Mechanism of action of mRNA-based vaccines

Iavarone, Carlo; O’Hagan, Derek T.; Yü, Dong; Delahaye, Nicolas; Ulmer, Jeffrey B.

doi:10.1080/14760584.2017.1355245

Cited by 183 publications

(157 citation statements)

References 110 publications

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“…173,181 The resultant RNA, termed replicon, usually contains two different ORFs, with one encoding nonstructural proteins that help RNA capping and replication and the other expressing the antigen that replaces the viral structural protein ( Figure 3B). 163 SAM vaccines have several attractive features, such as extending the duration (approximately 2 months) and magnitude of expression compared to their non-replicating counterparts. However, in order to maintain selfamplifying activity, these RNA replicons are not able to tolerate many of the synthetic nucleotide modifications and sequence alterations.…”

Section: Sam Vaccinesmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. mRNA holds the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, 1 significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. 2 The translatability and stability of mRNA as well as its immunostimulatory activity are the key factors to be optimized for specific therapeutic application. 3 Increased translation and stability can be affected by many regions of the RNA. mRNA 5 0 and 3 0 UTRs are responsible for recruiting RNA-binding proteins and microRNAs, and they can profoundly affect translational activity. 2,4 The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels. 5,6 Modification of the 5 0 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistance to enzymatic degradation. 7 Chemical modification of RNA bases can be used to modify mRNA immunostimulatory activity. 8,9 The importance of immunostimulation can depend on the application, 10 and, in some cases, it may actually improve performance, as in the case of vaccines. 11Finally, methods and vehicles for intracellular delivery remain the major barrier to the broad application of mRNA therapeutics. 12 With some exceptions, the intracellular delivery of mRNA is generally more challenging than that of small oligonucleotides, and it requires encapsulation into a delivery nanoparticle, in part due to the significantly larger size of mRNA molecules (300-5,000 kDa, 1-15 kb) as compared to other types of RNAs (small interfering RNAs [siRNAs], 14 kDa; antisense oligonucleotides [ASOs], 4-10 kDa). 10,13 In this review, we discuss the challenges for clinical translation of mRNAbased therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. Materials for mRNA Delivery Structural Aspects of Material DesignAmong the many barriers to function, mRNA must cross the cell membrane in order to reach the cytoplasm (Figure 1). The cell me...

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Section: Sam Vaccinesmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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“…excessive activation can also interfere with antigen expression and adaptive immunity. 61,62 For example, Karikó et al 57 and others 44,[63][64][65][66][67][68][69] have shown that pseudouridine-containing mRNAs reduce activation of Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2 0 -5 0 -oligoadenylate synthetase (OAS), while increasing translational activity, resistance to RNase L-mediated degradation, and in vivo stability. The highest levels of protein production and immunogenicity are observed when nucleoside-modified mRNA is also purified by high-performance liquid chromatography (HPLC) or fast protein liquid chromatography (FPLC), where aberrant double-stranded transcripts are removed.…”

Section: Cell-free Production and Purification Of Mrna Vaccinesmentioning

confidence: 99%

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases

et al. 2019

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“…Alternatively, we speculate that the lower potency of a highly attenuated or inactivated VEE RNA vaccine could be overcome by further improvement of the synthetic non-viral delivery system, for example, by optimizing CNE specifically for VEEV SAM vaccine or utilizing alternative delivery strategies such as LNPs. 8,10,42,43 On a related note, the attenuated LAV m -CNE vaccine was significantly less immunogenic than the parental LAV-CNE vaccine, whereas LAV m -VRPs was similar to LAV-VRPs. It is possible that the VRP presents glycoproteins authentically to allow for more efficient uptake of the particles as compared to CNE so that both LAV m -VRPs and LAV-VRPs could efficiently launch to induce robust immune responses.…”

Section: Discussionmentioning

confidence: 98%

Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice

et al. 2019

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Venezuelan equine encephalitis virus (VEEV) is a known biological defense threat. A live-attenuated investigational vaccine, TC-83, is available, but it has a high non-response rate and can also cause severe reactogenicity. We generated two novel VEE vaccine candidates using self-amplifying mRNA (SAM). LAV-CNE is a live-attenuated VEE SAM vaccine formulated with synthetic cationic nanoemulsion (CNE) and carrying the RNA genome of TC-83. IAV-CNE is an irreversibly-attenuated VEE SAM vaccine formulated with CNE, delivering a TC-83 genome lacking the capsid gene. LAV-CNE launches a TC-83 infection cycle in vaccinated subjects but eliminates the need for live-attenuated vaccine production and potentially reduces manufacturing time and complexity. IAV-CNE produces a single cycle of RNA amplification and antigen expression without generating infectious viruses in subjects, thereby creating a potentially safer alternative to live-attenuated vaccine. Here, we demonstrated that mice vaccinated with LAV-CNE elicited immune responses similar to those of TC-83, providing 100% protection against aerosol VEEV challenge. IAV-CNE was also immunogenic, resulting in significant protection against VEEV challenge. These studies demonstrate the proof of concept for using the SAM platform to streamline the development of effective attenuated vaccines against VEEV and closely related alphavirus pathogens such as western and eastern equine encephalitis and Chikungunya viruses.

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Mechanism of action of mRNA-based vaccines

Cited by 183 publications

References 110 publications

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases

Self-Amplifying RNA Vaccines for Venezuelan Equine Encephalitis Virus Induce Robust Protective Immunogenicity in Mice

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