Synthetic Messenger RNA-Based Vaccines: From Scorn to Hype

Pascolo, Steve

doi:10.3390/v13020270

Cited by 69 publications

(63 citation statements)

References 36 publications

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“…Adenovirus vector vaccines may elicit stronger immune response than DNA and mRNA vaccines, but their vaccine efficacy could reduce through pre-existing immunity against Ad vectors [44]. Compared to DNA vaccine, mRNA vaccine needs ultralow temperature for storage and transportation [45]. Hence, DNA vaccine could be a potential vaccine platform especially during emergency use.…”

Section: Discussionmentioning

confidence: 99%

DNA vaccination induced protective immunity against SARS CoV-2 infection in hamsterss

et al. 2021

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The development of efficient vaccines against COVID-19 is an emergent need for global public health. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major target for the COVID-19 vaccine. To quickly respond to the outbreak of the SARS-CoV-2 pandemic, a nucleic acid-based vaccine is a novel option, beyond the traditional inactivated virus vaccine or recombinant protein vaccine. Here, we report a DNA vaccine containing the spike gene for delivery via electroporation. The spike genes of SARS-CoV and SARS-CoV-2 were codon optimized for mammalian cell expression and then cloned into mammalian cell expression vectors, called pSARS-S and pSARS2-S, respectively. Spike protein expression was confirmed by immunoblotting after transient expression in HEK293T cells. After immunization, sera were collected for antigen-specific antibody and neutralizing antibody titer analyses. We found that both pSARS-S and pSARS2-S immunization induced similar levels of antibodies against S2 of SARS-CoV-2. In contrast, only pSARS2-S immunization induced antibodies against the receptor-binding domain of SARS-CoV-2. We further found that pSARS2-S immunization, but not pSARS-S immunization, could induce very high titers of neutralizing antibodies against SARS-CoV-2. We further analyzed SARS-CoV-2 S protein-specific T cell responses and found that the immune responses were biased toward Th1. Importantly, pSARS2-S immunization in hamsters could induce protective immunity against SARS-CoV-2 challenge in vivo. These data suggest that DNA vaccination could be a promising approach for protecting against COVID-19.

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Section: Discussionmentioning

confidence: 99%

DNA vaccination induced protective immunity against SARS CoV-2 infection in hamsterss

et al. 2021

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“…Interestingly, the high dose groups in LNP2 and LNP3 yielded responses with lower avidity indices compared to their respective low dose counterparts. Nominally, since the quality and quantity of the antibody response influence functional outcomes, to this end, the inhibition of liver stage development assay (ILSDA) was performed to detect antibody functionality directly against the P. falciparum malaria parasite in vitro 39 . For this experiment, individual mouse sera within each group were pooled and tested at a 1:40 dilution (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As seen with the SARS-CoV-2 Pfizer/BioNTech and Moderna mRNA vaccines 39 , mRNA vaccines have numerous advantages over conventional vaccine approaches. Nominally, offering the advantage of exacting in silico antigen design, engagement of the host immune system through MHC Class I and II pathways, and the flexibility and rapidity of manufacturing processes.…”

Section: Discussionmentioning

confidence: 99%

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice

et al. 2021

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Human malaria affects the vast majority of the world’s population with the Plasmodium falciparum species causing the highest rates of morbidity and mortality. With no licensed vaccine and leading candidates achieving suboptimal protection in the field, the need for an effective immunoprophylactic option continues to motivate the malaria research community to explore alternative technologies. Recent advances in the mRNA discipline have elevated the long-neglected platform to the forefront of infectious disease research. As the immunodominant coat protein of the invasive stage of the malaria parasite, circumsporozoite protein (PfCSP) was selected as the antigen of choice to assess the immunogenic and protective potential of an mRNA malaria vaccine. In mammalian cell transfection experiments, PfCSP mRNA was well expressed and cell associated. In the transition to an in vivo murine model, lipid nanoparticle (LNP) encapsulation was applied to protect and deliver the mRNA to the cell translation machinery and supply adjuvant activity. The immunogenic effect of an array of factors was explored, such as formulation, dose, number, and interval of immunizations. PfCSP mRNA-LNP achieved sterile protection against infection with two P. berghei PfCSP transgenic parasite strains, with mRNA dose and vaccination interval having a greater effect on outcome. This investigation serves as the assessment of pre-erythrocytic malaria, PfCSP mRNA vaccine candidate resulting in sterile protection, with numerous factors affecting protective efficacy, making it a compelling candidate for further investigation.

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“…The potential applications of LNPs as delivery vehicles have been extensively explored. Notably, this technology was crucial for the recent approval of an siRNA drug targeting transthyretin (TTR) mRNA for treatment of Transthyretin-induced amyloidosis (hTTR) [ 61 ] and has played an even more significant role in the development of the recent emergency use authorized mRNA vaccines [ 62 ]. Such successes will surely pave the way for accelerated preclinical and clinical development of new RNA therapeutics.…”

Section: Enabling Technologies For Oligonucleotide Therapeuticsmentioning

confidence: 99%

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Adachi

Hengesbach

et al. 2021

Biomedicines

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Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.

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Synthetic Messenger RNA-Based Vaccines: From Scorn to Hype

Cited by 69 publications

References 36 publications

DNA vaccination induced protective immunity against SARS CoV-2 infection in hamsterss

DNA vaccination induced protective immunity against SARS CoV-2 infection in hamsterss

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

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