy.
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Affiliation(s)
- Yingxue Mei
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China
| | - Xiang Wang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116044, Liaoning, People's Republic of China.
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13
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Yihunie W, Nibret G, Aschale Y. Recent Advances in Messenger Ribonucleic Acid (mRNA) Vaccines and Their Delivery Systems: A Review. Clin Pharmacol 2023; 15:77-98. [PMID: 37554660 PMCID: PMC10405914 DOI: 10.2147/cpaa.s418314] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/28/2023] [Indexed: 08/10/2023] Open
Abstract
Messenger ribonucleic acid (mRNA) was found as the intermediary that transfers genetic information from DNA to ribosomes for protein synthesis in 1961. The emergency use authorization of the two covid-19 mRNA vaccines, BNT162b2 and mRNA-1273, is a significant achievement in the history of vaccine development. Because they are generated in a cell-free environment using the in vitro transcription (IVT) process, mRNA vaccines are risk-free. Moreover, chemical modifications to the mRNA molecule, such as cap structures and changed nucleosides, have proved critical in overcoming immunogenicity concerns, achieving sustained stability, and achieving effective, accurate protein production in vivo. Several vaccine delivery strategies (including protamine, lipid nanoparticles (LNPs), polymers, nanoemulsions, and cell-based administration) were also optimized to load and transport RNA into the cytosol. LNPs, which are composed of a cationic or a pH-dependent ionizable lipid layer, a polyethylene glycol (PEG) component, phospholipids, and cholesterol, are the most advanced systems for delivering mRNA vaccines. Moreover, modifications of the four components that make up the LNPs showed to increase vaccine effectiveness and reduce side effects. Furthermore, the introduction of biodegradable lipids improved LNP biocompatibility. Furthermore, mRNA-based therapies are expected to be effective treatments for a variety of refractory conditions, including infectious diseases, metabolic genetic diseases, cancer, cardiovascular and cerebrovascular diseases. Therefore, the present review aims to provide the scientific community with up-to-date information on mRNA vaccines and their delivery systems.
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Affiliation(s)
- Wubetu Yihunie
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Getinet Nibret
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Yibeltal Aschale
- Department of Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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14
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Loh JT, Lam KP. Fungal infections: Immune defense, immunotherapies and vaccines. Adv Drug Deliv Rev 2023; 196:114775. [PMID: 36924530 DOI: 10.1016/j.addr.2023.114775] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/05/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
Invasive fungal infection is an under recognized and emerging global health threat. Recently, the World Health Organization (WHO) released the first ever list of health-threatening fungi to guide research and public health interventions to strengthen global response to fungi infections and antifungal resistance. Currently, antifungal drugs only demonstrate partial success in improving prognosis of infected patients, and this is compounded by the rapid evolution of drug resistance among fungi species. The increased prevalence of fungal infections in individuals with underlying immunological deficiencies reflects the importance of an intact host immune system in controlling mycoses, and further highlights immunomodulation as a potential new avenue for the treatment of disseminated fungal diseases. In this review, we will summarize how host innate immune cells sense invading fungi through their pattern recognition receptors, and subsequently initiate a series of effector mechanisms and adaptive immune responses to mediate fungal clearance. In addition, we will discuss emerging preclinical and clinical data on antifungal immunotherapies and fungal vaccines which can potentially expand our antifungal armamentarium in future.
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Affiliation(s)
- Jia Tong Loh
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, S138648, Republic of Singapore.
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science, Technology and Research, 8A Biomedical Grove, S138648, Republic of Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5, Science Drive 2, S117545, Republic of Singapore; School of Biological Sciences, College of Science, Nanyang Technological University, 60, Nanyang Drive, S637551, Republic of Singapore.
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15
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Mavrovouniotis I, Fylaktou A, Stagou M, Ouranos K, Lioulios G, Evgenikaki E, Exindari M, Gioula G. Cellular and Humoral Responses in Dialysis Patients after Vaccination with the BNT162b2 or mRNA-1273 Vaccines. Life (Basel) 2023; 13:life13020474. [PMID: 36836831 PMCID: PMC9967689 DOI: 10.3390/life13020474] [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: 12/22/2022] [Revised: 01/24/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
The outbreak of SARS-CoV-2 has raised considerable concern about the detrimental effects it can induce in public health, with the interest of the scientific community being focused on the development of preventive and therapeutic approaches. Patients with end-stage renal disease (ESRD) are amongst vulnerable populations for critical illness owing to the presence of other comorbidities, their defective immune system, and their inability of self-isolation. To date, vaccination constitutes the most promising method to manage viral dispersion. Therefore, it is particularly important to investigate the effectiveness of available vaccines against SARS-CoV-2 in this risk group. Here, we summarize initial experience regarding the humoral and cellular immune responses elicited in dialysis patients after completion of the recommended vaccination regimen, as well as after booster dose administration, with one of the two mRNA vaccines, namely, BNT162b2 and mRNA-1273. In conclusion, a significantly diminished and delayed immune pattern was observed in ESRD patients compared to healthy population, with a peak in antibody titers occurring 3-5 weeks after the second dose. A booster dose significantly augmented the immune response in dialysis patients with either mRNA-based vaccine. Variables adversely correlating with the weak immunogenicity observed in dialysis patients include immunosuppressive therapy, older age, comorbidities, longer time in hemodialysis treatment, and higher body mass index. On the contrary, previous COVID-19 infection and administration of the mRNA-1273 vaccine are deemed to induce a more favorable immune response. Further investigation is needed to thoroughly understand the efficacy of mRNA-based vaccines in hemodialysis patients and define predictive factors that can influence it.
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Affiliation(s)
- Ilias Mavrovouniotis
- Microbiology Department, Medical School, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Asimina Fylaktou
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, 54642 Thessaloniki, Greece
| | - Maria Stagou
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece
| | - Konstantinos Ouranos
- Microbiology Department, Medical School, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
- Correspondence:
| | - Georgios Lioulios
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece
| | - Efthimia Evgenikaki
- National Peripheral Histocompatibility Center, Immunology Department, Hippokration General Hospital, 54642 Thessaloniki, Greece
| | - Maria Exindari
- Microbiology Department, Medical School, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Georgia Gioula
- Microbiology Department, Medical School, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
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16
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Miao G, Chen Z, Cao H, Wu W, Chu X, Liu H, Zhang L, Zhu H, Cai H, Lu X, Shi J, Liu Y, Feng T. From Immunogen to COVID-19 vaccines: Prospects for the post-pandemic era. Biomed Pharmacother 2023; 158:114208. [PMID: 36800265 PMCID: PMC9805901 DOI: 10.1016/j.biopha.2022.114208] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/30/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023] Open
Abstract
The COVID-19 pandemic has affected millions of people and posed an unprecedented burden on healthcare systems and economies worldwide since the outbreak of the COVID-19. A considerable number of nations have investigated COVID-19 and proposed a series of prevention and treatment strategies thus far. The pandemic prevention strategies implemented in China have suggested that the spread of COVID-19 can be effectively reduced by restricting large-scale gathering, developing community-scale nucleic acid testing, and conducting epidemiological investigations, whereas sporadic cases have always been identified in numerous places. Currently, there is still no decisive therapy for COVID-19 or related complications. The development of COVID-19 vaccines has raised the hope for mitigating this pandemic based on the intercross immunity induced by COVID-19. Thus far, several types of COVID-19 vaccines have been developed and released to into financial markets. From the perspective of vaccine use in globe, COVID-19 vaccines are beneficial to mitigate the pandemic, whereas the relative adverse events have been reported progressively. This is a review about the development, challenges and prospects of COVID-19 vaccines, and it can provide more insights into all aspects of the vaccines.
