Balancing efficacy and safety: The challenges of mRNA drugs and vaccines in modern medicine

In a recent study published in the journal Nature Reviews Drug Discovery, researchers collate available literature on medical and industrial developments aimed at reducing the cellular toxicity of mRNA and their carrier vehicles - lipid nanoparticles. They focus on these substances' reactogenicity and their cell tropism- and tissue distribution-associated toxicity concerns. They discuss the challenges associated with reducing the toxicity of these conjugate entities and highlight the socioeconomic and medical benefits of de-risking focused mRNA research.

Study: Strategies to reduce the risks of mRNA drug and vaccine toxicity. Image Credit: Design_Cells / ShutterstockStudy: Strategies to reduce the risks of mRNA drug and vaccine toxicity. Image Credit: Design_Cells / Shutterstock

The mRNA therapeutic revolution

Messenger RNA (mRNA) is a type of single-stranded RNA essential for protein synthesis. Rapid recent developments in biomedical research have allowed clinicians and pharmaceutical companies to generate rRNA vaccines and drugs that instruct their target cells to produce the beneficial proteins encoded within them.

mRNA drugs and vaccines provide substantial benefits over their conventional counterparts – 1. Short manufacturing time, 2. Diverse mechanism-of-action changes through minor modifications in mRNA sequence. The ideal example of mRNA's pathogen-disruptive effect is that of the coronavirus disease 2019 (COVID-19), where billions of mRNA vaccinee doses successfully halted and even reversed the spread of a pandemic that claimed almost 7 million lives and infected more than 700 million.

"The rapid development of bivalent COVID-19 mRNA vaccines to target both the ancestral Wuhan-Hu-1 and omicron B.1.1.529 spike in under a year demonstrates the rapid timeline for modifications with mRNA technology in the clinic. Moreover, these bivalent vaccines elicit superior neutralizing antibody responses against omicron compared with the original vaccine, which targeted just the ancestral strain."

The COVID-19 pandemic presents the ideal example for another fact – as the English interpretation of Socrates' famous quote, "Our need will be the real creator," survival was the necessity that drove the rapid development of the mRNA vaccine invention. In reality, the technology remains novel, presenting genuine concerns about its clinical safety. As mRNA vaccines are increasingly used in medical applications beyond immunizations, the critical challenge is to access and mitigate potential toxicities associated with the technology.

About the review

The present review collates the pathogenicities and toxicities identified during mRNA drug and vaccine development. It delves into the association between mRNA components and these aforementioned observed outcomes. Finally, challenges to toxicity mitigation are explored, and under-developed, next-generation solutions to these problems are presented.

mRNA immunogenicity and its solution

Two scientific milestones were instrumental in successfully developing today's mRNA therapeutics – 1. Suppressing the immunogenicity of in vitro transcription (IVT) mRNA, and 2. The discovery of lipid nanoparticles, mRNA's ideal vehicle for host-cell delivery.

Due to its potential to form double-stranded structures (for example, a hairpin loop), single-stranded mRNA has been shown to induce the same nuclear factor κB (NF-κB)-activating effect as double-stranded RNA (dsRNA). This has been found to increase circulating tumor- and inflammation-inducing molecules in circulation. Thankfully, a solution was presented in the form of seminal work that proved that nucleoside methylation, along with pseudouridine incorporation, effectively masks IVT ssRNA from host immune regulation, eliminating toxicity outcomes. The industrial sector has adopted this approach, with dsRNA purification and nucleotide modifications the norm.

"Novel in vitro RNA engineering techniques such as circular mRNA has recently been proposed to improve on the relatively short intracellular half-life of linear mRNA."

Two of the biggest challenges in mRNA bioavailability were those of mRNA's size (long) and charge (negative), which substantially slowed their percolation through host cells, and its rapid degradation by intracellular ribonucleases (RNases) present in host blood and tissues. Both these challenges were overcome by encapsulating mRNA in lipid nanoparticles, the latter of which became the vehicle for the former.

