The clever evolution of vaccines

The English physician Edward Jenner is widely regarded as the father of modern vaccination. He inoculated a young man, James Phipps, with cowpox using variolation, in which pus was taken from a blister and introduced into a scratch in the skin. In doing so, he managed to confer immunity to smallpox.

This wasn’t the first time inoculation was used. It dates to much earlier times – around 1000 CE in the Middle East and China – but the fact Jenner was able to protect individuals from smallpox eventually lead to the eradication of the disease by 1980.

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Vaccines save many millions of people around the world from illnesses and death every year. Along with the eradication of smallpox, wild strains of polio are now considered extinct in all but two countries (Afghanistan and Pakistan) and the incidence of measles and other childhood diseases have been drastically reduced. Vaccines save lives.

But there are hurdles to developing new vaccines. The conventional approaches utilize either a live but attenuated version of the virus (Sabin’s polio virus) or a pathogen or sub-unit of a pathogen, which has been inactivated (for example, by heating the virus to a sufficient temperature to render it inert). Despite the success we have had in controlling or eliminating diseases, there are substantial difficulties in developing a vaccine against a specific infectious agent, especially one as aggressive as COVID-19.

In the early 1990s, nucleic acid therapeutics, which would essentially turn on or off certain aspects of a person’s metabolism, emerged as a promising alternative to conventional vaccines. Initial results looked promising but concerns over the stability of messenger RNA (mRNA), high innate immunogenicity, and inefficient mechanisms for the delivery of the compounds dampened prospects for mRNA to be used to effectively as a therapy. The few researchers in the field began to focus on DNA- and protein-base therapeutic approaches.

In the early 2000s, after years of getting grant applications rejected, University of Pennsylvania researcher Katalin Kariko took a slightly different approach. If RNA is synthesized outside of the body and introduced into a living organism, it gets ripped apart by the molecular defenses in our immune system. And worse, the resulting immune response could actually turn therapy with a particular strand of RNA into a health risk.

After a decade of trial and error, Kariko and collaborator Drew Weissman discovered a way around RNA degradation. The solution was the molecular equivalent of swapping tires. All RNA molecules are built using a set of four nucleosides. These building blocks combine one of four bases (guanine, uracil, adenine, and cytosine) with the sugar ribose. But it was only uracil that the immune system recognized. So by switching pseudouridine for the uridine (the uracil is attached to the ribose by a carbon-carbon bond instead of a carbon-nitrogen bond), Kariko and Weissman were able to fool the immune system into not recognizing the RNA. And perhaps more to the point, pseudouridine is a naturally occurring compound in cells so it does not have any potentially dangerous effects.

This trick allowed their mRNA to sneak past the body’s defenses and into cells. While the initial results published in 2005 flew under the radar, in 2009 Derrick Rossi (a Canadian) was able to show how this new mRNA could be introduced into mature cells reprogramming them to act like embryonic stem cells. In the world of biotechnology, this was a major breakthrough and from this a new biotech company, Moderna, was formed. (Its name is derived from modified and RNA).

Although not originally intended to be a vaccine company, Moderna has turned its expertise to generating an mRNA based vaccine to address COVID-19. Instead of using attenuated or dead viruses, their vaccine employs the body’s own biochemistry to make a spike protein found on the virus and then extrude it from cells. Our immune system takes over, recognizing the foreign protein as an invader and building anti-bodies to dispose of the offending material. A small number of our cells in muscle tissue are sacrificed to generate an immune response.

Initial trials demonstrated significant production of anti-bodies which was subsequently enhanced by a second dose of the vaccine. The results lead to a much broader trial and the recently announced result of a 94.5 per cent efficacy in treating COVID-19. And unlike conventional vaccines, the mRNA used is degraded back into nucleosides by our cellular recycling system once it has coded for the production of the protein in a ribosome. Essentially, the mRNA in these vaccines is in stealth mode the entire time, slipping into the body without getting noticed by the immune system, sneaking into a ribosome to produce a protein, and dissolving into its constituent parts to disappear once the job is done.

It is a sneaky, modern vaccine – far different from anything Edward Jenner could have imagined – but more than capable at protecting us from COVID-19. 

But until it is available, wear a mask!

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