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Affiliation(s)
- Ganggang Miao
- Department of General Surgery, The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Danyang, China,Department of General Surgery, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Zhiqiang Chen
- Department of Nuclear Medicine, The First Affiliated Hospital of Suzhou University, Suzhou, China
| | - Hengsong Cao
- Department of General Surgery, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Wenhao Wu
- Department of Clinical Medicine, Nanjing Medical University The First School of Clinical Medicine, Nanjing, China
| | - Xi Chu
- Department of Radiology, Nanjing Medical University The Fourth School of Clinical Medicine, Nanjing, China
| | - Hanyuan Liu
- Department of General Surgery, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, China
| | - Leyao Zhang
- Department of Clinical Medicine, Nanjing Medical University The First School of Clinical Medicine, Nanjing, China
| | - Hongfei Zhu
- Department of Clinical Medicine, Nanjing Medical University The First School of Clinical Medicine, Nanjing, China
| | - Hongzhou Cai
- Department of Urology, Jiangsu Cancer Hospital &The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Institute of Cancer Research, Nanjing, China.
| | - Xiaolan Lu
- Department of Clinical laboratory, Canglang Hospital of Suzhou, Suzhou, China.
| | - Junfeng Shi
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Department of Molecular and Celluar Biochemistry, Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
| | - Yuan Liu
- Department of Infectious Disease,The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Tingting Feng
- Jiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow University, Suzhou, China.
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17
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Musa HH, Musa TH. A systematic and thematic analysis of the top 100 cited articles on mRNA vaccine indexed in Scopus database. Hum Vaccin Immunother 2022; 18:2135927. [PMID: 36328513 DOI: 10.1080/21645515.2022.2135927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The success of mRNA vaccines against SARS-CoV-2 implies that this technology can be applied to target any pathogen. However, the scientific production and research trends using the bibliometric method are still unknown. The top 100 most cited articles on mRNA vaccine research were obtained from the Scopus database from 1995 to 2021. Bibliometrix, an R-Package, and VOSviewer 1.6.11 were used for data analysis. There is a rapid growth in scientific outputs with a gradual increase in 2021. The United States produced 45 (45%) of the articles, followed by Germany with 15 (15%) and Israel with 10 (10%). The New England Journal of Medicine published the most papers in this field 13 (13%), followed by Nature 6(6%). Barney S. Graham was the most productive author among the top 100 most cited mRNA vaccine articles. University of Pennsylvania Perelman School of Medicine, US, was the top ranking institution, having 37 (37%). The visualization map clearly and spontaneously displayed the current state and research hot spots of mRNA research from a specific perspective. The most frequent keywords were COVID-19, vaccine, mRNA vaccine, mRNA, SARS-CoV-2, and immunogenicity, among others. A systematic review of the articles provided evidence that out of 100 articles, approximately 25 (25%) were focused on vaccine production and evaluation, followed by 26 (26%) in mRNA vaccine safety and efficacy, 23 (23%) were into mRNA vaccination, 23 (23%) considered risk factors associated with mRNA vaccination, while 8 (8%) of the articles covered the issue of mRNA vaccine delivery. In addition, 42% of the articles focused on COVID-19, 17% on cancer, 8% on influenza virus, 4% on COVID-19 and kidney disease, 3% COVID-19 and myocarditis, and 3% on rabies virus, among others. The findings of this systematic and thematic analysis provided the knowledge basis for further research on mRNA vaccines globally.
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Affiliation(s)
- Hassan H Musa
- CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.,Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum, Sudan
| | - Taha H Musa
- Biomedical Research Institute, Darfur University College, Nyala, Sudan.,Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
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18
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Provine NM, Klenerman P. Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity. Eur J Immunol 2022:10.1002/eji.202250022. [PMID: 36330560 PMCID: PMC9877955 DOI: 10.1002/eji.202250022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/05/2022] [Accepted: 11/02/2022] [Indexed: 11/06/2022]
Abstract
Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real-world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8+ T cell and antibody responses are induced by each of these vaccine platforms, and how this can be impacted by specific vaccine construction techniques. Key gaps in our knowledge are also highlighted, which can hopefully focus future studies.
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Affiliation(s)
- Nicholas M. Provine
- Translational Gastroenterology UnitNuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Paul Klenerman
- Translational Gastroenterology UnitNuffield Department of MedicineUniversity of OxfordOxfordUK,Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUK
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19
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Papukashvili D, Rcheulishvili N, Liu C, Ji Y, He Y, Wang PG. Self-Amplifying RNA Approach for Protein Replacement Therapy. Int J Mol Sci 2022; 23:12884. [PMID: 36361673 PMCID: PMC9655356 DOI: 10.3390/ijms232112884] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 07/30/2023] Open
Abstract
Messenger RNA (mRNA) technology has already been successfully tested preclinically and there are ongoing clinical trials for protein replacement purposes; however, more effort has been put into the development of prevention strategies against infectious diseases. Apparently, mRNA vaccine approval against coronavirus disease 2019 (COVID-19) is a landmark for opening new opportunities for managing diverse health disorders based on this approach. Indeed, apart from infectious diseases, it has also been widely tested in numerous directions including cancer prevention and the treatment of inherited disorders. Interestingly, self-amplifying RNA (saRNA)-based technology is believed to display more developed RNA therapy compared with conventional mRNA technique in terms of its lower dosage requirements, relatively fewer side effects, and possessing long-lasting effects. Nevertheless, some challenges still exist that need to be overcome in order to achieve saRNA-based drug approval in clinics. Hence, the current review discusses the feasibility of saRNA utility for protein replacement therapy on various health disorders including rare hereditary diseases and also provides a detailed overview of saRNA advantages, its molecular structure, mechanism of action, and relevant delivery platforms.
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Affiliation(s)
| | | | | | | | - Yunjiao He
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China
| | - Peng George Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518000, China
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20
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Gao RY, Riley CM, Toth E, Blair RH, Gerold MN, McCormick C, Taylor AW, Hu T, Rowlen KL, Dawson ED. Rapid Identity and Quantity CQA Test for Multivalent mRNA Drug Product Formulations. Vaccines (Basel) 2022; 10:vaccines10101704. [PMID: 36298569 PMCID: PMC9612012 DOI: 10.3390/vaccines10101704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 09/29/2022] [Accepted: 10/09/2022] [Indexed: 01/09/2023] Open
Abstract
The COVID-19 pandemic highlighted mRNA as a promising platform for vaccines and therapeutics. Many of the analytical tools used to characterize the critical quality attributes of mRNA are inherently singleplex and are not necessarily optimal from a labor and cost perspective. Here, we demonstrate the feasibility of a multiplexed platform (VaxArray) for efficient identity verification and concentration determination for both monovalent and multivalent mRNA formulations. A model system comprising mRNA constructs for influenza hemagglutinin and neuraminidase was used to characterize the analytical performance metrics for a VaxArray mRNA assay. The assay presented herein had a time to result of less than 2 h, required no PCR-based amplification nor extraction of mRNA from lipid nanoparticles, and exhibited high construct specificity that enabled application to the bivalent mixture. The sensitivity for influenza hemagglutinin and neuraminidase mRNA was sub-µg/mL, which is vaccine-relevant, and the average accuracy (%recovery of a check standard) and precision were 104 ± 2% and 9 ± 2%, respectively.
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21
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Immunoprophylaxis using polypeptide chimera vaccines plus adjuvant system promote Th1 response controlling the spleen parasitism in hamster model of visceral leishmaniasis. Vaccine 2022; 40:5494-5503. [PMID: 35963820 DOI: 10.1016/j.vaccine.2022.08.005] [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: 03/24/2022] [Revised: 07/20/2022] [Accepted: 08/03/2022] [Indexed: 11/23/2022]
Abstract
In recent years, several advances have been observed in vaccinology especially for neglected tropical diseases (NTDs). One of the tools employed is epitope prediction by immunoinformatic approaches that reduce the time and cost to develop a vaccine. In this scenario, immunoinformatics is being more often used to develop vaccines for NTDs, in particular visceral leishmaniasis (VL) which is proven not to have an effective vaccine yet. Based on that, in a previous study, two predicted T-cell multi-epitope chimera vaccines were experimentally validated in BALB/c mice to evaluate the immunogenicity, central and effector memory and protection against VL. Considering the results obtained in the mouse model, we assessed the immune response of these chimeras inMesocricetus auratushamster, which displays, experimentally, similar pathological status to human and dog VL disease. Our findings indicate that both chimeras lead to a dominant Th1 response profile, inducing a strong cellular response by increasing the production of IFN-γ and TNF-α cytokines associated with a decrease in IL-10. Also, the chimeras reduced the spleen parasite load and the weight a correlation between protector immunological mechanisms and consistent reduction of the parasitic load was observed. Our results demonstrate that both chimeras were immunogenic and corroborate with findings in the mouse model. Therefore, we reinforce the use of the hamster as a pre-clinical model in vaccination trials for canine and human VL and the importance of immunoinformatic to identify epitopes to design vaccines for this important neglected disease.
