Coronavirus mutation disrupts vaccine trials

15 April 2020

Interview with 

David Matthews, University of Bristol

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Lots of institutions around the world are currently hard at work making tests and treatments - you can hear about a few of them on the Naked Scientists main show episode How COVID-19 Works. But very often, these tests and treatments are developed without anyone necessarily understanding how they work. Dave Matthews is a coronavirologist from the University of Bristol, and his mission has been to fully understand how the coronavirus functions, on a fundamental level. He told Phil Sansom how this “walk before you can run” approach has already picked out a hidden danger…

David - Together with my colleague Dr. Andrew Davidson here at Bristol and another colleague Professor Julian Hiscox, at the University of Liverpool. We are basically the only three human coronavirus people in the UK. We started working on this virus immediately and one of the things that we were interested in is what does the virus make and what does the virus do when it gets inside a living cell. What proteins does it produce and that is what we were interested in in the first instance.

Phil - How physically do you do that?

David - We take the virus into our containment laboratory where we've got a specialized cabinet with a series of airlocks in it and we take living cells. In this case we're using a monkey cell line and we add the virus and leave it for a few days until we start to see the cells are damaged and starting to float off and die. And then we harvest all the material inside the cells. The first thing we want to extract is the genetic material from the virus and the genetic material that the virus makes known as messenger RNA. And it's this messenger RNA that is interpreted by the cells and turned into proteins. And the other half of the sample that we want to take out is to extract the protein separately. And so these two samples, if you like, the genetic instructions that the virus is making and the proteins that virus is making are separated from each other and then analyzed separately.

Phil - So this is like a catalog of everything the virus is and everything it does.

David - Yes, that's right. You can ask the very direct question, what do you make and the instructions you are putting out there and are they actually turning into proteins and that's what we wanted to catalog.

Phil - So what did you find?

David - The things that you predict are being made for the most part that is actually what's happening and that may seem really rather dull and uninteresting but in terms of getting your basics right it's important to establish that the virus is doing what you think it's doing most of the time. It's making proteins that enable the virus to replicate its genetic material - that's very important. It's also making structural proteins, other instructions make the spike protein, which attaches to living cells and helps the virus gain entry to new cells. There's also a variety of proteins whose function we're not quite sure what they do, but we think some of them are involved in trying to slow down your immune response. And then there will be proteins whose job it is to simply make the cell a more amenable place for the virus to replicate in.

Phil - That's the stuff you expect. What stuff was there that you didn't?

David - So when we analyze the data in a little bit more detail, what we realized was that there was in fact two viruses now inside these monkey cells

Phil - What two coronaviruses?

David - Yes. One is the virus that is genetically identical to what we expect it to be, but the other one had missing just a very short section of instructions that makes a slightly different version of the spike protein, which we believe means that the virus that's growing in the monkey cells that has this slightly deleted version, can infect monkey cells more efficiently.

Phil - Oh, so you're saying that the bit of the virus that lets it get into cells - as you were investigating it, that bit changed so that it could get into the monkey cells better?

David - Yeah, that's what we believe.

Phil - What does that mean?

David - The issue is that when people are doing their vaccine studies, for example, typically people grow the virus in the laboratory in monkey cells. And what that means is that teams doing this could inadvertently have ended up with a mixture of two viruses, one that is the human virus and another one which is adapted slightly so that it infects monkeys a little bit better and it could completely wreck the study or give you a false idea of what's happening. That's the first problem.

Phil - I've heard plenty of stories of people already trying to get vaccines done and does that mean that these people could run into a problem that they wouldn't have otherwise realized was even there?

David - Yes, that's true. Although I think the news is out now, so I think people are definitely screening virus stocks carefully. The other problem is even more subtle. Let's say for example, you do grow large amounts of this virus and you check it and there's nothing wrong with it and it is all still human virus. Many of these vaccine studies will be done in monkeys eventually. It could be that in an individual monkey, the virus that you've given it adapts and changes and becomes a monkey version of the virus you gave it in the first place. So it means that not only do you need to check that the virus going into the monkeys is still a human virus, but also throughout the course of the vaccine study you're going to need to check that the virus hasn't mutated during your trial in each individual monkey. And it could again basically make a mess of your vaccine trial by creating anomalous results that you misinterpret as either the vaccine is working or it's not working.

Comments

This is very similar indeed to the mutations that happen to flu viruses when you grown them in avian cells (chicken embryos). Indeed, this is the reason why "acellular" vaccines were recommended in the most recent flu season...

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