[BioNOW] What Is the Mechanism Behind 'mRNA' Vaccines?

'Messenger' Role Delivering Protein Blueprints
Insert Virus 'Shell' Blueprints to Enable 'Practice Game'

Drawback of Rapid Disappearance in the Body
Overcome via Lipid Nanoparticles and Modified mRNA

Development Attempts by ST Pharm, Curetis, iGene, and Others in Korea

mRNA COVID-19 vaccines developed by Pfizer-BioNTech and Moderna [Image source=Reuters Yonhap News]

[Asia Economy Reporter Chunhee Lee] During the COVID-19 pandemic, at some point, we all became familiar with the term 'messenger ribonucleic acid (mRNA).' Although it was a term typically found only in biology textbooks, it gradually entered everyday language as COVID-19 vaccines were introduced domestically. However, since it is still a relatively unfamiliar concept, many people do not fully understand how mRNA functions inside our bodies.

As the name 'messenger' suggests, mRNA plays the role of transmitting information. For proteins to be produced, the genetic blueprint (genetic information) for making specific proteins from DNA inside the cell nucleus must first be transcribed into mRNA. The transcribed mRNA, carrying this genetic information, then moves into the ribosomes located in the cytoplasm outside the nucleus. Transfer RNA (tRNA) brings amino acids matching the mRNA's nucleotide sequence and links them together to form proteins. In this way, mRNA acts as a kind of blueprint distributed throughout our bodies.

Before the human genome project was completed, it was believed that all proteins constituting the human body were made solely based on the genetic information contained in DNA. mRNA was thought to merely transmit DNA's information as is. However, it was later discovered that RNA can independently cause genetic mutations. During transcription, new mutations not present in DNA can be created, or the order of nucleotides can change, resulting in new blueprints.

The idea of creating vaccines using mRNA might have been a natural progression. This is because artificially engineered mRNA containing the blueprint of a virus's shell, rather than the actual virus, can be introduced into the human body in advance. This leads to the production of spike proteins (antigens) that resemble the virus inside our bodies, which are then recognized as enemies, activating our immune system to eliminate them. This 'practice game' prepares our body to effectively remove the virus when the real virus invades later.

Moreover, traditional antibody-based vaccines required complex laboratory synthesis of viral shells. In contrast, mRNA vaccines only require inserting modified mRNA with the blueprint. This is where mRNA's greatest advantage emerges. Once the development principle is fully established, even if a new virus appears, its genetic material can be quickly extracted to develop a new vaccine rapidly. This concept was introduced in 1976 by Katalin Karik?, a professor at the University of Pennsylvania, who later served as BioNTech's vice president and led the joint development of Pfizer's mRNA COVID-19 vaccine.

[Image source=Yonhap News]

However, there was a significant drawback to this mRNA vaccine concept: it was difficult to effectively distribute the engineered mRNA inside the body. The purpose of introducing mRNA into the body is to conduct the 'practice game,' but before the virtual enemy could be created, the mRNA disappeared too quickly from the body.

This is also why early concerns that 'mRNA vaccines might affect our body's DNA and cause permanent side effects' were dismissed by the scientific community as baseless. This is because mRNA struggles to penetrate the cell nucleus and is rapidly degraded. However, until COVID-19, the lack of commercially available mRNA vaccines was largely due to this major obstacle in mRNA vaccine development.

But with the development of 'lipid nanoparticle (LNP)' technology, mRNA technology underwent a significant transformation. Developed by Robert Langer, a professor at the Massachusetts Institute of Technology (MIT), LNP technology encapsulates mRNA in lipid nanoparticles, safely delivering it into cells and allowing it to survive long enough to create the virtual enemy.

Additionally, in 2005, Professor Karik? and Professor Drew Weissman of the University of Pennsylvania succeeded in developing modified mRNA. They devised a method to suppress immune responses so that the immune system would not eliminate the mRNA before it could create the virtual enemy. They discovered that our immune system recognizes and removes specific RNA, and if this recognition could be avoided, attacks on mRNA could be prevented.

Professors Katalin Karik? and Drew Weissman of the University of Pennsylvania, who co-developed the modified mRNA technology (from left in the photo)

These ideas rapidly materialized with the advent of COVID-19. BioNTech, joined by Professor Karik?, partnered with Pfizer to produce the world's first mRNA vaccine to receive emergency use authorization, while Professor Langer co-founded Moderna, an mRNA-focused company, which also succeeded in developing an mRNA vaccine.

Both companies are now pursuing the development of various mRNA vaccines beyond COVID-19. Moderna is developing a vaccine that simultaneously prevents seasonal influenza and respiratory syncytial virus (RSV) in addition to COVID-19. Pfizer-BioNTech plans to start clinical trials for an mRNA vaccine against shingles within this year.

In South Korea, efforts to develop mRNA vaccines are ongoing. ST Pharm recently received approval for the phase 1 clinical trial plan of its mRNA-LNP-based COVID-19 vaccine 'STP2104' and is expected to enter clinical trials soon. To support development, the 'K-mRNA Consortium' was formed in June last year. Led by the Korea Innovative Medicines Consortium (KIMCo), it includes Hanmi Pharmaceutical and GC Green Cross. Hanmi Pharmaceutical synthesizes the spike gene (DNA) of the coronavirus, while GC Green Cross handles final product manufacturing. In September last year, Dong-A ST, a specialty pharmaceutical developer, and Icell, a bio raw material supplier, also joined the consortium.

Other companies are also developing mRNA vaccines. Curatis is recruiting participants for phase 1 clinical trials of its mRNA COVID-19 vaccine 'QTP104,' and iGene is recruiting participants for phase 1 and 2a clinical trials of its 'EG-COVID' vaccine.