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Vaccine Development Strategies and the Current Status of COVID-19 Vaccines
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Mohsen Akbarian, Kenneth Lundstrom, Elrashdy M. Redwan, Vladimir N. Uversky
The first DNA-based vaccines were already developed in 1983. DNA vaccines are based on plasmid DNA expressing antigens for the vaccine targets in transfected host cells. DNA plasmids are relatively stable and can replicate independently in host cells. However, low transfection efficacy and the need for delivery to the nucleus has hampered their efficacy as vaccine vectors. To address these issues, electroporation, jet injection, gene gun, and nanoparticle technologies have been applied. Numerous types of nanoparticles, such as lipid and polymer nanoparticles, lipid-polymer hybrid nanoparticles, DNA-polymer complexes, nanoparticles coated with polymeric materials and gold, and protein-DNA complexed nanoparticles have been formulated for improved DNA delivery [48]. MERS-CoV S and N proteins have been expressed from DNA plasmid as vaccine antigens [49]. Effective and specific immunogenic responses, including the production of γ-interferon, IL-2, CD4+, CD8+, and IL-2, and the induction of cytotoxic T lymphocytes have been reported in animal studies. One of the most important advantages is that production of plasmid DNA in bacteria is rapid and inexpensive [50]. Other important advantages are the possibility of combining DNA-based vaccines with other vaccine platforms (such as first generation vaccines), excellent heat and shelf-life stability, ease of DNA sequence engineering and reduced safety risk compared to viral vectors [48]. However, limited immune responses caused by low transfection efficiency of DNA vaccines is a disadvantage [19].
Adeno-Associated Virus-Based Delivery Systems
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Stable gene transduction in skeletal muscle would be desirable both as a treatment of primary muscle disorders and as an in vivo reservoir for soluble circulating proteins such as insulin in diabetes. One group has developed AAV gene transfer to cultured human myoblasts with the goal of later injection into skeletal muscle (163). AAV was the basis of the plasmid pCKM-gfp, a construct using the human CKMmuscle promoter and the green fluorescent protein cDNA as the reporter gene. The cell line was transfected using the gene gun (BioRad) and gold microspheres coated with plasmid DNA. This gene gun accomplished between 1% and 5% transfection efficiency after 4 days in culture. Injection of the naked plasmid DNA directly into murine quadriceps skeletal muscle resulted in much higher efficiency at 4 days, leading the authors to speculate that maximal activity may require differentiated or multinucleated cells. However, it has been observed with other vectors that naked plasmid DNA is very effective in skeletal and cardiac muscle in general (164-172).
Microneedles vs. Other Transdermal Technologies
Published in Boris Stoeber, Raja K Sivamani, Howard I. Maibach, Microneedling in Clinical Practice, 2020
Yeakuty Jhanker, James H.N. Tran, Heather A.E. Benson, Tarl W. Prow
The original biolistic particle delivery system, or gene gun, was designed for delivering exogenous DNA (transgenes) into plant cells. The payload is typically a particle of a heavy metal coated with DNA (typically plasmid DNA). This has been developed into biolistic injectors delivering a “shotgun” burst of nano- or microparticles into the skin (Figure 5.5 right), injectors that have been effective for the immunization of antigens including influenza and malaria, and also in anticancer applications in a range of animals (mice, rat, ferrets, monkeys, etc.) and humans (79–82). Clinical assessment of biolistic particle delivery reports transient localized pain and tissue damage (erythema, irritation, etc.); thus, like liquid biolistic injection, the technique is most suitable to vaccination.
Layer-by-Layer technique as a versatile tool for gene delivery applications
Published in Expert Opinion on Drug Delivery, 2021
Dmitrii S. Linnik, Yana V. Tarakanchikova, Mikhail V. Zyuzin, Kirill V. Lepik, Joeri L. Aerts, Gleb Sukhorukov, Alexander S. Timin
Messenger RNA (mRNA) is a biomolecule that mediates the translation of genetic information from genes encoded in DNA to proteins located throughout the cell. The physical and biological characteristics of mRNA allowed its use as a safe genetic material for gene-based therapy approaches, because mRNA, in contrast to DNA, does not require nuclear localization for gene expression and provides rapid protein expression, including in hard-to-transfect cells such as T cells, dendritic cells, and hematopoietic stem cells [102]. Therefore, mRNA is of great interest in immunotherapy application. Development of novel therapeutic methods based on mRNA has been limited due to its instability in ambient conditions. Thus, an intravenous injection of unmodified mRNA without a delivery material leads to rapid mRNA degradation by ribonucleases and can activate the immune system. Viral vectors have been widely used for delivery of mRNA but possess potential immunologic side effects and toxicities. Non-viral strategies such as electroporation, gene gun, and sonoporation offer a better perspective for mRNA delivery, however, they also have certain limitations.
Recent developments of RNA-based vaccines in cancer immunotherapy
Published in Expert Opinion on Biological Therapy, 2021
Elnaz Faghfuri, Farhad Pourfarzi, Amir Hossein Faghfouri, Mahdi Abdoli Shadbad, Khalil Hajiasgharzadeh, Behzad Baradaran
Two important methods for the delivery of RNA vaccines include loading of RNA into dendritic cells (DCs) ex vivo [24], and direct parenteral administration with or without a carrier. Sometimes physical approaches have been used to improve the efficacy of cellular uptake. In a micro-projectile method, the gold-conjugated mRNA could be delivered to tissues utilizing a gene gun [25]. Consistent with this, it has been shown that the gene gun is a potent RNA delivery approach in the vaccination of mouse models [26]. However, no studies have been conducted on its efficacy in large animals or humans. In vivo electroporation has also been utilized to enhance uptake of the RNA vaccine [27,28]. However, this technique was only effective in the immune-stimulating activity of saRNA and failed to induce the mRNA vaccine’s desired results. Increased cell death, and limited entrance to target cells, are the concrete limitations of physical methods. Currently, the field has instead favored the application of lipid- or polymer-based nanoparticles (NPs) as practical delivery carriers.
GOLD: human exposure and update on toxic risks
Published in Critical Reviews in Toxicology, 2018
Technology developed in the University of Wisconsin highlights a “gene gun” which was claimed to fire a DNA-tipped gold bullet to inhibit growth of murine tumours (Franklin 1965). This novel therapy was designed to alter the genome of cancers cells thereby making them susceptable to destruction by the body’s own immune system. Genes prepared using conventional cloning were then precipitated onto gold beads (1 nm) which were injected into tumors by a pulse of compressed helium. At the time, Professor Karol Sikora of Imperial College, London is reported as saying that “gene therapy is designed to get the foreign DNA to the right place. The gene gun is one of a number of approaches, each of which has advantages and disadvantages”. Sikora saw the gene gun as an interesting approach. Whilst gold has no clear action as a cytotoxic agent here, it is biocompatible in the human body and is potenially valuable as an anticancer therapy (Tiekink 2008; Powell et al. 2010; Paciotti et al. 2004; Gasull 2012; Murawala et al. 2014).