So can you say your name and your title? On Sunday, Douglas on a research group leader in the Jenner Institute.
Okay, thanks very much. So starting from your earliest interest in your subject,
can you just give me a kind of three or four sentence account of how you got to where you are now?
I'm looking in three or four senses.
So I first did a short project with the Gender Institute when I was a medical student, which would have been 2006 or 2007.
Yeah. So it just gave the thought that, you see, we were done and you were going to be a doctor.
Is that when you applied for medicine? Yeah, that's right. Yeah. So I was a clinical medical student in Oxford.
I graduated in 2007. I then did a short project alongside my clinical foundation training four month projects in the journal,
which turned into a three year Ph.D. on the development of vaccines against the blood stage of malaria.
That was 2009 to 2012. Subsequently, I.
Did some further clinical training in the NHS. I was a NHS trainee, an infectious disease in general medicine.
I did some postdoctoral research and then in 2016 I got a Wellcome Trust Fellowship and came
out to full time research and I've been leading my group in that in the journal since then,
working full time in research.
So as I understand this, two aspects to you is that you are actually interested in the the immune system and allergenicity and how vaccines work.
But you also have this interest in how you actually manufacture them to a point where you've got a product that can be delivered to the world.
Yeah. So that my original primary interest is also translational and clinical research.
So developing new malaria vaccines and then subsequently I've moved towards developing a new candidate rabies vaccine as well.
And the interest in money, my interest in manufacturing, I guess, has come from from two things.
The primary one was really an accident of fate.
And it was it was the need to solve a problem in my rabies vaccine programme.
So my rabies vaccine candidate is, is based upon an adenoviral vector very similar to Chadox1 COVID vaccine.
And I had said in a grant application that I would take a technology that had been developed by someone else in the DNA previously,
which could make bats make these up in the virus vaccine stable at room temperature for, you know, storage and distribution outside fridges.
And I'd said I'd do this with this rabies vaccine and I would do it to clinical grade,
such as good manufacturing practice with GMP compliant, easy, because really rabies vaccine is mainly needed in hot places, basically.
Exactly. Yeah. And I was quite naive about what it would take to do that.
But it turned out that to do that, we needed more vaccine and higher concentration and in a different mixture of salts and
sugars from what's our clinical biomanufacturing facility or a small in-house pilot,
clinical grade manufacturing vaccine manufacturing facility led by Cath Green.
We needed we needed more vaccine, a different vaccine from from the way they had made it before.
And so to try and do this project, to make this temperature stable, rabies vaccine,
which ultimately didn't work, or at least the temperature stable bits of it, I had to redevelop.
I had to develop a new way of making out in the virus for the placebo.
Can I just pause it? So through 2017, 2018, 2019.
I developed a new wave of for our CBF to make clinical grade adenovirus vaccines and previously the way the way
they had done it was really only suitable to make a few hundred or a couple of thousand doses of a vaccine.
It wasn't scalable, it was very manual and the way we developed was suitable to be scalable.
We were only planning to do it at small scale and for the rabies project we only did do it on a small scale,
but we did it in a way that could go to larger scale.
They have a big need it.
And we also did it using materials and equipment that was very standard, you know, off the shelf, single use disposable things,
which makes it much easier to set up in a new facility because you're not you're not trying to fit the manufacturing to a,
you know, whatever stainless steel, you know, equipment they already have installed.
You can just buy the off the shelf disposable things. So we we set the process up to be end to end and standard single use things and.
Whip it, and if I'm frank in large part because we need to make it quite simple so the CBF could execute it.
We kept a very simple way, avoided doing, you know, some things which might have made more vaccine or better and sexier,
but we compromised on something to keep it simple.
So the CBF had successfully run that process and made enough vaccine for a few thousand doses in I think 2019 for our rabies vaccine.
And subsequently I have been a co-investigator on a large grant,
the Oxford part of which was what was led by us on Sara Gilbert called the future vaccine manufacturing research job.
Yeah, and that was really, really important.
So tell me a bit about them, and I think that is important. So how did that help come to be?
So that started in 2017. I think I'm right in saying that something like didn't write it down, but yeah, something like that.
So I mean, why does that seem to be necessary?
So to be honest, I don't know the the sort of political background to it in great detail.
But around that time the the was.
Significant investment public funds in vaccine manufacturing.
And two things. One, one was the set up of the Vaccine Manufacturing Innovation Centre or the MCC, which was going to be built in Holywell.
