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Clinical Trials of COVID-19 Therapeutics and Vaccines
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Candan Hizel Perry, Havva Ö. Kılgöz, Şükrü Tüzmen
The RNA-based strategy might be deployed on either self-amplifying RNA (saRNA) derived from alphaviruses or conventional messenger RNA (mRNA) [27]. These RNA molecules are transfected into host cells, where immediate translation of the protein of interest takes place in the cytoplasm [25, 27].
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
siRNAs and their role in PTGS in plants was first discovered by David Baulcombe’s group at the Sainsbury Laboratory in Norwich (UK), and reported in the journal Science in 1999. Thomas Tuschl and colleagues subsequently reported in Nature that synthetic small (i.e., short) interfering RNAs (siRNAs) could induce an RNAi effect in mammalian cells. This discovery led to a surge in interest in harnessing the RNAi effect for biomedical research and drug development, although in vivo delivery remained a significant challenge. Further research uncovered completely new mechanisms for the RNAi effect. For example, it was discovered that dsRNA fragments could also activate gene expression under some circumstances, a mechanism known as “small RNA-induced gene activation” or “RNAa”. The double-stranded RNA constructs used in these experiments were known as “small activating RNAs” (saRNAs).
Theory of The Omnipresence of Cancer
Published in Carol L. Cox, Maya Zumstein-Shaha, A Theory of Cancer Care in Healthcare Settings, 2017
Life after a diagnosis of cancer holds many unknown aspects that constitute challenges patients and significant others must manage. Treatment effects are unknown; the disease trajectory and its influence on everyday life are difficult to foresee, despite information by healthcare providers (Shaha, 2003a; Shaha and Cox, 2003; Ramfelt et al., 2002; Cohen et al., 2004; Mishel et al., 2005; Sarna et al., 2005). Although the extent of the influence of cancer on patients and their significant others is well documented, a theoretical basis for caring has been lacking. Subsequently, helping patients and significant others on how to cope with these challenges is acute.
Modern vaccine strategies for emerging zoonotic viruses
Published in Expert Review of Vaccines, 2022
Atif Ahmed, Muhammad Safdar, Samran Sardar, Sahar Yousaf, Fiza Farooq, Ali Raza, Muhammad Shahid, Kausar Malik, Samia Afzal
The structure of self-amplifying (saRNA) closely resembles that of naRNA. Unlike naRNA vaccines, which contain only genes for antigen expression, saRNA-based vaccines contain viral RNA replication genes along with the genes for antigen expression to stay for a prolonged duration and enhanced antigen production even with a negligible dose of RNA [48]. When saRNA is delivered into the cytosol, it initially expresses the non-structural genes to assemble the replication complex quickly. The newly assembled replication machinery then transcribes the full-length negative-sense RNA into full-length genomic RNA and shorter sub-genomic RNAs. The entire stretch of genomic RNA mediates the translation of more replicates for auto-replication, while the expression of sub-genomic RNAs occurs at tremendously high levels for antigen protein production to stimulate vigorous immune responses in the host [10]. Apart from immense expression, the size of the transcript and the high degree of secondary structure limits the elevated production. The trans-amplifying method based on the bipartite RNA vector system was utilized to prepare the small-length RNAs and enhance stability [49,50]. In this technique, a replicase-encoding gene is present in one vector cassette, while the second molecule contains a gene to encode antigenic peptides. As a result, nano-gram doses of mRNA are sufficient to elicit a robust and protective immune response in vaccinated individuals [49].
Current status of COVID-19 vaccination: safety and liability concern for children, pregnant and lactating women
Published in Expert Review of Vaccines, 2022
Swagat Kumar Das, Manish Paul, Bikash Chandra Behera, Hrudayanath Thatoi
With increased efficacy, safety, faster production cycles, and lower manufacturing costs, the mRNA vaccine platform is seen as a potential technology and alternative to conventional vaccines. The different stages of mRNA vaccine development involve antigen selection, sequence optimization, modified nucleotides screening, delivery systems optimization, and evaluation of efficacy and safety of immune response. These vaccines contain antigen coding mRNAs which are translated inside the host cell and induce immunity. These vaccines have several advantages over traditional vaccines, including the absence of genome integration, improved immune responses, multimeric antigen synthesis, and quick development [22]. Different organizations like Stermirna Therapeutics, BDGENE Therapeutics, Guanhao Biotech, ZY Therapeutics Inc., CanSino Biologics Inc., Baylor College of Medicine, University of Texas, TongjiUniversityModerna/NIH, and CureVac are working on the development of mRNA vaccine. Fudan University, Shanghai Jiaotong University, and Bluebird Biopharmaceutical Company are using S protein and RBD domain of SARS-CoV-2 to develop an mRNA vaccine against COVID-19 [19]. Currently, self-amplifying RNA (saRNA) has emerged as an alternative strategy to alleviate the short half-life of mRNA. The saRNA utilizes viral derived elements and encodes both the antigen and viral proteins. McKay et al. [19] demonstrated that lipid nanoparticles (LNPs) encapsulating self-amplifying RNA capable of encoding the SARS-CoV-2 spike protein could be used against COVID-19 infection.
Vaccines on demand, part II: future reality
Published in Expert Opinion on Drug Discovery, 2023
Andrew J. Geall, Zoltan Kis, Jeffrey B. Ulmer
This article presents the current development state for the following three types of RNA vaccines: 1) conventional, non-amplifying mRNA molecules, 2) base-modified, non-amplifying bmRNA molecules, which incorporate chemically modified nucleotides, and 3) saRNA. The bmRNA vaccines were validated and deployed at record speeds during the COVID-19 pandemic. These bmRNA vaccines have also demonstrated very high efficacy during clinical trials and real-world effectiveness following emergency use authorization. The saRNA vaccines, by contrast, have lagged behind; however, a successful saRNA COVID-19 vaccine has recently shown promising results. saRNA vaccines produce longer duration transgene expression, higher potential for co-expressing multiple transgenes, enhanced adjuvant effect, and more potent antigen-specific adaptive immunity – particularly T cell responses. Moreover, due to their amplification, saRNA vaccines could be effective at lower RNA doses, which in turn would lead to higher manufacturing volumes, higher manufacturing rates, and lower costs, which could amount to as much as one to two orders of magnitude, respectively. However, in order to realize these benefits of the saRNA vaccines, the manufacturing challenges for producing the longer and less stable saRNA vaccines must be addressed alongside achieving the correct balance of innate immune stimulation. The latter could potentially be achieved by removing impurities during manufacturing, by replicon engineering (e.g. using a split-replicon) or by designing more effective formulation and delivery approaches. Overcoming these challenges for saRNA will enhance our toolbox of mRNA technologies and enable broader application to infectious and noninfectious diseases.