September 09, 2020

The making of a COVID-19 vaccine

By Conor McKechnie and Dodi Axelson

In this episode of Discovery Matters podcast, we learn how researchers primed for a pandemic got a jump-start on developing a COVID-19 vaccine.

DODI: Conor, it is summer 2020. But the days are already getting darker in the northern hemisphere. All those COVID graphs are, I think, gonna start going in the wrong direction again.

CONOR: Okay, this is always gonna be good for a radio audience. So, here we go. It's that fabulous Nordic trope that we have to live with: summer's over, and winter is coming. But look, let's not forget the rest of the world that lives below the 50th line of latitude, right?

DODI: Yeah, sure. But you know, what would brighten the dark season for us in the Nordics?

CONOR: Would it be a vaccine?

DODI: It would be a vaccine, for sure. You know, the very mention of darkness might be a bit depressing for our listeners to hear, because when all of this started when the COVID-19 pandemic really kicked off, we all clung to the hope that a vaccine could be created and manufactured quickly.

CONOR: Exactly. Yes, we did. But as we know, and as we've learned over the last months, it's something that really does take a lot of time. So are we going to dive into this gloom and doom, Dodi?

DODI: Well, we are here to talk about that precious thing called hope. That's much better. Yeah, the vaccine may not be here tomorrow. But there are so many scientists working around the clock to get a vaccine to us as quickly as possible. And I do mean us human beings, all of us. I chatted with two of those scientists, and we talked about their road to a possible vaccine.

CONOR: And I guess that's what matters on today's episode.

DODI: Yes, indeed.

CONOR: Okay, so let's start with a reality check, shall we?

DODI: Yes, the reality is that vaccines take time. The mumps vaccine, considered the fastest ever approved, took four years to make. And in terms of vaccine development, that is Porsche Ferrari Formula One fast. There are many leading candidates that look like they are on the verge of being examined by the American FDA. So, you know, things are really coming to a head quickly in terms of a COVID-19 vaccine.

CONOR: So, as we're recording we're six months into the process, it's early August.

DODI: That's right.

CONOR: And of the candidates that are in development, there are some that are looking pretty good. What's the so-called normal timeline, because the mumps vaccine was four years, but that was very quick? And that's not the case in normal vaccine development, is it?

DODI: That's right. For a good explanation of how long it takes to discover, develop, and produce a vaccine. I recommend that our listeners harken back to a previous episode of Discovery Matters. We spoke to our expert Daria Donati.

CONOR: Yeah, that was Episode 16 with Daria. The artistry of vaccine development, you can get that wherever you get your podcasts.

DODI: And that is some great information about safety of vaccines, about the entire process to test and verify. And then more recently, I spoke to two professors from Australia, who had more to say on that topic.

GUEST 1: Trying to describe what happened in the global scientific response to COVID and to any other parallels is probably just not possible. And I think the reason is because it spans vaccines to treatments to clinical best practice, you know, the whole range. Everything's changing so fast. What we're learning every day is changing fast.

GUEST 2: But I think the main thing is just the willingness of everyone. And when confronted with a pandemic in such a dreadful situation, just everyone put in 200% effort.

CONOR: So tell me who these gentlemen are.

GUEST 1: My name is Professor Trent Munro.

GUEST 2: I'm Keith Chappell.

DODI: So, while talking to Trent and Keith, I just kept thinking about how so many of us are emotional about COVID-19. And locked down.

CONOR: Yes, it's affected us completely, right? And not just from a health point of view, but a mental health point of view.

DODI: Exactly. How do we work? How are we dealing with our families? How are we dealing with education? It's completely transformative. And once again, so emotional. So I needed to know from Trenton, Keith, they're scientists, but they're also human beings. So I asked, How are they coping emotionally during this pandemic?

KEITH: I find it really interesting from a psychological point of view, the way that we can all first of all come together. There's a problem. It needs to be solved. So, everyone jumps in, does absolutely everything they can. But you know, it's hard to stay in that mindset for too long, because your mind changes over time, which I've thought has been interesting in a number of ways. It's hard to see the fear associated with the pandemic for six months straight. You can see the complacency of people, you just get desensitized to the issue.

That's a problem in its own right that needs to be addressed. And then, also, the other thing is that the collaboration has been fantastic. But after six months of effort, you do get attached to what you're doing. You do want to be the one to solve the problem. There are a lot of factors in psychology that come into this as well. I keep both things in my mind. I want our platform to succeed, but at the same time, I want this crisis to be over. And if someone else has a better vaccine, I think that would be great. But it also in some ways is bittersweet. Naturally, you want to be the one to do this.

