Science on the Attack: The Vaccine Revolution Spurred by Messenger RNA

The lightning speed with which biotech companies Pfizer-BioNTech and Moderna developed a safe and effective COVID-19 vaccine is testament not only to scientific perseverance, but to the previously unrealized potential of messenger RNA (mRNA) to revolutionize medicine. Today’s blog post in my series showcasing science on the attack rather than under attack highlights the genetic breakthrough behind this transformational discovery.

Genetic vaccines are a relative newcomer to the immunization scene. Unlike traditional vaccines that use killed or weakened versions of the virus to stimulate the body’s immune system into action, genetic vaccines deliver a single virus gene or part of its genetic code into human cells. The genetic instructions induce the cells to make viral proteins that constitute only a small piece of the virus, but have the same effect on the immune system as the whole virus molecule.

But, until 2020, the only approved genetic vaccines – based on DNA, not RNA – were for animal diseases. It was the urgent need to come up with a vaccine to protect against COVID-19 in humans that triggered the worldwide quest to bring an mRNA vaccine to market.

The job of mRNA in the body is to transcribe the DNA code for one or more genes contained in a cell nucleus, and then deliver the encoded information to the protein factory in the cell’s outer reaches. There, the message is decoded and the requisite protein manufactured. DNA contains the blueprint for making nearly all the proteins in the body, while mRNA acts as a delivery service.

The concept of harnessing mRNA to fight disease goes back to the early 1990s, but hopes raised by promising early experiments on mice were dashed when multiple roadblocks arose to working with synthetic mRNA injected into the human body. The primary obstacle was the immune system’s overreaction to mRNA engineered to manufacture virus proteins. The immune system often destroyed the foreign mRNA altogether, as well as causing excessive inflammation in some people. Other problems were that the mRNA degraded quickly in the body and didn’t produce enough of the crucial virus protein for a vaccine to be effective.

So scientific attention switched instead to development of DNA vaccines, which cause fewer problems though are clunky compared to their mRNA cousins. Then, in a series of papers starting in 2005, two scientists at the University of Pennsylvania, Katalin Karikó and Drew Weissman, reported groundbreaking research that brought mRNA back into the limelight.

Karikó and Weissman found that tweaking the structure of the mRNA molecule could overcome most of the earlier obstacles. By exchanging one of mRNA’s four building blocks called nucleosides, they were able to create a hybrid mRNA that drastically suppressed the immune system’s reaction to the intruder and boosted production of the viral protein. In their own words, their monumental achievement was “the biological equivalent of swapping out a tire.”      

Their discovery, however, was initially received with a big yawn by many of their peers, who were still preoccupied with DNA. Karikó found herself snubbed by the research funding community and demoted from her university position. Eventually, in 2013 she was hired by the German company BioNTech to help oversee its mRNA research.

In the meantime, work proceeded on the final impediment to exploiting synthetic mRNA for vaccines: preventing its degradation in the human body. To reach the so-called cytoplasm of a cell where proteins are manufactured, the artificial mRNA needs to penetrate the lipid membrane barrier protecting the cell. Karikó, Weissman and others solved this problem by encasing the mRNA in small bubbles of fat known as lipid nanoparticles.

Armed with these leaps forward, researchers have now developed mRNA vaccines for at least four infectious diseases: rabies, influenza, cytomegalovirus and Zika. But testing in humans has been disappointing so far. The immune response has been weaker than expected from animal studies – just as with DNA vaccines – and serious side effects have occurred.

Nevertheless, COVID-19 mRNA vaccines have been a stunning success story. The major advantage of mRNA vaccines over their traditional counterparts is the relative ease and speed with which they can be produced. But until now, no mRNA vaccine or drug has ever won approval.

Maybe COVID-19 is the exception and synthetic coronavirus mRNA generates a stronger immune response with fewer adverse effects than the other viral mRNA vaccines investigated to date. Mass production of a beneficial and safely tolerated COVID-19 vaccine in less than 12 months is certainly an amazing accomplishment, considering that it’s taken several years to develop a new vaccine in the past. But whether the potential of mRNA vaccines to ward off other diseases or even cancer remains to be seen.

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