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22
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Venter JC, Glass JI, Hutchison CA, Vashee S. Synthetic chromosomes, genomes, viruses, and cells. Cell 2022; 185:2708-2724. [PMID: 35868275 PMCID: PMC9347161 DOI: 10.1016/j.cell.2022.06.046] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 10/17/2022]
Abstract
Synthetic genomics is the construction of viruses, bacteria, and eukaryotic cells with synthetic genomes. It involves two basic processes: synthesis of complete genomes or chromosomes and booting up of those synthetic nucleic acids to make viruses or living cells. The first synthetic genomics efforts resulted in the construction of viruses. This led to a revolution in viral reverse genetics and improvements in vaccine design and manufacture. The first bacterium with a synthetic genome led to construction of a minimal bacterial cell and recoded Escherichia coli strains able to incorporate multiple non-standard amino acids in proteins and resistant to phage infection. Further advances led to a yeast strain with a synthetic genome and new approaches for animal and plant artificial chromosomes. On the horizon there are dramatic advances in DNA synthesis that will enable extraordinary new opportunities in medicine, industry, agriculture, and research.
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Affiliation(s)
- J Craig Venter
- The J. Craig Venter Institute, La Jolla, CA, and Rockville, MD, USA.
| | - John I Glass
- The J. Craig Venter Institute, La Jolla, CA, and Rockville, MD, USA
| | | | - Sanjay Vashee
- The J. Craig Venter Institute, La Jolla, CA, and Rockville, MD, USA
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23
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Rice A, Verma M, Voigt E, Battisti P, Beaver S, Reed S, Dinkins K, Mody S, Zakin L, Tanaka S, Morimoto B, Olson CA, Gabitzsch E, Safrit JT, Spilman P, Casper C, Soon-Shiong P. Heterologous saRNA Prime, DNA Dual-Antigen Boost SARS-CoV-2 Vaccination Elicits Robust Cellular Immunogenicity and Cross-Variant Neutralizing Antibodies. Front Immunol 2022; 13:910136. [PMID: 35911728 PMCID: PMC9335885 DOI: 10.3389/fimmu.2022.910136] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/22/2022] [Indexed: 11/21/2022] Open
Abstract
We assessed if immune responses are enhanced in CD-1 mice by heterologous vaccination with two different nucleic acid-based COVID-19 vaccines: a next-generation human adenovirus serotype 5 (hAd5)-vectored dual-antigen spike (S) and nucleocapsid (N) vaccine (AdS+N) and a self-amplifying and -adjuvanted S RNA vaccine (AAHI-SC2) delivered by a nanostructured lipid carrier. The AdS+N vaccine encodes S modified with a fusion motif to increase cell-surface expression and an N antigen modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal compartment and increase MHC class I and II stimulation potential. The S sequence in the AAHI-SC2 vaccine comprises the D614G mutation, two prolines to stabilize S in the prefusion conformation, and 3 glutamines in the furin cleavage region to confer protease resistance. CD-1 mice received vaccination by homologous and heterologous prime > boost combinations. Humoral responses to S were the highest with any regimen that included the AAHI-SC2 vaccine, and IgG bound to wild type and Delta (B.1.617.2) variant S1 at similar levels. An AAHI-SC2 prime followed by an AdS+N boost particularly enhanced CD4+ and CD8+ T-cell responses to both wild type and Delta S peptides relative to all other vaccine regimens. Sera from mice receiving AAHI-SC2 homologous or heterologous vaccination were found to be highly neutralizing for all pseudovirus strains tested: Wuhan, Beta, Delta, and Omicron strains. The findings here, taken in consideration with the availability of both vaccines in thermostable formulations, support the testing of heterologous vaccination by an AAHI-SC2 > AdS+N regimen in animal models of SARS-CoV-2 infection to assess its potential to provide increased protection against emerging SARS-CoV-2 variants particularly in regions of the world where the need for cold-chain storage has limited the distribution of other vaccines.
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Affiliation(s)
- Adrian Rice
- ImmunityBio, Inc., Culver City, CA, United States
| | - Mohit Verma
- ImmunityBio, Inc., Culver City, CA, United States
| | - Emily Voigt
- Access to Advanced Health Institute (AAHI), Seattle, WA, United States
| | - Peter Battisti
- Access to Advanced Health Institute (AAHI), Seattle, WA, United States
| | - Sam Beaver
- Access to Advanced Health Institute (AAHI), Seattle, WA, United States
| | - Sierra Reed
- Access to Advanced Health Institute (AAHI), Seattle, WA, United States
| | - Kyle Dinkins
- ImmunityBio, Inc., Culver City, CA, United States
| | - Shivani Mody
- ImmunityBio, Inc., Culver City, CA, United States
| | - Lise Zakin
- ImmunityBio, Inc., Culver City, CA, United States
| | - Shiho Tanaka
- ImmunityBio, Inc., Culver City, CA, United States
| | | | | | | | | | | | - Corey Casper
- Access to Advanced Health Institute (AAHI), Seattle, WA, United States
- Departments of Medicine and Global Health, University of Washington, Seattle, WA, United States
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24
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Janowski M, Andrzejewska A. The legacy of mRNA engineering: A lineup of pioneers for the Nobel Prize. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 29:272-284. [PMID: 35855896 PMCID: PMC9278038 DOI: 10.1016/j.omtn.2022.07.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
mRNA is like Hermes, delivering the genetic code to cellular construction sites, so it has long been of interest, but only to a small group of scientists, and only demonstrating its remarkable efficacy in coronavirus disease 2019 (COVID-19) vaccines allowed it to go out into the open. Therefore, now is the right timing to delve into the stepping stones that underpin this success and pay tribute to the underlying scientists. From this perspective, advances in mRNA engineering have proven crucial to the rapidly growing role of this molecule in healthcare. Development of consecutive generations of cap analogs, including anti-reverse cap analogs (ARCAs), has significantly boosted translation efficacy and maintained an enthusiasm for mRNA research. Nucleotide modification to protect mRNA molecules from the host's immune system, followed by finding appropriate purification and packaging methods, were other links in the chain enabling medical breakthroughs. Currently, vaccines are the central area of mRNA research, but it will reach far beyond COVID-19. Supplementation of missing or abnormal proteins is another large field of mRNA research. Ex vivo cell engineering and genome editing have been expanding recently. Thus, it is time to recognize mRNA pioneers while building upon their legacy.
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Affiliation(s)
- Miroslaw Janowski
- Program in Image Guided Neurointerventions, Center for Advanced Imaging Research, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA,Tumor Immunology and Immunotherapy Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Institute, PAS, 5 Pawinskiego Street, 02-106 Warsaw, Poland,Corresponding author Anna Andrzejewska, NeuroRepair Department, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland.
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25
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Reina J. The new generation of messenger RNA (mRNA) vaccines against influenza. ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2022; 41:301-304. [PMID: 35906174 PMCID: PMC9315338 DOI: 10.1016/j.eimce.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/08/2021] [Accepted: 07/13/2021] [Indexed: 11/25/2022]
Abstract
Today there are multiple types of flu vaccines. The emergence of nucleic acid technology used in vaccines against SARS-CoV-2 suggests its future application against this infection. Against influenza, two types of vaccines have been developed based on messenger RNA (mRNA): conventional or non-replicative and self-amplifying or replicative (auRNA), both included in lipid nanoparticles. Animal studies carried out with the former have shown their strong capacity to induce Th-1 antibodies and cellular immunity against influenza haemagglutinin (HA) with few side effects. Human trials have shown 87% seroconversion and 100% seroprotection. The auRNA vaccines have obtained similar results in animals but at a concentration 64 times lower than the conventional one. Vaccines based on mRNA platforms meet the WHO requirements for next generation influenza vaccines.
