Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines

Nance, Kellie D.; Meier, Jordan L.

doi:10.1021/acscentsci.1c00197

Cited by 269 publications

(324 citation statements)

References 69 publications

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“…Both mRNA vaccines have modulated 5′ and 3′ untranslated sequences to optimize mRNA stability and translation efficiency 44 , 45 , and all uridines are replaced by N1-methylpseudouridine (m1Ψ) to further increase RNA stability and to reduce innate immune responses (Fig. 3a ; see section “Vaccine-specific differences of innate responses”) 51 , 52 . Details of manufacturing processes may differ between the companies, and subtle product-specific variations of RNA sequences were recently confirmed by comparative analyses of RNA extracted from original vials of the two vaccines ( https://github.com/NAalytics/Assemblies-of-putative-SARS-CoV2-spike-encoding-mRNA-sequences-for-vaccines-BNT-162b2-and-mRNA-1273/blob/main/Assemblies%20of%20putative%20SARS-CoV2-spike-encoding%20mRNA%20sequences%20for%20vaccines%20BNT-162b2%20and%20mRNA-1273.docx.pdf ).…”

Section: Vaccine-specific Differences Of S-antigen Structure and Presentationmentioning

confidence: 99%

Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action

2021

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COVID-19 vaccines were developed with an unprecedented pace since the beginning of the pandemic. Several of them have reached market authorization and mass production, leading to their global application on a large scale. This enormous progress was achieved with fundamentally different vaccine technologies used in parallel. mRNA, adenoviral vector as well as inactivated whole-virus vaccines are now in widespread use, and a subunit vaccine is in a final stage of authorization. They all rely on the native viral spike protein (S) of SARS-CoV-2 for inducing potently neutralizing antibodies, but the presentation of this key antigen to the immune system differs substantially between the different categories of vaccines. In this article, we review the relevance of structural modifications of S in different vaccines and the different modes of antigen expression after vaccination with genetic adenovirus-vector and mRNA vaccines. Distinguishing characteristics and unknown features are highlighted in the context of protective antibody responses and reactogenicity of vaccines.

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Section: Vaccine-specific Differences Of S-antigen Structure and Presentationmentioning

confidence: 99%

Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action

2021

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“…However, the main motivation in the field has been the use of CL-based NA vectors in gene therapeutics [ 44 , 45 , 46 ], a concept explored in numerous clinical trials [ 45 , 47 , 48 ]. Major discoveries in the biochemical arena, such as gene silencing via RNA interference (RNAi) [ 49 , 50 ] induced by double-stranded small interfering RNA (siRNA) [ 18 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ] and microRNA [ 59 ], gene editing via CRISPR/Cas-9 [ 60 , 61 , 62 ], and expression of base-modified mRNA [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ], have greatly expanded the therapeutic potential of NAs. The first culmination of these efforts was the FDA approval of a lipid-based siRNA vector (patisiran/ONPATTRO ® , Alnylam Pharmaceuticals) in 2018 for treatment of the polyneuropathy caused by hereditary transthyretin amyloidosis [ 71 , 72 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the scale of this first breakthrough was dwarfed by the success and use (in potentially billions of patients) of two lipid-based mRNA vaccines [ 73 ] against SARS-CoV2. Building on decades of work on both the lipid vector [ 72 , 74 , 75 ] and the mRNA payload [ 70 ], the vaccines developed by Pfizer/BioNTech [ 76 , 77 , 78 ] and Moderna [ 79 , 80 ] became the first vaccines approved against COVID-19 in December 2020. The lipid compositions of the vaccine nanoparticles are similar to that of patisiran [ 81 , 82 ], albeit employing ionizable cationic lipids with branched rather than unsaturated tails and different PEG-lipids ( Figure 2 and Figure 3 ).…”

Section: Introductionmentioning

confidence: 99%

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

et al. 2021

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Cationic liposomes (CLs) are effective carriers of a variety of therapeutics. Their applications as vectors of nucleic acids (NAs), from long DNA and mRNA to short interfering RNA (siRNA), have been pursued for decades to realize the promise of gene therapy, with approvals of the siRNA therapeutic patisiran and two mRNA vaccines against COVID-19 as recent milestones. The long-term goal of developing optimized CL-based NA carriers for a broad range of medical applications requires a comprehensive understanding of the structure of these vectors and their interactions with cell membranes and components that lead to the release and activity of the NAs within the cell. Structure–activity relationships of lipids for CL-based NA and drug delivery must take into account that these lipids act not individually but as components of an assembly of many molecules. This review summarizes our current understanding of how the choice of the constituting lipids governs the structure of their CL–NA self-assemblies, which constitute distinct liquid crystalline phases, and the relation of these structures to their efficacy for delivery. In addition, we review progress toward CL–NA nanoparticles for targeted NA delivery in vivo and close with an outlook on CL-based carriers of hydrophobic drugs, which may eventually lead to combination therapies with NAs and drugs for cancer and other diseases.

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“…The PSC mRNA vaccine constructs resulted in elevated antigen‐specific T‐cells and are the first vaccine approved by the FDA against prostate cancer. Recently, Nance and the group have proposed modifications in mRNA vaccines developed against COVID‐19 (Nance & Meier, 2021 ). In these mRNA vaccines, the uridine nucleobase suggested being replaced with N1‐methylpseudouridine (m1Ψ) to augment the efficacy of these mRNA vaccines.…”

Section: Posttranslational Modifications In Vaccine Candidatesmentioning

confidence: 99%

Cognizance of posttranslational modifications in vaccines: A way to enhanced immunogenicity

Ojha

Prajapati

2021

Journal Cellular Physiology

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Vaccination is a significant advancement or preventative strategy for controlling the spread of various severe infectious and noninfectious diseases. The purpose of vaccination is to stimulate or activate the immune system by injecting antigens, i.e., either whole microorganisms or using the pathogen's antigenic part or macromolecules. Over time, researchers have made tremendous efforts to reduce vaccine side effects or failure by developing different strategies combining with immunoinformatic and molecular biology. These newly designed vaccines are composed of single or several antigenic molecules derived from a pathogenic organism. Although, whole‐cell vaccines are still in use against various diseases but due to their ineffectiveness, other vaccines like DNA‐based, RNA‐based, and protein‐based vaccines, with the addition of immunostimulatory agents, are in the limelight. Despite this, many researchers escape the most common fundamental phenomenon of protein posttranslational modifications during the development of vaccines, which regulates protein functional behavior, evokes immunogenicity and stability, etc. The negligence about post translational modification (PTM) during vaccine development may affect the vaccine's efficacy and immune responses. Therefore, it becomes imperative to consider these modifications of macromolecules before finalizing the antigenic vaccine construct. Here, we have discussed different types of posttranslational/transcriptional modifications that are usually considered during vaccine construct designing: Glycosylation, Acetylation, Sulfation, Methylation, Amidation, SUMOylation, Ubiquitylation, Lipidation, Formylation, and Phosphorylation. Based on the available research information, we firmly believe that considering these modifications will generate a potential and highly immunogenic antigenic molecule against communicable and noncommunicable diseases compared to the unmodified macromolecules.

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Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines

Cited by 269 publications

References 69 publications

Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action

Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action

Cationic Liposomes as Vectors for Nucleic Acid and Hydrophobic Drug Therapeutics

Cognizance of posttranslational modifications in vaccines: A way to enhanced immunogenicity

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