Review portrays clinical journey of messenger RNA vaccines and mRNA-based therapies

By Neha MathurMay 11 2022Reviewed by Aimee Molineux

In a recent study published in the journal Nature Biotechnology, researchers reviewed the messenger ribonucleic acid (mRNA) technology and highlighted its clinical applications.

Background

Two mRNA-based coronavirus disease 2019 (COVID-19) vaccines, BNT162b2 and mRNA-1273, received the emergency use authorizations (EUAs) ~11 months after the publication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome sequence. This remarkable accomplishment was possible because researchers already had extensive experience with mRNA technology.

It is noteworthy that both BNT162b2 and mRNA-1273 are the most clinically advanced non-replicating mRNA-based vaccines with chemically modified uradine bases. Conversely, all the unmodified mRNA-based COVID-19 vaccines, such as CureVac, have yielded disappointing results in their clinical trials.

Furthermore, mRNA vaccines do not present the risk of insertional mutagenesis like deoxyribonucleic acid (DNA) or viral vector-based vaccines. Also, similar to recombinant protein vaccines, they do not produce infectious particles nullifying the risk of causing some form of the exacerbated disease.

Other advantages are that mRNA vaccines encode an immunogenic protein of interest in the absence of a live virus. Thus, they do not need biosafety laboratories for manufacturing. In fact, it is possible to produce mRNA vaccines in cell-free systems with minimal risk of bacterial contaminants. Also, they are safe for individuals with egg allergies.

Furthermore, the manufacturing of different mRNA vaccines relies on the same chemical components. They readily adapt to new pathogens and could be used for making seasonal vaccines and preparing for future epidemics. Due to its efficiency and flexibility, the mRNA platform also appears to be more cost-effective than other methods.

The dosage range of SARS-CoV-2 mRNA vaccines and for other pathogenic viruses is equally broad. Accordingly, both BNT162b2 and mRNA-1273 successfully prevented close to 95% of COVID-19 cases at low doses of 30 μg and 100 μg, respectively. Given the flexibility of dosage regimens of mRNA vaccines and the advantages with respect to their storage logistics, they have massive implications for global immunization plans.

The study and findings

The present review broadly discussed the massive clinical landscape of mRNA-based vaccines, drugs, and other immunotherapies. In particular, the technological innovations in vaccine manufacturing, the lessons from the clinical trials, and envisioned challenges in future research. Although biomedical applications of mRNA would continue to evolve, the researchers focused on its three main applications, as follows:

       i.           mRNA vaccines for prevention of infectious diseases

     ii.           mRNA as a therapeutic for cancer

   iii.           mRNA-encoded proteins for immunotherapies

The study data highlighted the transformative potential of mRNA technology. mRNA formulations have inherent immunostimulatory properties, which facilitates their use to encode proteins for vaccination and protein replacement therapies.

The intracellular delivery of the mRNA vaccine moiety to the target cells is challenging while preserving its stability. After a decade’s toiling with several approaches, researchers identified lipid nanoparticle (LNP) formulation as efficient in intracellular delivery. Likewise, polymeric nanoparticles (PNPs) have shown promise as delivery systems. Interestingly, LNP and PNP may be modified with ligands to facilitate cell-specific targeting.

Moreover, mRNA can be a powerful stimulus to the innate immune system. Specifically, mRNA stimulates the toll-like receptor (TLR) system and the retinoic acid-inducible gene I (RIG-I)-like receptors to induce the production of type I interferons (IFNs) and inflammatory cytokines. The extent to which an mRNA-based medicinal product activates these pathways is a key aspect of the development of mRNA medicines.

As the mRNA technology would refine further, mRNA-based therapies will likely become available for more diseases. Its use will expand further with refinements in non-human, artificially engineered protein constructs.

mRNA therapies could be the novel intracellular therapeutics as mRNA only transiently expresses genes, thereby subduing side effects from persistent expression. The intracellular expression of antibodies could emerge as a distinct therapeutic class that can be combined with, for example, the cell nucleus to direct the activities of the encoded protein.

The mRNA therapies have extraordinary potential concerning their routes of administration. Subsequently, they could be administered via several routes, such as intramuscular, intradermal, subcutaneous, and intravenous, and could be inhaled as well. In the future, eye drops or nose drops, skin ointments, etc., may also be available, although this would greatly depend on advancements in delivery materials.

Nevertheless, all the technological advancements in tissue targeting and delivery of nanoparticles will open doors for more mRNA-based therapeutics.