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26
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Hadj Hassine I. Covid-19 vaccines and variants of concern: A review. Rev Med Virol 2022; 32:e2313. [PMID: 34755408 PMCID: PMC8646685 DOI: 10.1002/rmv.2313] [Citation(s) in RCA: 203] [Impact Index Per Article: 67.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/25/2021] [Accepted: 10/25/2021] [Indexed: 12/20/2022]
Abstract
Since the outbreak of coronavirus disease 2019 (Covid-19) in December 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the number of confirmed infections has risen to more than 242 million worldwide, with nearly 5 million deaths. Currently, nine Covid-19 vaccine candidates based on the original Wuhan-Hu-1 strain are at the forefront of vaccine research. All nine had an efficacy over 50% against symptomatic Covid-19 disease: NVX-CoV2373 (∼96%), BNT162b2 (∼95%), mRNA-1273 (∼94%), Sputnik V (∼92%), AZD1222 (∼81%), BBIBP-CorV (∼79%), Covaxin (∼78%), Ad26.CoV.S (∼66%) and CoronaVac (∼51%). However, vaccine efficacy (VE) can be jeopardised by the rapid emergence and spread of SARS-CoV-2 variants of concern (VOCs) that could escape from neutralising antibodies and/or cell-mediated immunity. Rare adverse events have also been reported soon after administration of viral vector and mRNA vaccines. Although many Covid-19 vaccines have been developed, additional effective vaccines are still needed to meet the global demand. Promising Covid-19 vaccines such as WIBP-CorV, AD5-nCOV, ZyCoV-D, CVnCoV, EpiVacCorona and ZF2001 have advanced to clinical studies. This review describes the most relevant mutations in the SARS-CoV-2 spike protein, discusses VE against VOCs, presents rare adverse events after Covid-19 vaccination and introduces some promising Covid-19 vaccine candidates.
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Affiliation(s)
- Ikbel Hadj Hassine
- Unité de Recherche UR17ES30 ‘Génomique, Biotechnologie et Stratégies Antivirales‘Institut Supérieur de Biotechnologie, Université de MonastirMonastirTunisia
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Antibody Response Induced by BNT162b2 and mRNA-1273 Vaccines against the SARS-CoV-2 in a Cohort of Healthcare Workers. Viruses 2022; 14:v14061235. [PMID: 35746706 PMCID: PMC9229196 DOI: 10.3390/v14061235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/16/2022] [Accepted: 05/27/2022] [Indexed: 02/04/2023] Open
Abstract
The aim of this study was to characterize the antibody response induced by SARS-CoV-2 mRNA vaccines in a cohort of healthcare workers. A total of 2247 serum samples were analyzed using the Elecsys® Anti-SARS-CoV-2 S-test (Roche Diagnostics International Ltd., Rotkreuz, Switzerland). Sex, age, body mass index (BMI), arterial hypertension, smoking and time between infection and/or vaccination and serology were considered the confounding factors. Regarding the medians, subjects previously infected with SARS-CoV-2 who preserved their response to the nucleocapsid (N) protein showed higher humoral immunogenicity (BNT162b2: 6456.0 U/mL median; mRNA-1273: 2505.0 U/mL) compared with non-infected (BNT162b2: 867.0 U/mL; mRNA-1273: 2300.5 U/mL) and infected subjects with a lost response to N protein (BNT162b2: 2992.0 U/mL). After controlling for the confounders, a higher response was still observed for mRNA-1273 compared with BNT162b2 in uninfected individuals (FC = 2.35, p < 0.0001) but not in previously infected subjects (1.11 FC, p = 0.1862). The lowest levels of antibodies were detected in previously infected non-vaccinated individuals (39.4 U/mL). Clinical variables previously linked to poor prognoses regarding SARS-CoV-2 infection, such as age, BMI and arterial hypertension, were positively associated with increasing levels of anti-S protein antibody exclusively in infected subjects. The mRNA-1273 vaccine generated a higher antibody response to the S protein than BNT162b2 in non-infected subjects only.
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Abstract
Heteroduplexes composed of all-DNA and all-2′-OMe RNA strands do not occur in nature, but they have found application in the development of molecular beacons and could also be used as aptamers or elements of nucleic acid-based nanostructures that will contain such structural motifs. The crystallization experiments performed have shown that the introduction of overhangs at the ends of the duplex has a great influence on the success of crystallization, as well as on the DNA:2′-OMe-RNA heteroduplex crystal packing. The molecular and crystal structure of the DNA:2′-O-methyl-RNA heteroduplex in its overhanging and blunt-ended versions was determined at 100 K using synchrotron radiation with a resolution of 1.91 and 1.55 Å, respectively. The Zn-SAD method was used to resolve the original duplex structure when molecular replacement by many existing models of duplex structures failed. Both molecules analyzed adopted a conformation close to the A-RNA double helix. The presented structures provide the first insight into this type of heteroduplexes and allowed a comparative analysis with existing nucleic acid homo- and heteroduplex structures. The results of our research expand the knowledge of the structural properties of new heteroduplexes and may be useful for future applications, such as therapies using this class of compounds.
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Dayie TK, Olenginski LT, Taiwo KM. Isotope Labels Combined with Solution NMR Spectroscopy Make Visible the Invisible Conformations of Small-to-Large RNAs. Chem Rev 2022; 122:9357-9394. [PMID: 35442658 PMCID: PMC9136934 DOI: 10.1021/acs.chemrev.1c00845] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Indexed: 02/07/2023]
Abstract
RNA is central to the proper function of cellular processes important for life on earth and implicated in various medical dysfunctions. Yet, RNA structural biology lags significantly behind that of proteins, limiting mechanistic understanding of RNA chemical biology. Fortunately, solution NMR spectroscopy can probe the structural dynamics of RNA in solution at atomic resolution, opening the door to their functional understanding. However, NMR analysis of RNA, with only four unique ribonucleotide building blocks, suffers from spectral crowding and broad linewidths, especially as RNAs grow in size. One effective strategy to overcome these challenges is to introduce NMR-active stable isotopes into RNA. However, traditional uniform labeling methods introduce scalar and dipolar couplings that complicate the implementation and analysis of NMR measurements. This challenge can be circumvented with selective isotope labeling. In this review, we outline the development of labeling technologies and their application to study biologically relevant RNAs and their complexes ranging in size from 5 to 300 kDa by NMR spectroscopy.
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Affiliation(s)
- Theodore K. Dayie
- Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
| | - Lukasz T. Olenginski
- Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
| | - Kehinde M. Taiwo
- Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
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Bruch A, Kelani AA, Blango MG. RNA-based therapeutics to treat human fungal infections. Trends Microbiol 2022; 30:411-420. [PMID: 34635448 PMCID: PMC8498853 DOI: 10.1016/j.tim.2021.09.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 09/03/2021] [Accepted: 09/14/2021] [Indexed: 01/09/2023]
Abstract
In recent decades, RNA-based therapeutics have transitioned from a near impossibility to a compelling treatment alternative for genetic disorders and infectious diseases. The mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are truly groundbreaking, and new adaptations are already being proposed to fight other microbes. Unfortunately, the potential of RNA-based therapeutics to treat human fungal infections has remained mostly absent from the conversation, despite the fact that invasive fungal infections kill as many per year as tuberculosis and even more than malaria. Here, we argue that RNA-based therapeutics should be investigated for the treatment of human fungal infections and discuss several major roadblocks and potential circumventions that may allow for the realization of RNA-based therapies against human fungal pathogens.
