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The Long and Unexpected Journey – The Story of mRNA Vaccine Development

A weird game of Scrabble

Over the course of the last half-century, a number of threatening infectious diseases have escaped scientific efforts for a cure. The HIV virus is perhaps among the most notable, but others existed as well. Though rare in occurrence, Ebola and Zika viruses have created concerns among public health officials. Similarly, influenza virus strains continue to cause hundreds of thousands of deaths each year worldwide. Therefore, it might be perplexing how researchers from around the globe developed incredibly effective vaccines for COVID-19 in record time. But the mRNA technology that enabled these new vaccines didn’t just emerge from nowhere. In fact, mRNA vaccine development began more than six decades earlier.

(Read more about the COVID vaccine that will protect against all variants in this Bold story!)

The history of mRNA vaccine development isn’t one that’s filled with a repeated chain of continued successes. Scientists faced setbacks throughout their development, often contributing in ways they didn’t even realize. Many actually gave up on their work and explored other areas of research. And none, until perhaps today, expected to receive any recognition or fame for their accomplishments. But without question, without the work of dozens of researchers, mRNA technology wouldn’t be where it is today. And in all likelihood, we would still be without an effective vaccine to address the COVID-19 pandemic.

“There weren’t many people in the mRNA therapeutics world who would have imagined 95% initial efficacy rates in this emergency [pandemic] scenario”. – Kathryn Whitehead, Associate Professor of Chemical Engineering and Biomedical Engineering, Carnegie Mellon University

The Early Work in Genetics and mRNA Technology

If one is looking for a starting point for mRNA vaccine development, they would likely target 1960. This was the year that mRNA was first discovered. These tiny fragments of ribonucleic acid serve as templates from which cells make proteins. Once isolated, scientists realized mRNA fragments served an important purpose, not just for human cells but for viruses as well. By inserting their own mRNA pieces into human cells, viruses could “trick” the cells to make more viral particles. But at the same time, these same mRNA pieces might offer a way to attack the viruses themselves. This is where mRNA vaccine development had its first considerations.

I bunch of COVID vaccines marching off to war
Thanks to advances in mRNA technology, we had COVID vaccines in record time. What’s next?

Early challenges related to mRNA technology involved the marked instability of mRNA itself. If present outside of cells, the body’s immune system would quickly destroy it. As a result, scientists began exploring liposomes, which are small bubbles surrounded by fatty lipids, as carrier molecules. Thus, in 1978, scientists were first able to successfully transfer a mRNA fragment safely into a cell using liposomes. This was then following by successful synthesis of mRNA particles themselves in a lab. Some researchers began seeing mRNA vaccine development as the future. If they could just create the right mRNA pieces and get them into cells, the human immune system could do the rest.

“A lot of people were skeptical as to whether [mRNA technology] could ever work”. [Today], the whole field of mRNA is just exploding. It’s a game changer in medicine.” Anna Blakney, Assistant Professor, University of British Columbia, Canada

The Dark Years in mRNA Vaccine Development

Despite early optimism regarding mRNA technology, the years to follow were surrounded by disappointment. After researchers at Harvard University had successfully synthesized mRNA, the process was believed to be straightforward. First, identify a mRNA fragment that characterized the virus in question. Second, coat that mRNA particle in a liposome and place it in a cell. Third, let the human cells produce the protein fragment from the mRNA piece. And lastly, allow the immune system to develop a response against the protein produced. This response would them provide the human host with protection against the virus should it ever infect that person.

Unfortunately, the process wasn’t that simplistic or feasible in terms of scalability and cost. mRNA technology at the time was quite expensive and cumbersome. Many labs and researchers found it difficult to attain funding as a result. In addition, liposomes had their own challenges, including that of instability and toxicity. Scientists continued to pursue mRNA vaccine development at the time, particularly in relation to HIV and influenza. But the results were quite disappointing due to unwanted side effects and lack of effectiveness. It was during this time many researchers decided to move onto other pursuits rather than continuing with mRNA vaccine development.

“Once all the pieces came together, it was like, holy smoke, finally we’ve got a process we can scale.” – Andrew Geall, Chief Development Officer, Replicate Bioscience, San Diego

A Final Common Pathway to Success

There was some concern in the late 1990s and early 2000s that mRNA vaccine development may be a dead-end path. Interestingly, however, several separate and powerful events changed these perspectives. In 1997, some scientists began using mRNA approaches in cancer patients as a potential treatment. Tumor proteins were made from mRNA fragments, which could then be used to stimulate immune cell attacks against cancers. This prompted many researchers who had place mRNA vaccine development on the backburner to reconsider. If oncologists had found a way to use mRNA technology, perhaps infectious disease therapies might indeed be feasible.

In addition, two major breakthroughs occurred in the 2000s that completely changed perspectives as well. The first involved modifications made to the mRNA to make it less toxic and less immunogenic. Modified mRNA technology allowed mRNA to be administered without unwanted side effects. The second development involved the creation of a lipid nanoparticle to replace liposomes. These nano particles had 4 components, of which 3 were important for stability. The fourth component, however, enabled mRNA to access cells without causing toxic reactions in the body. These were the final two pieces of the puzzle needed to make mRNA vaccine development practical. It was only a few years prior to the pandemic that these events occurred, which is indeed fortunate for all.

“The other category [besides viruses] is autoimmune diseases. That is intriguing because it’s verging beyond the very strict definition of a vaccine.” – Dragony Fu, Associate Professor in Biology, University of Rochester

A World of Possibilities for mRNA Technology

With Operation Warp Speed, mRNA vaccine development took place in record time. Massive funding allowed mRNA technology to be scaled like never before. Fortunately, this happened at precisely the right time, not only because of the pandemic but because of recent scientific developments. But for many in the field, mRNA technology for infectious disease vaccines is imply the tip of the iceberg. As noted, this same technology can be used to combat cancers. But it is now being considered for a variety of other conditions. This not only included various autoimmune disease like multiple sclerosis and genetic ones like cystic fibrosis. But it is also being evaluated to reduce heart disease risks and asthma. Without question, few would have ever suspected these potential uses six decades earlier. But thanks to some fortuitous discoveries and years of hard work, this is a very probable reality for the future.


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