9 Jul 2021

Covid Connections – Variant or Villain

By Alison Cranage, Science Writer at the Wellcome Sanger Institute. Illustrations by Laura Olivares Boldú, Graphic Designer and Illustrator at the Wellcome Genome Campus.

In the second event of the COVID connections series, organised by Wellcome Connecting Science and the COVID-19 Genomics UK (COG-UK) Consortium, researchers discussed variants of SARS-CoV-2. The event was chaired by science broadcaster Alex Lathbridge, who invited panellists Professor Ravi Gupta, Professor Emma Thomson and Dr Qianxin Wu to the virtual stage.

Alex broke the ice by noting his shirt and headphones made him look like he was from the 70’s and said he’d perhaps rather be back in the 70’s, when there wasn’t a pandemic.

Before turning to audience questions about coronavirus variants, Alex’s first question to the panellists was – what have been the biggest moments in COVID research so far?

You can read a summary of some of the discussions on variants below, or watch the event in full on YouTube. The next event is on 14th July “From mild to mortal: Unlocking the mystery of Covid19 symptoms”.

The most significant moments

Dr Qianxin Wu is a Staff Scientist at the Sanger Institute. Over the past 18 months, she has been developing a new diagnostic test for coronavirus that uses saliva1. The method also enables the post point of care diagnosis tests to be pooled together for genome sequencing.

“The sweetest moment for me is when I saw that my technology worked. The results are comparable in terms of the limit of detection with the PCR tests used by Public Health England.”

“And personally, I think it’s the moment when I saw people that were queuing up for the vaccine. There are so many scientists who had been working towards that goal. For me, that was a touching moment.”

Ravi Gupta is a Professor of Clinical Microbiology at the Cambridge Institute for Therapeutic Immunology and Infectious Diseases. Before the pandemic, he was working on HIV. Now his attention has turned to COVID and he is working on diagnostics as well as understanding the immune response to the virus.

“For the field – a couple of things have stood out. One was the demonstration that the vaccines are highly effective – that was the trial data that we were all waiting for. And then the data from dexamethasone for the treatment of COVID-19 disease. Those are the big moments.”

“For me personally in terms of our research, one of them is stumbling upon B.1.1.7. It was a total accident. We were studying how the virus evolved within a person with a compromised immune system. This person was infected for a very long time – months. Most people are infected for a couple of weeks with the virus, even if symptoms continue after that.  At the same time, PHE were investigating this big outbreak of infections that were defying logic in South East England. Along with COG-UK, they had identified this was caused by a new variant.

“We saw that the virus could evolve within a person to become a new variant. I mean that was just amazing, because we just didn’t know that this could happen. We saw this happening within a single individual, and then within weeks we suddenly saw the whole explosion of a variant in the real world. It was really sort of strange in that it coincided so closely.”

Professor Emma Thomson is a researcher at the MRC University of Glasgow Centre for Virus Research working to sequence coronavirus genomes and analyse outbreaks and variants. She also works as an NHS consultant, looking after people with infectious diseases including COVID-19.

“I think scientifically the biggest moment for me has been the emergence of mRNA vaccine technology. You can literally look at the genetic sequence of a virus or another pathogen, and then you can program that into a vaccine. It’s a huge revolution. Instead of having to spend a very long time producing protein for more traditional vaccines, you actually inject the recipe for that protein into someone’s arm. The protein is manufactured using their arm as a factory if you like. And that means that the whole process can be so much faster. I think it’s extraordinary, and I think it’s going to revolutionise vaccines for other diseases as well.”

“Personally speaking, another memorable moment was when I was called by Sharon Peacock to join the first meeting where we decided to set up COG-UK. I just remember the feeling in the room when we realised that this was going to be something serious, and it was going to wash over us and change our lives. I think a shiver ran down my spine actually.”

Alex then turned to questions from the audience – focussing on SARS-CoV-2 variants.

What actually is a variant?

“There are a couple of key terms to understand. The first is mutation. A mutation usually means just one change in the genome. Virus genomes mutate all the time as they naturally replicate. A single mutation might change the shape of the virus slightly in one place.

“A variant will contain many mutations. We think about these as like constellations in the stars. We noticed these variations of the virus with multiple mutations first popping up at the beginning of last year. We have created ‘laws’ for classifying them and each genome sequence can be placed on an ‘ancestral tree’ to show its lineage. Then when a new genome is sequenced we can assign it to a particular linage and determine which variant it is, or which variant it is related to.”

– Emma Thomson

What drives a variant to become a variant? How does a variant become ‘successful’?

“Well, it’s natural selection at the end of the day. We see evidence of it all around us. Organic entities change because they make mistakes when they copy their genomes to replicate. Some of those genetic mistakes give an advantage to that organism. Some of them are bad for the organism. So the mutations that give an advantage are more likely to survive.  SARS-Cov-2 has a very rapid turnover time. It infects someone, and within six to 12 hours it’s already made millions of copies of itself. So the number of mistakes is also large. At the same time, you’ve got an immune system trying to destroy it. Some of the mistakes – variations – in the virus, will allow it to survive better against an immune response. Others may allow it to make copies of itself more rapidly, so it is more easily passed on. If it does then get passed on to someone else,  then that same process starts again in them and then the next person and so on. You can think of this like the virus is undergoing ‘training’ in each person it infects.

When a virus is better at avoiding our defences, or better at replicating itself, or being passed on, that’s when it is classified as a new variant.”

– Ravi Gupta

What effect will vaccines have on virus mutations and variants?

“We don’t yet know exactly, but they probably will have an effect. They are like a pressure on the virus. But it’s important to say that new variants are arising where there is lots of transmission, and a lot of virus. And we’re starting to see that vaccines do hinder transmission. So in fact they are going to reduce the chances of new variants arising, because they reduce the amount of virus around.”

“The balance is definitely in favour of the vaccines.”

– Qianxin Wu

In what ways does a vaccine need to change to overcome virus mutations?

“So a vaccine will induce an immune response in a person, so that when they encounter the virus, their immune system quickly recognises and kills it.

“The spike protein of the virus is the most important part of the virus that our immune system, including our antibodies, recognise. It sticks out from the virus surface. When a mutation occurs in the virus that affects the spike protein you can imagine if that changes shape slightly, you don’t get such strong recognition. It’s a gradual process as the virus accumulates changes that means it can start to evade our antibody response

“We can see those mutations in the genome sequence data from COG-UK, it’s like an early warning system. Then there needs to be laboratory experiments to test if antibodies from vaccinated people do neutralise that particular version or variant of the virus. Finally, data from clinical trials and studies of vaccinated populations are most important. These all take time – but once you put all that together, you can figure out which are the precise changes, usually in the spike protein, that are causing the problem.”

“Once you have that information, you can program that into the next vaccine. This last step is a fairly quick process, especially for the new mRNA vaccines although it takes longer to test out how well they work in clinical trials.

– Emma Thomson

Is it possible that a variant becomes so different it’s another strain?

“It is possible, yes. It could happen as a result of changes in the virus that take it in different directions in different parts of the globe, for example, under different selection pressures. It’s the process of evolution – it’s just a matter of how far it goes.” – Emma

“For other viruses that rapidly change there are strains – like Hepatitis A, B or C. The same could happen for SARS-CoV-2. Things might get complicated quite quickly. Although I think they already have.”

– Ravi Gupta

Can you see where variants are in the world?

“You can view variants around the world at GISAID. But the caveat is that a country that doesn’t do any sequencing has no variants at all. So, the more information you get, the more understanding you have of what’s actually circulating.”

– Qianxin Wu

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