And we should probably come back to that.
But that was a £67 million investment of public funds to build the facility, you know, bricks of bricks and mortar and bus largely.
And the second was investment of about £17 million in these two vaccine manufacturing research hubs.
So the had one being at UCL. So there was one at Imperial.
Imperial, and there was one of the one we're involved in is actually technically led by UCL because it was an imperial one and a UCL, Oxford one.
So my understanding is that those things were driven by something called the UK Vaccines Network, which I think Chris Whitty may have led.
But I think others of my colleagues would be able to give you the history of more pumps.
Adrian Hill And I know Sara Gilbert was involved and so anyway, there's this future vaccine manufacturing research Hall,
Oxford in UCL, I think about seven and a half million pounds and.
There were four strands of work being done in Oxford, some of which I ended up doing two,
essentially because they matched what I'd been doing on the rabies programme. So one of them was to continue to develop.
Better ways of making on the horse vectors. And the other was better ways of making them temperature stable.
And. It's probably worth mentioning that that funding was, I believe, overseas development aid funding,
and it was very much targeted development in developing manufacturing methods that would be suitable for vaccine production in developing countries,
which is what we did.
And I think that probably is one of the best investments the UK has ever made, perhaps in terms of both benefit for low and middle income countries.
LMI sees benefit for the UK itself because if we hadn't had that funding, we would not have an oxford-astrazeneca vaccine.
So the reason I say that is that we had.
I think I think the future vaccine manufacturing research I only really got on the way and in 20 know those parts were all I'd had
one postdoc working on it it was called Sophia Fellowship and she so she had finished off what we'd started doing for rabies,
the basic first version of our manufacturing process.
Finished off in 2018, early 2019.
What was the first bits of what we did in The Hub?
And then Sophie, I wanted to move on to something else, and I hired a new post-doc who's called Carina Jo.
She's Indonesian. She just finished a PhD in Australia and I.
Felt that what we should focus on to improve our manufacturing process was the what's called the upstream process,
which is how much vaccine is made by the cells that are making them making the vaccine virus.
The the other bit, the downstream process, which is how you purify the virus away.
I thought what we had was was okay and actually what was limiting how much we could get was the upstream.
So I went looking for a postdoc with the relevant experience to do that.
And Carina had quite a bit of experience in culturing mammalian cells,
the type of cells we used to make the vaccine in a sort of industrial biotechnology type setting.
And so she arrived in, I think, August 2019.
And more or less the first experiment she ever did was to try some different culture media with the cells,
which we'd always used, quite old culture media.
And she said all these various more modern ones, we should we should try.
And to be honest, I was a bit doubtful about it.
I wanted, but I thought probably we'd get better results by doing it the way that Johnson and Johnson make that happen,
of course, vectored vaccines, which is using a much more complicated technique called perfusion.
But Carina said was, let's try this new modern medium.
And she did it. And she brought me the results in, I think late November or early December 2019.
And they were really good. I didn't really believe they were so good.
I didn't really believe they could be real. So it was less replicate, less repeat the experiments.
She went away. Not a all. I came back in January and she brought me the the repeat data and I think late January or early February.
And it was just as good. So what was the medium?
It was simply making making cells grow faster, reproduce more quickly,
making the cells happier at a higher density as well, and ensure it was what it was doing.
So the. The, you know, dogma in the field about the virus.
Vaccine manufacturing for a long time has been at a certain level of cell density.
The cells stopped making the vaccine efficiently.
And it's not just not just dogma. There's lots of evidence to show that was the case and that was what I was doubtful for.
It would work. But it turned out that it hasn't been done a lot believe hadn't been sort of retested since all of the media had been developed.
So. We got pretty lucky, to be honest.
You know, incredibly lucky. The thing that worked.
And so. What they enables is what's called a Fed balance process,
which is essentially the plain vanilla of the global biopharmaceutical manufacturing industry.
It's very similar to the way that monoclonal antibodies, which, you know, the most common biopharma group of products in the world,
are made and you just put cells into a big part of either reactor and you grow them.
You add some extra supplements to keep them happy when they get tired and sitting and you take out your products at the end and it's much more
is much simpler than the alternative way of making out the virus in a large scale would have been regarded as the industrial gold standard,
which was the fusion which JNJ had developed, JNJ had been working on on Novartis manufacturing for a change,
and companies they had bought have been working on manufacturing since the nineties.
I had it really fantastically, you know, brilliant process, you know, very, very elegant.