"mRNA formulated in lipid nanoparticles (LNP–mRNA) is protected from biodegradation and exhibits improved half-life, increased cellular uptake and protein translation compared with naked mRNA delivery."

LNP-mRNA synthesis involves the use of a complex mixture of ionizable (amino) lipids, polyethylene glycol-linked (PEGylated), a helper lipid, and cholesterol. Unfortunately, while their individual contributions are well documented, the relative concentrations and impacts of these lipid concoctions on the bioavailability and toxicity of the mRNA intervention were, until recently, poorly understood. The necessity presented by the COVID-19 pandemic solved this issue, with intensive research focused on the clinically safe development of mRNA vaccines conducted in a matter of months.

Can mRNA administration be optimized?

With the deployment of mRNA interventions beyond vaccinations, research is investigating the effects of application-specific administration routes on the toxicity of mRNA therapies. Studies have revealed that application-specific size and lipid composition changes can substantially alter mRNA therapy's organ tropism and other biopharmaceutical profiles. Hitherto, most mRNA research has utilized intramuscular and intratumoral administration due to their observed efficacy improvements over conventional subcutaneous delivery routes.

Intradermal and subcutaneous delivery remains the technique of choice for vaccine delivery (as in the case of most commercial COVID-19 vaccines), and some cancer therapies. By contrast, intravenous administration presents a poor choice of mRNA and LNP-mRNA delivery – intravenous administration is followed by a concentration of mRNA products in the liver and spleen rather than the target tissue. Even when the liver or the spleen is the intended target, intravenous administration presents an inefficient delivery system due to the half-life of LNP-mRNA in blood. The oral administration route shares the latter concern, with the acidic pH of the gastric digestion phase disrupting the LNP barrier, causing premature mRNA release.

Toxicity

Despite the impressive recent advances in the field, most mRNA preclinical trials never progress beyond phase I or II, with lower-than-expected efficacy and toxicity being the most cited reasons. Recent research on mRNA-associated liver and spleen pathogenicity reveals that toxicity can arise from both intravenous and intramuscular LNP-mRNA administration. Autoimmune reactions to mRNA products are another concern, but nucleotide modifications have largely eliminated this issue.

Conclusions

In the present review, 269 recent publications, reviews, and meta-analyses on mRNA-induced toxicity were summarised to reveal the challenges posed by mRNA therapies and the technological advancements that allow these novel interventions to remain safe and successful. After almost a decade of stagnancy, the mRNA intervention's rapid development, mobilization, and observable success during the COVID-19 pandemic have highlighted its benefits over conventional vaccines and drugs. Future advances in LNP delivery systems and optimizations to lipid compositions and administration routes may establish mRNA therapy as a critical clinical intervention in the future.

Journal reference:
  • Bitounis, D., Jacquinet, E., Rogers, M. A., & Amiji, M. M. (2024). Strategies to reduce the risks of mRNA drug and vaccine toxicity. Nature Reviews Drug Discovery, 1-20, DOI – 10.1038/s41573-023-00859-3, https://www.nature.com/articles/s41573-023-00859-3
Hugo Francisco de Souza

Written by

Hugo Francisco de Souza

Hugo Francisco de Souza is a scientific writer based in Bangalore, Karnataka, India. His academic passions lie in biogeography, evolutionary biology, and herpetology. He is currently pursuing his Ph.D. from the Centre for Ecological Sciences, Indian Institute of Science, where he studies the origins, dispersal, and speciation of wetland-associated snakes. Hugo has received, amongst others, the DST-INSPIRE fellowship for his doctoral research and the Gold Medal from Pondicherry University for academic excellence during his Masters. His research has been published in high-impact peer-reviewed journals, including PLOS Neglected Tropical Diseases and Systematic Biology. When not working or writing, Hugo can be found consuming copious amounts of anime and manga, composing and making music with his bass guitar, shredding trails on his MTB, playing video games (he prefers the term ‘gaming’), or tinkering with all things tech.

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