The Coming Age of RNA Vaccines

The Coming Age of RNA Vaccines November 25, 2020

The COVID-19 pandemic continues to take a devastating toll on the U.S. and the world, but there’s a light at the end of the tunnel. The vaccines being developed by Pfizer and Moderna have both shown better than 90% efficacy in clinical trials, which is as good as we could possibly have hoped for.

What’s more impressive is that these vaccines went from concept to reality in less than a year, an astounding and historically unprecedented speed. Until now, the fastest vaccine ever created was for the mumps, and that took four years.

This acceleration isn’t just because of the greater urgency. It’s because the vaccines that will soon be rolling out are RNA vaccines, a brand-new technology that will fundamentally change the way we respond to future epidemics.

The central dogma of biology is that the DNA instructions in a cell’s nucleus are transcribed into messenger RNA, or mRNA, which travels to the cell’s ribosomes where it’s translated into proteins. The scientific insight behind an RNA vaccine is that we can create our own mRNA strings that code for whatever protein we want – in this case, the SARS-CoV-2 spike protein that enables it to enter human cells.

Once these artificial mRNA strings are injected into our cells, the ribosomes process them like any other mRNA, churning out copies of the viral spike protein. That’s where the immune system enters the picture.

A family of molecules called the major histocompatibility complex displays proteins from within the cell on the exterior surface, where they’re checked by patrolling T cells that recognize which proteins belong to the body and which don’t. If the T cells detect an unknown protein, indicating a bacterial or viral infection or a developing cancer, they unleash an immune response: cytotoxic T cells force infected or mutated cells to commit suicide, while helper T cells stimulate B cells to begin producing antibodies against the foreign protein. (If you’re curious how such a wonderfully complex system could evolve, see Evolving Immunity on TalkDesign.)

The idea behind RNA vaccines was the brainchild of the biochemist Katalin Karikó. Like many great scientific ideas, it was initially dismissed as impractical, and Karikó waged a lonely crusade on its behalf throughout the 1990s.

One early stumbling block was that injecting mRNA provoked an inflammatory response that would degrade it before it could be taken up by cells. Karikó and her research partner Drew Weissman found a way to tweak the chemical structure of RNA to make it more tolerable, which they laid out in a 2005 paper that ought to put them in the running for a Nobel Prize.

RNA vaccines are a new technology, and as such, they come with some unanswered questions and new difficulties. RNA is more fragile than traditional protein vaccines, meaning the vaccines have to be stored at ultracold temperatures, which may hinder their distribution in developing countries. It’s also an open question how long the immunity they confer will last.

Still, this technology has enormous potential to revolutionize medicine. In the future, when other previously unknown diseases jump the species barrier into humans – and they will – it will give us the ability to respond with incredible speed and versatility.

For example, the annual flu vaccine is made by cultivating the virus in millions of chicken eggs, a delicate and time-consuming process. Because it takes months to make a batch of vaccine, and because the flu mutates so quickly, scientists have to guess which strains will dominate the next flu season. If they guess wrong, the vaccine provides only partial immunity.

By contrast, an RNA vaccine factory can be reconfigured on the fly to adapt a vaccine for a mutant strain of an existing disease or even a brand-new disease. It’s easy to create custom synthetic DNA strands with any sequence of our choice, and then use an enzyme like RNA polymerase to transcribe the information into RNA. Scientists don’t even need samples of the actual pathogen. The first candidate RNA vaccines for SARS-CoV-2 were created just days after the virus’ genetic sequence was published.

This paper from the Journal of Advanced Manufacturing and Processing says:

Based on our techno-economic assessment, the RNA vaccine production process can be two to three orders of magnitude smaller than conventional vaccine production processes in terms of facility scale, and can be constructed in less than half the time with 1/20 to 1/35 of the upfront capital investment… Due to its small scale, the RNA vaccine drug substance production process could be placed in a small part of an existing conventional vaccine facility, for example in a room, and still produce more doses worth of drug substance than the entire original conventional vaccine production facility.

And why stop there? It may soon be possible to create custom-tailored RNA vaccines for an individual person – for example, to treat cancer, by genetically sequencing a person’s tumor and creating a vaccine based on that tumor to teach their immune system to respond. Or we could use this technology to turn the body’s cells into drug factories, correcting inherited disorders like hemophilia or cystic fibrosis, or churning out custom pharmaceuticals of our devising. It’s likely that it will have even more uses we haven’t conceived of yet.

Image credit: U.S. Army, released under CC BY 2.0 license

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