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Affiliation(s)
- Alexander Bruch
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Abdulrahman A. Kelani
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Matthew G. Blango
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI), Jena, Germany,Correspondence:
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McKinsey DS, McKinsey JP, Hampson NB, Enriquez M. COVID-19 in Missouri 2020-2021: A Perspective on Origins, Spread & Controversies Part II. MISSOURI MEDICINE 2022; 119:176-184. [PMID: 36035578 PMCID: PMC9324729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Affiliation(s)
| | | | | | - Maithe Enriquez
- Research College of Nursing, Kansas City, Missouri, and University of Missouri - Columbia, Columbia, Missouri
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Sandbrink JB, Koblentz GD. Biosecurity risks associated with vaccine platform technologies. Vaccine 2022; 40:2514-2523. [PMID: 33640142 PMCID: PMC7904460 DOI: 10.1016/j.vaccine.2021.02.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/18/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Abstract
Vaccine platforms have been critical for accelerating the timeline of COVID-19 vaccine development. Faster vaccine timelines demand further development of these technologies. Currently investigated platform approaches include virally vectored and RNA-based vaccines, as well as DNA vaccines and recombinant protein expression system platforms, each featuring different advantages and challenges. Viral vector-based and DNA vaccines in particular have received a large share of research funding to date. Platform vaccine technologies may feature dual-use potential through informing or enabling pathogen engineering, which may raise the risk for the occurrence of deliberate, anthropogenic biological events. Research on virally vectored vaccines exhibits relatively high dual-use potential for two reasons. First, development of virally vectored vaccines may generate insights of particular dual-use concern such as techniques for circumventing pre-existing anti-vector immunity. Second, while the amount of work on viral vectors for gene therapy exceeds that for vaccine research, work on virally vectored vaccines may increase the number of individuals capable of engineering viruses of particular concern, such as ones closely related to smallpox. Other platform vaccine approaches, such as RNA vaccines, feature relatively little dual-use potential. The biosecurity risk associated with platform advancement may be minimised by focusing preferentially on circumventing anti-vector immunity with non-genetic rather than genetic modifications, using vectors that are not based on viruses pathogenic to humans, or preferential investment into promising RNA-based vaccine approaches. To reduce the risk of anthropogenic pandemics, structures for the governance of biotechnology and life science research with dual-use potential need to be reworked. Scientists outside of the pathogen research community, for instance those who work on viral vectors or oncolytic viruses, need to become more aware of the dual-use risks associated with their research. Both public and private research-funding bodies need to prioritise the evaluation and reduction of biosecurity risks.
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Affiliation(s)
- Jonas B Sandbrink
- Future of Humanity Institute, University of Oxford, Trajan House, Mill St, Oxford, OX2 0AN, UK; Medical Sciences Division, University of Oxford, Medical Sciences Office, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
| | - Gregory D Koblentz
- Schar School of Policy and Government, George Mason University, Van Metre Hall, 678 3351 Fairfax Drive Arlington, VA 22201, USA.
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Tai W, Zhang X, Yang Y, Zhu J, Du L. Advances in mRNA and other vaccines against MERS-CoV. Transl Res 2022; 242:20-37. [PMID: 34801748 PMCID: PMC8603276 DOI: 10.1016/j.trsl.2021.11.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 11/03/2022]
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human coronavirus (CoV). Belonging to the same beta-CoV genus as severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) and SARS-CoV-2, MERS-CoV has a significantly higher fatality rate with limited human-to-human transmissibility. MERS-CoV causes sporadic outbreaks, but no vaccines have yet been approved for use in humans, thus calling for continued efforts to develop effective vaccines against this important CoV. Similar to SARS-CoV-1 and SARS-CoV-2, MERS-CoV contains 4 structural proteins, among which the surface spike (S) protein has been used as a core component in the majority of currently developed MERS-CoV vaccines. Here, we illustrate the importance of the MERS-CoV S protein as a key vaccine target and provide an update on the currently developed MERS-CoV vaccines, including those based on DNAs, proteins, virus-like particles or nanoparticles, and viral vectors. Additionally, we describe approaches for designing MERS-CoV mRNA vaccines and explore the role and importance of naturally occurring pseudo-nucleosides in the design of effective MERS-CoV mRNA vaccines. This review also provides useful insights into designing and evaluating mRNA vaccines against other viral pathogens.
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Affiliation(s)
- Wanbo Tai
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York
| | - Xiujuan Zhang
- Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York
| | - Yang Yang
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa
| | - Jiang Zhu
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, Califonia; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California
| | - Lanying Du
- Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia.
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Pollock KM, Cheeseman HM, Szubert AJ, Libri V, Boffito M, Owen D, Bern H, O'Hara J, McFarlane LR, Lemm NM, McKay PF, Rampling T, Yim YTN, Milinkovic A, Kingsley C, Cole T, Fagerbrink S, Aban M, Tanaka M, Mehdipour S, Robbins A, Budd W, Faust SN, Hassanin H, Cosgrove CA, Winston A, Fidler S, Dunn DT, McCormack S, Shattock RJ. Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial. EClinicalMedicine 2022; 44:101262. [PMID: 35043093 PMCID: PMC8759012 DOI: 10.1016/j.eclinm.2021.101262] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/08/2021] [Accepted: 12/16/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. METHODS A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). FINDINGS 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1μg) to 61% (14/23; 10.0μg) in ELISA and 46% (18/39; 0.3μg) to 87% (20/23; 5.0μg and 10.0μg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1μg to 1023 (468-2236) ng/mL at 5.0μg (p<0.001) and was not higher at 10.0μg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1μg) to 48% (11/23; 5.0μg) depending on dose level received. INTERPRETATION Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2. FUNDING This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.
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Affiliation(s)
- Katrina M. Pollock
- Department of Infectious Disease, Imperial College London
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | | | | | - Vincenzo Libri
- NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, London, UK
| | - Marta Boffito
- Department of Infectious Disease, Imperial College London
- Chelsea & Westminster Hospital, London
| | - David Owen
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - Henry Bern
- MRC Clinical Trials Unit at UCL, London, UK
| | - Jessica O'Hara
- Department of Infectious Disease, Imperial College London
| | | | | | - Paul F. McKay
- Department of Infectious Disease, Imperial College London
| | - Tommy Rampling
- NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, London, UK
| | - Yee Ting N. Yim
- NIHR UCLH Clinical Research Facility and NIHR UCLH Biomedical Research Centre, London, UK
| | | | | | - Tom Cole
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - Susanne Fagerbrink
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - Marites Aban
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - Maniola Tanaka
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - Savviz Mehdipour
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - Alexander Robbins
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - William Budd
- NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, London, UK
| | - Saul N. Faust
- NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
| | - Hana Hassanin
- Surrey Clinical Research Facility, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | | | - Alan Winston
- Department of Infectious Disease, Imperial College London
| | - Sarah Fidler
- Department of Infectious Disease, Imperial College London
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Zhao X, Zhong Y, Wang X, Shen J, An W. Advances in Circular RNA and Its Applications. Int J Med Sci 2022; 19:975-985. [PMID: 35813288 PMCID: PMC9254372 DOI: 10.7150/ijms.71840] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/15/2022] [Indexed: 11/17/2022] Open
Abstract
Circular RNA (circRNA) is a novel endogenous non-coding RNA (ncRNA) that, like microRNA (miRNA), is a rapidly emerging RNA research topic. CircRNA, unlike traditional linear RNAs (which have 5' and 3' ends), has a closed-loop structure that is unaffected by RNA exonucleases. Thus, circRNA has sustained expression and is less sensitive to degradation. Since circRNAs have many miRNAs binding sites, eliminating their repressive effects on their target genes can strongly enhance their expression. CircRNAs serve an important regulatory role in disease onset and progression via specific circRNA-miRNA interactions. We summarized the current progress in elucidating mechanisms and biogenesis of circRNAs in this review. In particular, circRNAs can function mainly as miRNA sponges, regulating host gene expression and protein transportation. Finally, we discussed the application prospects and significant challenges for the development of circRNA-based therapeutics.
