Chemistry in the News Coronavirus Medicinal Chemistry

What are the COVID-19 RNA vaccines and how do they work?

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By now, we’re all familiar with the image of coronavirus. The spikey blob peppers news websites, looms behind reporters during bulletins and frequently punctuates your Twitter doom-scrolling. More recently, the news accompanying this image has taken a positive turn, with promising results from the COVID-19 vaccine trials. It’s the iconic spikes of the coronavirus spikey blob that are a key part of how these vaccines work.

Let’s backtrack a little and start with the broader COVID-19 vaccine picture. As of 1 December 2020, thirteen vaccines have reached the final stage of testing: where they are being given to thousands of people to test if they protect against the SARS-CoV-2 virus. Though the end goal is the same, these vaccines vary in the ways in which they try to trigger our immune system to recognise the virus. All of these ways have been used in licensed vaccines for other diseases previously – except RNA vaccines.

Two vaccines which have recently reported results are RNA vaccines produced by Moderna and by Pfizer & BioNTech. Other RNA vaccines in the pipeline include those produced by CureVac, Imperial College London, and Arcturus. Results so far have been overwhelmingly positive. At the start of December, Pifzer’s vaccine became the first RNA vaccine licensed for widespread use in the UK.

Other types of vaccines often use inactive or weakened forms of a virus to trigger an immune response. But RNA vaccines use a virus’s own genetic code against it. RNA stands for ribonucleic acid; you’re probably more familiar with DNA, the molecule which makes up human genetic code. RNA makes up the virus genetic code, which contains instructions for the proteins the virus needs to make.

Early in the pandemic, Chinese scientists were able to isolate samples of the SARS-CoV-2 virus and determine its genetic code. This catalogued all the instructions the virus uses to make its various proteins. These include the spikes of the coronavirus ‘spikey blob’: its spike proteins. The spike proteins are the structures that the virus uses to penetrate cells and kick off an infection.

Spike proteins are also key to how RNA vaccines work. Scientists are able to make synthetic RNA in a lab which codes for the virus spike protein. Using this synthetic RNA, we can hijack the processes which create proteins in our own cells.

The genetic material in our bodies is DNA. In the nucleus of our cells, an enzyme splits apart the two strands that form DNA to form single-stranded messenger RNA. The mRNA moves out of the nucleus to our cells’ cytoplasm. Here, molecules called ribosomes translate the RNA’s code into proteins. In short, the ribosome is like a protein-making factory, and the mRNA created from our DNA is the blueprint for the proteins it makes.

RNA vaccines take advantage of the fact that our ribosome factory doesn’t care where a blueprint comes from. So if we can smuggle a new blueprint for the virus spike protein into this factory, the ribosome will assemble the protein without question. Once it’s manufactured, the spike protein sticks to the surface of our cells and triggers a response from our immune system.

Smuggling the blueprint into our cells isn’t straightforward. If we simply inject the RNA on its own, enzymes in our bodies would break it down before it could enter our cells. For this reason, it’s encapsulated in lipid nanoparticles: tiny fat droplets around one billionth of a metre in diameter. These nanoparticles shield the RNA, stopping it from breaking down, and help it get taken up by our cells.

Amongst the COVID-19 vaccines, there are two types of RNA vaccine. These are messenger RNA (mRNA) vaccines, like those produced by Moderna and Pfizer/BioNTech, and self-amplifying RNA (saRNA) vaccines, like that developed by Imperial College London.

The structures of mRNA and saRNA used in the vaccines are very similar but have one key difference. Both contain the region of the RNA which codes for the virus spike protein. Both also contain a cap, which stops the RNA breaking down and helps start protein synthesis in our cells, and a tail which helps stabilise the RNA. Unlike mRNA, saRNA also contains the code for a virus enzyme. This enzyme helps create multiple copies of the virus RNA once it’s in our cells, leading to quicker protein production.

As saRNA produces more copies of itself once it’s in a cell, it means that we can give vaccines containing it in smaller doses than mRNA vaccines. This means that the cost per dose is lower and that the same volume of vaccine produces more doses.

RNA stability is an important consideration for the way in which we store and transport these vaccines. Some need low-temperature storage to remain stable. The Pfizer/BioNTech vaccine requires a transportation temperature of –70 ˚C and can be stored for up to five days in a fridge after delivery. The Moderna vaccine requires a transportation temperature of –20 ˚C, and after thawing can be stored at refrigerator temperature for 30 days. Temperature matters: chemical reactions happen more quickly at higher temperatures, so low temperatures ensure the RNA remains intact.

Though these vaccines will be the first licensed RNA vaccines, they are not the first to be developed. They’ve been under development for several years for other viruses, including influenza, HIV and Zika. They’re also not the first RNA-based medication to gain approval. That title goes to Onpattro, a medication approved in the US and EU in 2018, which treats nerve damage.

RNA vaccines have several benefits over other vaccine types. The most obvious is the pace at which we can make them. COVID-19 vaccines are setting new records for the speed with which a vaccine has gone from development to approval. Synthetic RNA is straightforward to make in a lab, so it doesn’t take long to design and produce these vaccines. Take Moderna: they finalised the RNA sequence for their vaccine just two days after Chinese scientists shared the genetic sequence of SARS-CoV-2, and they made the first clinical batch of the vaccine just 25 days after this.

RNA vaccines also have safety benefits. The synthetic RNA can’t cause illness – though it’s a blueprint for virus spike protein production in our bodies’ cells, production of this protein alone can’t trigger an infection. The RNA itself gets broken down by normal processes in our cells, so it doesn’t hang around for long anyway.

There’s good evidence from the trials that these RNA vaccines are effective in preventing COVID-19. Moderna’s vaccine has shown 100% efficacy against severe disease, and general efficacy of 94.1% – a higher figure than perhaps expected. The Pfizer/BioNTech vaccine has reported similarly impressive results of 95% efficacy. This compares pretty well with vaccine efficacies for other diseases. For example, the average influenza vaccine effectiveness since 2010 is 42%.

Like vaccinations for many diseases, the RNA vaccines for COVID-19 need two doses. The body’s immune response, when confronted with the coronavirus spike protein, is to produce antibodies and memory cells. This response helps the body respond quickly if it spots the virus. Multiple doses increase the quantities of memory cells created, meaning a faster and more effective response if we encounter the virus.

It’s tempting to feel like the battle is won now that a vaccine has gained approval. It’s an important step, but the process of vaccinating enough of the population to stymy the spread of the virus will take time. The UK has ordered enough of the Pfizer/BioNTech vaccine to vaccinate 20 million people, but with the current UK population standing at over 65 million, we’ll still need more doses or additional vaccines. The ordered doses won’t all arrive at once, either – the first delivery of doses will only be enough for 400,000 people.

Still, the approval of a vaccine is positive news in a year that’s contained far too little of it. While Boris Johnson’s suggestion in July that we’d be ‘back to normal by Christmas’ now looks laughable (and, to be honest, looked laughable at the time, too), having safe, effective vaccines means that perhaps during 2021 we can gradually return to something a bit closer to pre-pandemic life.

This graphic was developed in partnership with the Royal Society of Chemistry.

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