Good. They've done great work on it, but.
You know, I don't think they've been developing it. And nobody nobody had been developing a process on it.
If we're honest for something, the scale of the pandemic and change process was relatively complicated.
So in that sort of brings us to early February 2020.
Right. By which time. And we already knew it.
So it would be just I'm always just asking everybody this question. Can you remember when you first heard that there was a pandemic in the offing?
I can't remember the very first time I ever heard about the virus, but I was certainly aware of it in January.
And I can remember having a conversation with Sara Gilbert and just in passing in the office and Jan saying, Oh,
you know, there's this virus in and in Wuhan and you're making any vaccine, you know, because I was there as remote.
And I if I'm honest, I had never been very honest, very, very been very honest.
I'd never been very interested in you know, it was it wasn't my thing.
Emergent pathogens and outbreaks. And I was.
I have been during the Ebola pandemic, for example.
I had been quite. Sceptical.
You know, there have been lots of Ebola outbreaks and it has not caused a pandemic.
You know, we we I think a lot of the things which people are worried about,
or at least in the media, there's been concern about epidemics that actually have fizzled out.
And they've been proven to be viruses that maybe didn't have the potential for for causing such serious problems.
And that's not not to say that I didn't regard a pandemic from some virus as an existential threat.
I had had a clinical tutor in in medical school, Alan Townsend, who I remember impressed on me.
Very, very. You know, it really stuck in my mind.
He was viscerally scared about the potential for a flu pandemic and how that would overwhelm the NHS.
I'm not really stuck with that, but I.
My sort of prior belief hearing about this virus in Wuhan was that it would probably fizzle out like we talked about before.
And so that initial conversation was there. It was on. I don't think either of us really thought it was going.
You know, she was working on it because I'm sort of thing. But I don't think either of us really thought it was a serious.
It was. What changed that for me?
I read an article in the New York Times on the 2nd of February.
I don't know what pulled the graph. The really.
Got me scared. I pulled the graph out of it and I got a slide showing up and it was a graph of the R value of all on those
with no values versus the infection fatality rate percentage of people who would die after getting infected.
I showed the estimate for became SARS-CoV-2 you know with wide ranges of uncertainty on both of those based on the early data
from China and it showed by comparison those those numbers for the original songs and for Mars and for Ebola and for flu and.
It was very apparent for that from the plausible ranges of R an inflection of style fatality rates included at the centre of the range,
the most likely number,
but certainly the less favourable ones as well, included things which were very, very, very scary and worse than anything the world had seen.
And. You know, worse than, you know, any flu pandemic in living memory.
And. To me, that was all that was needed to.
It became like my little brother.
And, you know, it was apparent from the.
This was something the world needed to take very, very seriously.
And. If I'm honest, I'm uncertain how.
Governments were not on maximum alert at that point.
I think there was sufficient data in early February in The New York Times to merit, you know, treating this as a huge, huge global emergency.
And I wasn't sure what to do for a few days because it wasn't my area of research.
I realised then that actually it didn't take very long to sort of, you know,
I the chimpanzee adenovirus platform we have here, we've used it for literally hundreds of things in preclinical work.
And, you know, it's, it's, it's simply molecular based.
You can put a new antigen from whatever pathogen you like, put a new antigen into it, and you can get an immune response.
It's very simple. And I knew, you know, whichever whichever antigen we done and I think there have been ten or 12 of them in clinical trials.
It's safe and you got an immune response. And I knew also that Sarah had done nothing worse.
And that was protective in monkeys.
I got an immune response and people and I knew also that for Ebola vaccines,
it actually proved there's a big, huge question of how was it going to be possible to make a vaccine?
That was that was critically important. And in February of 2020, in deciding what should be done, you know,
how likely it was that a vaccine could be developed quickly enough to make it worth doing lockdown, for example.
So there's no point looking down if everyone's going to get it anyway.
It has to be on an accelerated. And.
On you, for example, in. For Ebola.
That being really the opposite experience for HIV.
You know, some some some diseases. It's very hard to make a vaccine against HIV, for example.
There's umpteen different ways of protecting a monkey. But it's nobody's got an effective HIV vaccine for people.
But the experience for Ebola have been the reverse. It was relatively challenging to protect monkeys.
But then when Ebola vaccines actually deployed in West Africa, more or less anything, you know, it wasn't that hard to protect.
And the reason for that was that the the animal challenge model was very, very stringent.