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Affiliation(s)
- Xian Zhao
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), No. 38 Jing Hai Second Road, Beijing, 101111, China
| | - Youxiu Zhong
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), No. 38 Jing Hai Second Road, Beijing, 101111, China
| | - Xudong Wang
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), No. 38 Jing Hai Second Road, Beijing, 101111, China
| | - Jiuheng Shen
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), No. 38 Jing Hai Second Road, Beijing, 101111, China
| | - Wenlin An
- National Vaccine & Serum Institute (NVSI), China National Biotech Group (CNBG), No. 38 Jing Hai Second Road, Beijing, 101111, China
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Jain S, Venkataraman A, Wechsler ME, Peppas NA. Messenger RNA-based vaccines: Past, present, and future directions in the context of the COVID-19 pandemic. Adv Drug Deliv Rev 2021; 179:114000. [PMID: 34637846 PMCID: PMC8502079 DOI: 10.1016/j.addr.2021.114000] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/27/2021] [Accepted: 10/06/2021] [Indexed: 12/27/2022]
Abstract
mRNA vaccines have received major attention in the fight against COVID-19. Formulations from companies such as Moderna and BioNTech/Pfizer have allowed us to slowly ease the social distancing measures, mask requirements, and lockdowns that have been prevalent since early 2020. This past year's focused work on mRNA vaccines has catapulted this technology to the forefront of public awareness and additional research pursuits, thus leading to new potential for bionanotechnology principles to help drive further innovation using mRNA. In addition to alleviating the burden of COVID-19, mRNA vaccines could potentially provide long-term solutions all over the world for diseases ranging from influenza to AIDS. Herein, we provide a brief commentary based on the history and development of mRNA vaccines in the context of the COVID-19 pandemic. Furthermore, we address current research using the technology and future directions of mRNA vaccine research.
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Affiliation(s)
- Samagra Jain
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
| | - Abhijeet Venkataraman
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
| | - Marissa E. Wechsler
- Department of Biomedical Engineering and Chemical Engineering, The University of Texas at San Antonio, San Antonio, TX, USA
| | - Nicholas A. Peppas
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA,Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA,Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA,Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA,Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX, USA,Corresponding author
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Machado BAS, Hodel KVS, Fonseca LMDS, Mascarenhas LAB, Andrade LPCDS, Rocha VPC, Soares MBP, Berglund P, Duthie MS, Reed SG, Badaró R. The Importance of RNA-Based Vaccines in the Fight against COVID-19: An Overview. Vaccines (Basel) 2021; 9:1345. [PMID: 34835276 PMCID: PMC8623509 DOI: 10.3390/vaccines9111345] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/02/2021] [Accepted: 11/15/2021] [Indexed: 12/23/2022] Open
Abstract
In recent years, vaccine development using ribonucleic acid (RNA) has become the most promising and studied approach to produce safe and effective new vaccines, not only for prophylaxis but also as a treatment. The use of messenger RNA (mRNA) as an immunogenic has several advantages to vaccine development compared to other platforms, such as lower coast, the absence of cell cultures, and the possibility to combine different targets. During the COVID-19 pandemic, the use of mRNA as a vaccine became more relevant; two out of the four most widely applied vaccines against COVID-19 in the world are based on this platform. However, even though it presents advantages for vaccine application, mRNA technology faces several pivotal challenges to improve mRNA stability, delivery, and the potential to generate the related protein needed to induce a humoral- and T-cell-mediated immune response. The application of mRNA to vaccine development emerged as a powerful tool to fight against cancer and non-infectious and infectious diseases, for example, and represents a relevant research field for future decades. Based on these advantages, this review emphasizes mRNA and self-amplifying RNA (saRNA) for vaccine development, mainly to fight against COVID-19, together with the challenges related to this approach.
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Affiliation(s)
- Bruna Aparecida Souza Machado
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
| | - Katharine Valéria Saraiva Hodel
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
| | - Larissa Moraes dos Santos Fonseca
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
| | - Luís Alberto Brêda Mascarenhas
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
| | - Leone Peter Correia da Silva Andrade
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
| | - Vinícius Pinto Costa Rocha
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
| | - Milena Botelho Pereira Soares
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador 40296-710, Brazil
| | - Peter Berglund
- HDT Bio, 1616 Eastlake Ave E, Seattle, WA 98102, USA; (P.B.); (M.S.D.); (S.G.R.)
| | - Malcolm S. Duthie
- HDT Bio, 1616 Eastlake Ave E, Seattle, WA 98102, USA; (P.B.); (M.S.D.); (S.G.R.)
| | - Steven G. Reed
- HDT Bio, 1616 Eastlake Ave E, Seattle, WA 98102, USA; (P.B.); (M.S.D.); (S.G.R.)
| | - Roberto Badaró
- SENAI Institute of Innovation (ISI) in Health Advanced Systems (CIMATEC ISI SAS), University Center SENAI/CIMATEC, Salvador 41650-010, Brazil; (K.V.S.H.); (L.M.d.S.F.); (L.A.B.M.); (L.P.C.d.S.A.); (V.P.C.R.); (M.B.P.S.); (R.B.)
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Echeverría N, Comas V, Aldunate F, Perbolianachis P, Moreno P, Cristina J. In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet? World J Hepatol 2021; 13:1234-1268. [PMID: 34786164 PMCID: PMC8568586 DOI: 10.4254/wjh.v13.i10.1234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/14/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is responsible for no less than 71 million people chronically infected and is one of the most frequent indications for liver transplantation worldwide. Despite direct-acting antiviral therapies fuel optimism in controlling HCV infections, there are several obstacles regarding treatment accessibility and reinfection continues to remain a possibility. Indeed, the majority of new HCV infections in developed countries occur in people who inject drugs and are more plausible to get reinfected. To achieve global epidemic control of this virus the development of an effective prophylactic or therapeutic vaccine becomes a must. The coronavirus disease 19 (COVID-19) pandemic led to auspicious vaccine development against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which has renewed interest on fighting HCV epidemic with vaccination. The aim of this review is to highlight the current situation of HCV vaccine candidates designed to prevent and/or to reduce HCV infectious cases and their complications. We will emphasize on some of the crossroads encountered during vaccine development against this insidious virus, together with some key aspects of HCV immunology which have, so far, hampered the progress in this area. The main focus will be on nucleic acid-based as well as recombinant viral vector-based vaccine candidates as the most novel vaccine approaches, some of which have been recently and successfully employed for SARS-CoV-2 vaccines. Finally, some ideas will be presented on which methods to explore for the design of live-attenuated vaccines against HCV.
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Affiliation(s)
- Natalia Echeverría
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Victoria Comas
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Fabián Aldunate
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Paula Perbolianachis
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Pilar Moreno
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Juan Cristina
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
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Musunuri S, Sandbrink JB, Monrad JT, Palmer MJ, Koblentz GD. Rapid Proliferation of Pandemic Research: Implications for Dual-Use Risks. mBio 2021; 12:e0186421. [PMID: 34663091 PMCID: PMC8524337 DOI: 10.1128/mbio.01864-21] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The COVID-19 pandemic has demonstrated the world's vulnerability to biological catastrophe and elicited unprecedented scientific efforts. Some of this work and its derivatives, however, present dual-use risks (i.e., potential harm from misapplication of beneficial research) that have largely gone unaddressed. For instance, gain-of-function studies and reverse genetics protocols may facilitate the engineering of concerning SARS-CoV-2 variants and other pathogens. The risk of accidental or deliberate release of dangerous pathogens may be increased by large-scale collection and characterization of zoonotic viruses undertaken in an effort to understand what enables animal-to-human transmission. These concerns are exacerbated by the rise of preprint publishing that circumvents a late-stage opportunity for dual-use oversight. To prevent the next global health emergency, we must avoid inadvertently increasing the threat of future biological events. This requires a nuanced and proactive approach to dual-use evaluation throughout the research life cycle, including the conception, funding, conduct, and dissemination of research.