TRENT: There are two words that people keep using. They're overused, but they're good ones. I think one is rollercoaster, emotional rollercoaster. I mean, we've had times where we've got results, and we've been on the highest of highs. And then we've had challenges where I think okay, let's pick ourselves up and find the solution to whatever it is. And it could be something really small. It could be a technical thing. You know, that's been a real challenge.

And I think the other word is unprecedented, right? Whether it's working with Cytiva or working with other companies, we work with so many different companies in this process. You know, I think that all of that willingness has kind of given us a big boost, especially as a university group. And we're doing everything, whether it was the preclinical, whether it was the manufacturing, whether it was the R and D. It was all happening here. And then I think the last human element is that, you know, we started to have people in the team who were touched by COVID in various ways. I think Keith had one staff member who lost a family member in New York. That happened pretty early on. So those kinds of things really bring home purpose, but they also bring home how big a responsibility this whole thing is.

CONOR: So, what did it look like for them in the lab in the days, months leading up to, well, I guess all hell breaking loose. And then the World Health Organization actually declaring COVID-19 a full blown pandemic.

KEITH: We had our eyes out for new viruses emerging. We would have been doing sort of dry runs, practices over 2019 on novel viruses. So, when we first saw this pop up, we thought this will be a great proof of principle. We'll pretend as though it's a real emergency and try to make a vaccine as quickly as we can. I think it was only a week or so since it first got to the news that we started thinking, this is getting bigger and bigger and then realize this is the real thing. And that's when it got very scary and a lot more pressure. But luckily we were watching, and we started work as soon as we saw the virus pop up.

DODI: You know, so many of us were taken by surprise by this pandemic. But for Keith and Trent, they were as ready as anybody could be. They had a bunch of groups that were set up to do vaccine response to an emerging pandemic. And this is because of a coalition called CEPI. And can we remind our listeners what CEPI stands for?

KEITH: It stands for The Coalition of Epidemic Preparedness Innovations. We were funded by CEPI to produce a pipeline. And then if there was to be an emergency, such as the coronavirus, that would allow us to produce a vaccine as quickly as possible. That funding was absolutely essential for us to bring together all of the various parties that form the individual components of this vaccine and allow us to go as quickly as possible from a virus sequence all the way through to producing the antigen studies in animals. Then on to manufacturing clinical trials, and hopefully moving forward into large-scale manufacture in later-stage clinical trials.

CONOR: And so what were some of the options that Keith and Trent were considering at the beginning?

DODI: A lot of the work had to do with antigens and proteins.

KEITH: We needed to manufacture the protein and work out the process involved in the manufacture, the purification, getting it ready and up to the clinical standards. There are just a lot more steps along the way. We also didn't want to move forward until we had an optimal lead candidate. So, a lot of our energy in the early days was put into screening different antigens. We screened around 200 iterations of the antigen within five weeks before we locked in our lead candidate, which was quite a lot of work and pretty impressive in its own right.

DODI: Conor, as you know, before our company became Cytiva we had several hundred candidates for naming it.

CONOR: Oh yes, there were thousands. There was Acme Life Sciences and Altiza, and there was even Biojoy.

DODI: I remember that one.

CONOR: So, from thousands of suggestions by our colleagues, we had to narrow them down. And we did that based on the characteristics and qualities that our customers told us that they loved about us as a team and what we wanted to emphasize in the company.

DODI: Exactly. So, I started thinking back to this name change when chatting with Trent and Keith.

CONOR: Okay, so how come?

DODI: Well, we only have a name to choose. For Keith and Trent they had over 200 candidates in front of them. And so I just wondered how they whittled that down to one candidate to something they really could focus on and believed in to go further. This is what they called the molecular clamp.

CONOR: Okay, so they're not focusing on choosing just a name and not sounding ridiculous. But they've got something called a molecular clamp. I've heard of it. I've heard the name, but I'm not sure what it is.

DODI: We're going to get to that. But first, Keith is going to explain how they whittled it down to just that one molecular clamp.

KEITH: Our platform technology, the molecular clamp, that's a trimerization domain that allows stability to viral fusion proteins. There are a whole range of regions you can modify and change that may give you different properties. The properties we were looking for was the overall expression level. So, we wanted to produce as much material as we could, because we knew that would translate into more doses down the line. And the other thing we wanted was it to be a homogeneous preparation, so it all existed in the correct conformation, the correct size and shape that's present on the viral surface. The theory is that if the vaccine looks like a virus, then the immune response you generate will be more likely to protect against that virus.

CONOR: So, how exactly is the choice made? Are Keith and Trent saying that it's like choosing colors in their wardrobe? Or what kind of car to drive or what to eat for dinner? How are they making that choice?

