Challenges and Opportunities of mRNA Vaccines Against SARS-CoV-2

Mueller, Siguna

doi:10.1007/978-3-031-18903-6

Cited by 8 publications

(23 citation statements)

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“…In addition, the incorporation of pseudouridine in particular has been shown to facilitate evasion of recognition by Toll-like receptors ( Karikó et al, 2005 ), although the molecular differences contributing to this mechanism has not yet been elucidated. Although the implementation of pseudouridine increases the stability of the mRNA and its translational capacity, it is important to note the disadvantages of replacing uridine with pseudouridine ( Xia, 2021 ; Mueller, 2023 ). A recent study has shown that the presence of pseudouridine in IVT mRNA increases ribosomal + 1 frameshifting during mRNA translation.…”

Section: The Effect Of Codon Optimization On Immunogenicitymentioning

confidence: 99%

Codon-optimization in gene therapy: promises, prospects and challenges

Paremskaia,

Kogan,

Murashkina

et al. 2024

Front. Bioeng. Biotechnol.

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Codon optimization has evolved to enhance protein expression efficiency by exploiting the genetic code’s redundancy, allowing for multiple codon options for a single amino acid. Initially observed in E. coli, optimal codon usage correlates with high gene expression, which has propelled applications expanding from basic research to biopharmaceuticals and vaccine development. The method is especially valuable for adjusting immune responses in gene therapies and has the potenial to create tissue-specific therapies. However, challenges persist, such as the risk of unintended effects on protein function and the complexity of evaluating optimization effectiveness. Despite these issues, codon optimization is crucial in advancing gene therapeutics. This study provides a comprehensive review of the current metrics for codon-optimization, and its practical usage in research and clinical applications, in the context of gene therapy.

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Section: The Effect Of Codon Optimization On Immunogenicitymentioning

confidence: 99%

Codon-optimization in gene therapy: promises, prospects and challenges

Paremskaia,

Kogan,

Murashkina

et al. 2024

Front. Bioeng. Biotechnol.

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“…The problem of too many test cycles leading to false signals is well established, and for SARS-CoV-2, any samples with Ct values in the high 20s and above have been clinically irrelevant and false [14].…”

Section: A Cdc Analysis Of the H5n1 Virus In Cattle And Cats Supports...mentioning

confidence: 99%

“…In essence, these steps are very similar to those employed during the COVID-19 pandemic to identify SARS-CoV-2. In addition to issues with PCR testing [14], even then there were substantial concerns with genetic testing such as inaccuracies of sequences used to determine the first SARS-CoV-2 reference genome, early sequencing errors, and unaccounted flaws and vulnerabilities underlying whole-genome sequencing protocols [15]. Importantly, and especially crucial for the recent bird flu infections, the presence of environmental contaminants throughout the testing and analysis does not seem to have been considered.…”

Section: Introductionmentioning

confidence: 99%

Bird Flu in Cattle - Strong Evidence the Alleged Infection is a Technical Falsehood

Mueller

2024

Preprint

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The recent reports of bird flu infection in cattle in the U.S. have triggered concerns that (unpasteurized) milk or meat from affected animals could be unsafe for consumption and raised fear the virus could further evolve, spill over to humans, and cause another major pandemic with an expected fatality much higher than for COVID-19. The identification of the viral infection in cattle, based on PCR testing of mild or asymptomatic cases, raises similar questions as during the COVID-19 pandemic. Meanwhile, the USDA has publicized the genetic information of the bird flu virus, apparently isolated from numerous hosts including birds, cattle, and other mammals.This article gives an independent analysis of what is meant by “positive cases” and the “confirmed” presence of the virus. Specifically, a closer inspection of the genetic analysis reveals several gaps similar to those only recently discovered involving whole-genome sequencing protocols that remain largely unaccounted. The infection in cattle poses an additional challenge via environmentally derived viral genome fragments that these animals are constantly exposed to. The issue of contamination via off-target gene fragments during whole-genome sequencing has previously been widely underappreciated, even in much simpler contexts such as the sequencing of bacterial isolates. The type of contamination in the context of H5N1 and cattle is more complex and does not seem to ever have been considered before and appears technically challenging to resolve, if at all possible.Combined with several other considerations, this gives strong evidence the presumed confirmed positive cases are simply the result of some technological errors. The publicly available genomic data from WGS are likely severely biased and will, therefore, adversely affect any downstream analyses. The article closes with recommendations to help regain public trust in public health agencies and their recommendations.

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“…Before the pandemic, and as late as in 2019, some of the main challenges with mRNA technologies that are relevant to their potential environmental impact were [13,35,38,58]:…”

Section: Basic Unknownsmentioning

confidence: 99%

“…In my prior work [38], I suggested that mRNA vaccines might be able to impair the human microbiome, based on the following rationale: (a) The wide dissemination and stable persistence of biologically active material (the targeted mRNA, unintended RNA/DNA byproducts from manufacturing, as well as various components of the lipid nanoparticles) derived from the vaccines. (b) The finding that mRNA vaccines, despite being intramuscularly injected, reach mucosal effector sites and trigger mucosal immunity to some extent, (c) Adverse events post-jab reported globally which affect the GI system, (d)…”

Section: Introductionmentioning

confidence: 99%

Existing and Emerging mRNA Vaccines and their Environmental Impact - a Transdisciplinary Assessment

Mueller

2024

Preprint

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mRNA vaccines have played a momentous role during the COVID-19 pandemic and are now being developed for numerous other applications for humans, animals, and wildlife. Yet, their potential ramifications on the environment lack scrutiny and regulation. On 14 July 2020, the EU decided to temporarily exclude the clinical trials with COVID-19 vaccines from prior environmental risk assessment.Even though billions of doses have been administered and large-scale agricultural and wildlife RNA applications are fast-tracked, there is no knowledge of their environmental impact via the dispersion of vaccine-derived material or their wastage.This knowledge gap calls for a transdisciplinary approach, done here via a critical assessment of (1) the pharmacokinetic properties of these products, (2) their impact on the human microbiota, (3) novel risk factors exemplified by the human gut bacterium Escherichia coli resulting in pathogen evolution in the guts of wild animals, and (4) studies on mRNA-LNP platforms that implicate extracellular vesicles (EVs) as superior carriers. Thereby, I obtain the first extrapolation of the magnitude and likelihood of environmental risk as characterized by the FDA in 2015 for products that facilitate their action by transcription and/or translation of transferred genetic material or related processes.This analysis shows that the vaccine-derived bioactive material dispersed by EVs or impacted human microbiota is prone to exacerbate known risks in the existing context of genetic or chemical pollution, fostering pathogen evolution and dissemination in the open environment and driving widespread ecosystem disturbances. Additionally highlighting specific open questions, I anticipate this analysis to be the starting point for open dialogue and more in-depth studies to get a clear picture in the EU and globally, to most effectively gauge the environmental impact of existing and emerging human, animal, and wildlife mRNA technologies. Regulatory measures are urgently needed to remediate potentially large-scale damage to public and ecosystem health as well as adverse societal, economic, and legal implications.

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Challenges and Opportunities of mRNA Vaccines Against SARS-CoV-2

Cited by 8 publications

References 0 publications

Codon-optimization in gene therapy: promises, prospects and challenges

Codon-optimization in gene therapy: promises, prospects and challenges

Bird Flu in Cattle - Strong Evidence the Alleged Infection is a Technical Falsehood

Existing and Emerging mRNA Vaccines and their Environmental Impact - a Transdisciplinary Assessment

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