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Affiliation(s)
| | - Jonas B. Sandbrink
- Future of Humanity Institute, University of Oxford, Oxford, United Kingdom
- Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Joshua Teperowski Monrad
- Future of Humanity Institute, University of Oxford, Oxford, United Kingdom
- Faculty of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Health Policy, London School of Economics, London, United Kingdom
| | - Megan J. Palmer
- Department of Bioengineering, Stanford University, Stanford, California, USA
- Center for International Security and Cooperation (CISAC), Stanford University, Stanford, California, USA
| | - Gregory D. Koblentz
- Schar School of Policy and Government, George Mason University, Fairfax, Virginia, USA
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Abstract
PURPOSE OF REVIEW Due to the impact of the COVID-19 pandemic this past year, we have witnessed a significant acceleration in the science, technology, and policy of global health security. This review highlights important progress made toward the mitigation of Zika, Ebola, and COVID-19 outbreaks. These epidemics and their shared features suggest a unified policy and technology agenda that could broadly improve global health security. RECENT FINDINGS Molecular epidemiology is not yet in widespread use, but shows promise toward informing on-the-ground decision-making during outbreaks. Point-of-care (POC) diagnostics have been achieved for each of these threats; however, deployment of Zika and Ebola diagnostics lags behind those for COVID-19. POC metagenomics offers the possibility of identifying novel viruses. Vaccines have been successfully approved for Ebola and COVID-19, due in large part to public-private partnerships and advance purchase commitments. Therapeutics trials conducted during ongoing epidemics have identified effective antibody therapeutics for Ebola, as well as steroids (both inhaled and oral) and a broad-spectrum antiviral for COVID-19. SUMMARY Achieving global health security remains a challenge, though headway has been made over the past years. Promising policy and technology strategies that would increase resilience across emerging viral pathogens should be pursued.
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Affiliation(s)
| | - Michele Barry
- School of Medicine
- Center for Innovation in Global Health, Stanford University, Stanford, California, USA
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Zhang H, Chen P, Ma H, Woińska M, Liu D, Cooper DR, Peng G, Peng Y, Deng L, Minor W, Zheng H. virusMED: an atlas of hotspots of viral proteins. IUCRJ 2021; 8:S2052252521009076. [PMID: 34614039 PMCID: PMC8479994 DOI: 10.1107/s2052252521009076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/02/2021] [Indexed: 06/13/2023]
Abstract
Metal binding sites, antigen epitopes and drug binding sites are the hotspots in viral proteins that control how viruses interact with their hosts. virusMED (virus Metal binding sites, Epitopes and Drug binding sites) is a rich internet application based on a database of atomic interactions around hotspots in 7041 experimentally determined viral protein structures. 25306 hotspots from 805 virus strains from 75 virus families were characterized, including influenza, HIV-1 and SARS-CoV-2 viruses. Just as Google Maps organizes and annotates points of interest, virusMED presents the positions of individual hotspots on each viral protein and creates an atlas upon which newly characterized functional sites can be placed as they are being discovered. virusMED contains an extensive set of annotation tags about the virus species and strains, viral hosts, viral proteins, metal ions, specific antibodies and FDA-approved drugs, which permits rapid screening of hotspots on viral proteins tailored to a particular research problem. The virusMED portal (https://virusmed.biocloud.top) can serve as a window to a valuable resource for many areas of virus research and play a critical role in the rational design of new preventative and therapeutic agents targeting viral infections.
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Affiliation(s)
- HuiHui Zhang
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
| | - Pei Chen
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
| | - Haojie Ma
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
| | - Magdalena Woińska
- Biological and Chemical Research Centre, Chemistry Department, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland
- University of Virginia, Charlottesville, VA 22908, USA
| | - Dejian Liu
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
| | | | - Guo Peng
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
| | - Yousong Peng
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
| | - Lei Deng
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
- Hunan Provincial Key Laboratory of Medical Virology, People’s Republic of China
| | - Wladek Minor
- University of Virginia, Charlottesville, VA 22908, USA
| | - Heping Zheng
- Hunan University College of Biology, Bioinformatics Center, Hunan 410082, People’s Republic of China
- Hunan Provincial Key Laboratory of Medical Virology, People’s Republic of China
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Rasouli M, Vakilian F, Ranjbari J. Therapeutic and protective potential of mesenchymal stem cells, pharmaceutical agents and current vaccines against covid-19. Curr Stem Cell Res Ther 2021; 17:166-185. [PMID: 33349221 DOI: 10.2174/1574888x16666201221151853] [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: 03/19/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 11/22/2022]
Abstract
It has been almost 18 months since the first outbreak of COVID-19 disease was reported in Wuhan, China. This unexpected devastating phenomenon, raised a great deal of concerns and anxiety among people around the world and imposed a huge economic burden on the nations' health care systems. Accordingly, clinical scientists, pharmacologists and physicians worldwide felt an urgent demand for a safe, effective therapeutic agent, treatment strategy or vaccine in order to prevent or cure the recently-emerged disease. Initially, due to lack of specific pharmacological agents and approved vaccines to combat the COVID-19, the disease control in the confirmed cases was limited to supportive care. Accordingly, repositioning or repurposing current drugs and examining their possible therapeutic efficacy received a great deal of attention. Despite revealing promising results in some clinical trials, the overall results are conflicting. For this reason, there is an urgent to seek and investigate other potential therapeutics. Mesenchymal stem cells (MSC) representing immunomodulatory and regenerative capacity to treat both curable and intractable diseases, have been investigated in COVID-19 clinical trials carried out in different parts of the world. Nevertheless, up to now, none of MSC-based approaches has been approved in controlling COVID-19 infection. Thanks to the fact that the final solution for defeating the pandemic is developing a safe, effective vaccine, enormous efforts and clinical research have been carried out. In this review, we will concisely discuss the safety and efficacy of the most relevant pharmacological agents, MSC-based approaches and candidate vaccines for treating and preventing COVID-19 infection.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | | | - Javad Ranjbari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
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Son YM, Sun J. Co-Ordination of Mucosal B Cell and CD8 T Cell Memory by Tissue-Resident CD4 Helper T Cells. Cells 2021; 10:cells10092355. [PMID: 34572004 PMCID: PMC8471972 DOI: 10.3390/cells10092355] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 12/25/2022] Open
Abstract
Adaptive cellular immunity plays a major role in clearing microbial invasion of mucosal tissues in mammals. Following the clearance of primary pathogens, memory lymphocytes are established both systemically and locally at pathogen entry sites. Recently, resident memory CD8 T and B cells (TRM and BRM respectively), which are parked mainly in non-lymphoid mucosal tissues, were characterized and demonstrated to be essential for protection against secondary microbial invasion. Here we reviewed the current understanding of the cellular and molecular cues regulating CD8 TRM and BRM development, maintenance and function. We focused particularly on elucidating the role of a novel tissue-resident helper T (TRH) cell population in assisting TRM and BRM responses in the respiratory mucosa following viral infection. Finally, we argue that the promotion of TRH responses by future mucosal vaccines would be key to the development of successful universal influenza or coronavirus vaccines, providing long-lasting immunity against a broad spectrum of viral strains.