TRENT: You could say it's something as basic as getting dressed for what you're going to face out there in the day, right? So, whether it's going to be rain, or whether you're facing snow, whether you're facing heat. Those parameters then sort of set a range of things that are going to be optimal for what you want to present. Right. And I think it was, in a silly way, what we were trying to do in a very complex protein engineering effort to make sure that what we produced at the end of the day was going to be fit for purpose for the conditions that it was going to need to face. And one day, hopefully, it had potential to actually be a vaccine for this disease.

CONOR: Okay, got it. So can we get to the molecular clamp? Like I said, I've heard the phrase, but I don't know what it is. And I hate not knowing what something is. So what do Keith and Trent actually do here, and how does this particular vaccine platform work?

KEITH: We make proteins in the laboratory that have the same size and shape as what's on the surface of the virus. We use what we call the molecular clamp as part of the production that allows us to ensure that they are maintained in the correct shape. And it also allows us to pull those out of solution to make sure they're highly purified. Because we're delivering a protein and a very small amount of protein, the body would not naturally make an immune response against that. So, what we need to include is what's called an adjuvant, and that triggers the danger signal when it's injected into the body. Then you'll make an immune response as though it's an invading pathogen. And that immune response will likely protect against the virus, because the protein we've purified is essentially the same size and shape as what's on the surface of the virus.

CONOR: So they send in an imitator.

DODI: That's right.

CONOR: And the body treats this imitator as if it was a real threat, creating the safety system that the body needs to protect itself from the real invader.

DODI: You've got it, Conor.

CONOR: So, as we know, we've been reading and hearing that there might not just be one vaccine, there may in fact be six or seven different vaccines rolled out eventually.

DODI: That's right. And for Keith and Trent, they think that's super exciting. It's the more the merrier.

TRENT: I think that's phenomenal. That's what we should be aiming for. There are many reasons why that is the best approach. Firstly, to meet the demands. We need 7 billion or 14 billion doses because everyone's probably going to need two. Also, having multiple opportunities allows us to hopefully select which one is the best. And WHO is moving forward with what they and calling Solidarity Trials where vaccines can be trialed head to head, which gives us the goal of arriving at the safest and the most effective vaccine. And the third option is that if you have multiple approved vaccines, is there a potential to use one dose of one and another dose of another to get even better effects? So, an apple plus a banana gives you the best of both?

CONOR: So, are we ahead of the game? Or, you know, are we behind as we are with every pandemic and in many senses from a development of a vaccine point of view? What happens with the next one, I suppose, is what I'm asking.

KEITH: Yeah, I think we're definitely ahead of the game in that these novel technologies can move quicker, be it ours or Oxford or Moderna or or any of the others. This will be a proof of principle that these technologies work, because they can work and we know what to do to move quickly. And we show that these are safe. It will definitely be easier the next time there's an outbreak or pandemic. But as well as that, there are a lot of viruses out there that are in our community or in certain populations that haven't received the attention that they need from big pharma. Just because it's so expensive and may not be a commercial return ever on a lassa fever that's in Africa or something like that, by being able to move quickly. That also works to bring down the cost. So, that means we may be able to treat viruses that have been around causing problems.

CONOR: It sounds like what he's saying is that If we just do the right thing as people, as humans, and as a scientists, that will end up being the right thing for the world economy, I suppose.

KEITH: Absolutely. I think it will give us a boost to be able to produce vaccines and treatments more cheaply. And with less input going in, it will mean we're able to do that more often. And for everyone who needs a certain treatment, not just for problems in the developed world.

CONOR: Okay, that's absolutely fascinating.

DODI: Yeah, I think the one thing we can take away from this particular episode, we really went into the story of one vaccine, even though there are several that are up and coming that are slated for examination or approval by the American FDA coming up in the next few weeks. Believe it or not, this has been an incredibly fast process.

CONOR: It has not just been fast, but the idea is that we're spreading bets as a biotech community across multiple different vaccine options in order to really hope that at least a few of them are successful and can follow on through to really help alleviate the situation. It makes you feel a little bit more hopeful than you might if it was just one vaccine in development.

DODI: And it comes around to something that, and I'm going to get patriotic for a moment, we at Cytiva have been saying. This is a very special time for the industry, because people are coming together for the good of humanity, indeed. And do you see all that flag waving going on?

CONOR: I see it. And of course, it makes you feel good. It's a real honor. And it's humbling to work in this industry. And we understand that behind every vaccine, every potential therapeutic, every diagnostic, there's an incredible team of people working with the interests of improving human health at the very heart of what they do. And it's just an astounding opportunity to really shine through at a moment when the world is really looking to the industry for answers out of this hole. I mean, you know, we can't magic our way out of this hole. We're going to have to science and biotech our way out of this hole.

DODI: And we're trying to meet those fantastic people one at a time here on Discovery Matters.

CONOR: Now I really look forward to the next one.

DODI: Thanks for listening.

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