The tale of mRNA vaccines: Turning calamity into opportunity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease (COVID-19) pandemic caught the world off guard – completely.

Despite considerable research on the genomes of its distant cousins like SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV), showing a 70-80% similarity with the current SARS-CoV-2, the entire world was initially clueless on how to prevent the spread of this novel virus.

In contrast to the SARS and MERS epidemics that were well controlled and disappeared within months, SARS-CoV-2 was on the rise, and containing it was becoming increasingly difficult. Thus, a universal preventative strategy – such as a vaccine – became increasingly necessary.

Vaccines have been the single most effective way to contain and prevent severe infection by pathogenic microbes. The past few decades have been instrumental in proving the potential for messenger RNA (mRNA) vaccines, with conditions like influenza, different forms of lung cancer, prostate cancer, melanoma, Ebola and even HIV strains being under trials in mice, monkeys, and humans.

During the COVID era, the development of mRNA vaccines was a significant development that continues to impact globally.  With current vaccination drives across countries, there is a potential to reduce severe disease and hospitalization, as per reports of clinical trials conducted with the vaccines.

In a review paper published in the journal Nature Reviews, researchers from Carnegie Mellon University and the University of Pennsylvania have described the underlying technologies for mRNA vaccines and their future prospects with improved delivery systems and applications in diseases beyond the ongoing COVID-19 pandemic.

What is the technology behind mRNA Vaccines? What makes them revolutionary?

mRNA stands for messenger Ribonucleic Acid (RNA) which is used by ribosomes, present in the nucleus of the cell, to make proteins and release into the bloodstream. This is the principle that viruses use for replicating themselves when they enter host cells. This is no different for the (SARS) coronavirus 2 (SARS-CoV-2).

It is now known that the SARS-CoV-2 uses its spike protein to attach to a specific receptor on the host cell called angiotensin-converting enzyme 2 (ACE2). The SARS-CoV-2 mRNA vaccines currently available use synthetic mRNAs which mimic the viral mRNAs.

COVID-19 mRNA vaccines are administered in the upper arm muscle first.  Once the instructions (mRNA) are inside the muscle cells, the cells use them to make the protein piece. Once the protein piece is made, the cell digests the instructions and discards them.

Next, the cell displays the protein piece on its surface. Antibodies are made when our immune systems recognize the protein does not belong there, like when we are infected with SARS-CoV-2.

After the process is complete, our bodies have learned how to fight future SARS-CoV-2 infections. mRNA vaccines, like all vaccines, provide protection without exposing the recipients to the severe consequences of contracting COVID-19 disease.

Since the synthetic mRNA vaccines do not need the actual virus particles, they can be considered safer than those using live or attenuated (weakened) proteins from the actual virus. This, along with a host of other features, makes them a revolutionary concept for vaccine development.

How did mRNA vaccines become a lifeline in the COVID-19 pandemic?

The idea to use nucleic acid vaccines based on mRNA was conceived more than three decades ago in the hope of generating safe and versatile vaccines that are easy to produce.

mRNA vaccines carry the added advantage of being highly potent, easy to manufacture in large volumes, and cost-effective. With so many proof-of-concept trials having been conducted on other viruses in both humans and animals, mRNA vaccines were the chosen candidates to combat the cOVID-19 pandemic.

Additionally, the SARS-CoV-2 vaccine development improved on previous research on the MERS-CoV and SARS-CoV, which pointed towards the spike protein as the most likely candidate for vaccine development. Its amino acid sequence (which makes up for the whole protein) should be slightly modified to lock the protein in its prefusion conformation, when it is most potent, maximizing its immunogenicity (capacity to trigger an immune response). This way, the maximum number of antibodies could be generated.

These studies enabled researchers at Moderna (one of the major players in global COVID-19 vaccine delivery) to ramp up their operation and generate the mRNA-1273 sequence in 2 days and start phase I trials in 66 days.

To date, the development of the mumps vaccines had been the fastest, which took 4 years from conception to production and administration. However, the Pfizer and Moderna vaccines made it to the market at a record speed of 11 months, all thanks to the relentless work of scientists and researchers over the years and the Governments and investors who churned out vast sums of money for the vaccines to be manufactured.

Lessons learned from the mRNA vaccines

By the end of 2019, there were 15 mRNA vaccine candidates against infectious diseases which had entered clinical trials, but none could go beyond phase II. Therefore, there was little possibility of these vaccines being approved before 5-6 years subsequently.

The approval of the COVID-19 vaccines in 11 months uprooted this belief and opened a world of possibilities to the entire scientific community. On the one hand, this landmark event successfully convinced researchers of the efficacy of these vaccines, which would provide protection from a host of harmful pathogens. On the other, it debunked all doubts pertaining to development, manufacture and deployment processes involving the commercial viability of the vaccines. A calamity opened many opportunities.

Some of the other mRNA vaccine candidates under trial include those for cytomegalovirus (CMV) human immunodeficiency virus (HIV), human metapneumovirus (hMPV), parainfluenza virus type 3 (PIV3), Rabies, Influenza A, Chikungunya, and respiratory syncytial virus (RSV).

Current research in mRNA therapeutics focuses on better delivery systems to ensure the mRNA is delivered unaffected for maximum immunogenicity, making the vaccines more robust and thermostable as mass cold storage is not an option with many countries around the globe and ensuring the longer lifespan of antibodies to ensure continued protection.

Nonetheless, the story of the COVID-19 vaccine will remain a significant scientific landmark and continue to entrust people with the belief that we will see the end to this pandemic soon!

Written by

Sreetama Dutt

Sreetama Dutt has completed her B.Tech. in Biotechnology from SRM University in Chennai, India and holds an M.Sc. in Medical Microbiology from the University of Manchester, UK. Initially decided upon building her career in laboratory-based research, medical writing and communications happened to catch her when she least expected it. Of course, nothing is a coincidence.