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Affiliation(s)
- Young Min Son
- Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jie Sun
- Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
- Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA
- Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
- Correspondence: or
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Aggarwal A, Aggarwal R. Covid-19 Vaccines: Several technologies at work. NATIONAL MEDICAL JOURNAL OF INDIA 2021; 34:1-3. [PMID: 34396995 DOI: 10.4103/0970-258x.323453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Amita Aggarwal
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Rakesh Aggarwal
- Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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45
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Reina J. [The new generation of messenger RNA (mRNA) vaccines against influenza]. Enferm Infecc Microbiol Clin 2021; 41:301-304. [PMID: 34483424 PMCID: PMC8397276 DOI: 10.1016/j.eimc.2021.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/13/2021] [Indexed: 11/29/2022]
Abstract
En la actualidad existen múltiples tipos de vacunas frente a la gripe. La irrupción de la tecnología de ácidos nucleicos utilizada en las vacunas frente al SARS-CoV-2 hace pensar en su aplicación futura frente a esta infección. Frente a la gripe se han desarrollado 2 tipos de vacunas basadas en el ARN mensajero (ARNm): las convencionales o no replicativas y las autoamplificables o replicativas (auARNm), ambas incluidas en nanopartículas lipídicas. Los estudios en animales realizados con las primeras han mostrado su intensa capacidad para inducir anticuerpos e inmunidad celular Th-1 frente a la hemaglutinina gripal con escasos efectos secundarios. Los ensayos en humanos han mostrado una seroconversión del 87% y una seroprotección del 100%. Las vacunas auARNm han obtenido resultados en animales semejantes, pero a una concentración 64 veces inferior a la convencional. Las vacunas basadas en las plataformas de ARNm cumplen los requisitos establecidos por la OMS para vacunas de gripe de la generación siguiente.
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Affiliation(s)
- Jordi Reina
- Unidad de Virología, Servicio de Microbiología, Hospital Universitario Son Espases, Facultad de Medicina UIB, Palma de Mallorca, España
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46
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Aars OK, Clark M, Schwalbe N. Increasing efficiency in vaccine Production: A primer for change. Vaccine X 2021; 8:100104. [PMID: 34151248 PMCID: PMC8206571 DOI: 10.1016/j.jvacx.2021.100104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 05/24/2021] [Accepted: 06/11/2021] [Indexed: 11/06/2022] Open
Abstract
The COVID-19 pandemic has highlighted the importance of vaccines as public health and pandemic preparedness tools and amplified the importance of issues ranging from equitable distribution to reliable supply of quality, affordable vaccines. These issues however are not new. Delays in time from the first dose in a high-income country to introduction at scale in a low-income country can take years. These delays are driven by several challenges, some of which are unique to the vaccine development ecosystem. The patenting and overall intellectual property (IP) protection are complex, regulatory oversight is rigorous, manufacturing processes require technical support or know-how transfer from the innovator, and market dynamics create obstacles to delivering at scale. However, there are opportunities to accelerate the introduction of vaccines at scale in low and middle-income countries. To identify those opportunities, this paper provides an overview of the vaccine research and development process and where reform of the current system could increase access.
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Affiliation(s)
- Ole Kristian Aars
- Spark Street Advisors, New York, NY, United States.,University of Oslo, Oslo, Norway
| | | | - Nina Schwalbe
- Spark Street Advisors, New York, NY, United States.,Mailman School of Public Health, Columbia University, New York, NY, United States.,University of the Witwatersrand, Johannesburg-Braamfontein, Gauteng, ZA, South Africa
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47
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Ciliberto G. Emerging therapeutics. J Transl Med 2021; 19:195. [PMID: 33952311 PMCID: PMC8098640 DOI: 10.1186/s12967-021-02864-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 11/10/2022] Open
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Anand P, Stahel VP. Review the safety of Covid-19 mRNA vaccines: a review. Patient Saf Surg 2021; 15:20. [PMID: 33933145 PMCID: PMC8087878 DOI: 10.1186/s13037-021-00291-9] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/11/2021] [Indexed: 12/12/2022] Open
Abstract
The novel coronavirus disease 2019 (COVID-19) has infected more than 100 million people globally within the first year of the pandemic. With a death toll surpassing 500,000 in the United States alone, containing the pandemic is predicated on achieving herd immunity on a global scale. This implies that at least 70-80 % of the population must achieve active immunity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), either as a result of a previous COVID-19 infection or by vaccination against SARS-CoV-2. In December 2020, the first two vaccines were approved by the FDA through emergency use authorization in the United States. These vaccines are based on the mRNA vaccine platform and were developed by Pfizer/BioNTech and Moderna. Published safety and efficacy trials reported high efficacy rates of 94-95 % after two interval doses, in conjunction with limited side effects and a low rate of adverse reactions. The rapid pace of vaccine development and the uncertainty of potential long-term adverse effects raised some level of hesitation against mRNA vaccines in the global community. A successful vaccination campaign is contingent on widespread access to the vaccine under appropriate storage conditions, deployment of a sufficient number of vaccinators, and the willingness of the population to be vaccinated. Thus, it is important to clarify the objective data related to vaccine safety, including known side effects and potential adverse reactions. The present review was designed to provide an update on the current state of science related to the safety and efficacy of SARS-CoV-2 mRNA vaccines.
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Affiliation(s)
- Pratibha Anand
- University of Colorado (CU) School of Medicine, 13001 E 17th Place, Aurora, CO, 80045, USA.
| | - Vincent P Stahel
- University of Colorado (CU) Boulder Undergraduate Program, Boulder, CO, 80309, USA
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49
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Excler JL, Saville M, Berkley S, Kim JH. Vaccine development for emerging infectious diseases. Nat Med 2021; 27:591-600. [PMID: 33846611 DOI: 10.1038/s41591-021-01301-0] [Citation(s) in RCA: 194] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/01/2021] [Indexed: 01/19/2023]
Abstract
Examination of the vaccine strategies and technical platforms used for the COVID-19 pandemic in the context of those used for previous emerging and reemerging infectious diseases and pandemics may offer some mutually beneficial lessons. The unprecedented scale and rapidity of dissemination of recent emerging infectious diseases pose new challenges for vaccine developers, regulators, health authorities and political constituencies. Vaccine manufacturing and distribution are complex and challenging. While speed is essential, clinical development to emergency use authorization and licensure, pharmacovigilance of vaccine safety and surveillance of virus variants are also critical. Access to vaccines and vaccination needs to be prioritized in low- and middle-income countries. The combination of these factors will weigh heavily on the ultimate success of efforts to bring the current and any future emerging infectious disease pandemics to a close.
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Affiliation(s)
| | - Melanie Saville
- Coalition for Epidemic Preparedness Innovations (CEPI), London, UK
| | | | - Jerome H Kim
- International Vaccine Institute, Seoul, Republic of Korea.
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50
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Alves AMB, Costa SM, Pinto PBA. Dengue Virus and Vaccines: How Can DNA Immunization Contribute to This Challenge? FRONTIERS IN MEDICAL TECHNOLOGY 2021; 3:640964. [PMID: 35047911 PMCID: PMC8757892 DOI: 10.3389/fmedt.2021.640964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/17/2021] [Indexed: 01/02/2023] Open
Abstract
Dengue infections still have a tremendous impact on public health systems in most countries in tropical and subtropical regions. The disease is systemic and dynamic with broad range of manifestations, varying from mild symptoms to severe dengue (Dengue Hemorrhagic Fever and Dengue Shock Syndrome). The only licensed tetravalent dengue vaccine, Dengvaxia, is a chimeric yellow fever virus with prM and E genes from the different dengue serotypes. However, recent results indicated that seronegative individuals became more susceptible to develop severe dengue when infected after vaccination, and now WHO recommends vaccination only to dengue seropositive people. One possibility to explain these data is the lack of robust T-cell responses and antibody-dependent enhancement of virus replication in vaccinated people. On the other hand, DNA vaccines are excellent inducers of T-cell responses in experimental animals and it can also elicit antibody production. Clinical trials with DNA vaccines have improved and shown promising results regarding the use of this approach for human vaccination. Therefore, in this paper we review preclinical and clinical tests with DNA vaccines against the dengue virus. Most of the studies are based on the E protein since this antigen is the main target for neutralizing antibody production. Yet, there are other reports with DNA vaccines based on non-structural dengue proteins with protective results, as well. Combining structural and non-structural genes may be a solution for inducing immune responses aging in different infection moments. Furthermore, DNA immunizations are also a very good approach in combining strategies for vaccines against dengue, in heterologous prime/boost regimen or even administering different vaccines at the same time, in order to induce efficient humoral and cellular immune responses.
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Affiliation(s)
- Ada Maria Barcelos Alves
- Laboratory of Biotechnology and Physiology of Viral Infections, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
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