I don't know how true this is, but some someone someone told me the animal challenge model was, you know,
developed for bioterrorism purposes, you know, to to mimic, you know, a baseball stadium being sprayed with Ebola in huge quantities.
Whereas in reality, in the in the real world, if you're exposed, you, you know, you're exposed to very tiny amounts of that.
So it was actually actually pretty easier to protect people and.
For, you know, generally speaking for acute infections, which.
You know, the natural history of infection is that it resolves you know,
the normal outcome of infection is that people develop immunity and they get better.
And we you know, we knew that was going to happen, that 90 plus percent of people that got this infection for that.
All you're trying to do with a vaccine is emulate what natural infection does.
And that's not hard to do.
There's obviously lots of complications and reasons that might prove problematic, but fundamentally, a lot can usually be done.
And it's fundamentally different from something like HIV, where the natural immune response doesn't protect.
So my feeling in February 2020 was that the technology platform we had had a very good chance of being effective.
I wouldn't put a percentage on that, but, you know,
I would have I would certainly have taken a bet of 5050 having some effect against severe disease and death.
And the real problem, you know, I knew there the vaccine had already been made by the you know, we already had it.
So the challenge is, how did you get it out of the lab and into the real world?
And I actually would probably personally in a world with no vaccine regulation.
And an uncontrolled pandemic. Personally as a as a well and, you know, relatively well informed person was there.
I would probably have taken the vaccine blind in February or March 2020.
I would have been confident, with no evidence that the the risk benefit balance of having had the, you know, no new evidence specific plant vaccine.
But what I know about the virus vaccines before and vaccines against all the coronaviruses,
I would have been convinced that the risk benefit balance of having some of the vaccine made in the lab,
you know, was that the manufacturing standards that we apply in the lab, that would have been more beneficial and risky to me.
But that's clearly not how things work for and shouldn't be, how things work for, for deploying vaccines for these millions of people.
So the real the real challenge is, is not making the vaccine.
It's, you know, the groundwork on making the vaccine to create the technology platform not been done over the preceding ten years.
You know, that was hard, but it wasn't hard in February 2020 was hard in February 2020 was how to do a rapid clinical trial and.
Actually even that I felt might be very, very fast.
We had a sort of slightly skipping ahead, but we had an extraordinary meeting in early March 2020 when we were designing the Phase one clinical trial,
and we were designing the Phase one trial, which was, you know, the idea was to vaccinate something like 40 people.
We normally for a phase one trial with small numbers like that, we don't do controls.
We don't give people placebo because you're just looking for safety.
And then in response, yeah, and you measure an immune response and it's not possible in a phase one to measure efficacy against infection.
But we have this extraordinary experience of designing a Phase one trial with with controls and thinking, well, it was quite possible.
And the government wasn't looking down at that point that if we vaccinated people in April, you know,
20, 30% of the people in the trial might be exposed to the virus in the course of a couple of months.
And actually, statistically, that would be sufficient to give an efficacy rate on those tiny numbers.
So the. It was.
I felt that because we had the prior safety experience on and given the similar,
very similar vaccines to lots of people because the clinical need was huge.
You know, if you've got a 10% risk of dying, if you're an older person and you've got this this virus, you know,
how much safety data do you need to know to know that some protection from a vaccine is better than whatever the risk is from a vaccine?
You know, if the stakes are very, very high in terms of risk of the infection, you know,
if you've got if you've given the given the vaccine 2000 people and followed them up for a month,
and, you know that, you know, you're, you know, considering vaccinating a population with a 10% risk of death if they get an infection.
Well, actually, that's probably sufficient safety data.
So it seemed in this very unusual context that it might be possible to provide adequate data to motivate,
you know, adequate data to support deploying the vaccine in high risk populations,
you know, health care workers very, very rapidly, because both safety, you know,
we knew the platform was fairly safe and we might get an efficacy result very, very quickly.
At the speed with which we got an efficacy result was a function essentially of how quickly
we could get people vaccinated and how many cases of the virus there were in the population.
The only reason we didn't get an efficacy result sooner was because of lockdown.
Yeah. So this wasn't enough circulating infection and I.
Talk about a bit more about lockdown in a minute maybe.
Clearly, it was good that it happened, but we would have had an efficacy results and in summer 2020,
had there been a large wave of infection on lockdown.
So I felt like in February 2020 that, you know, technologically, the button Oxford's vaccine technology was getting off target crocodiles.
I knew that the university was Andy Card in particular experience of running large trials during
the swine flu pandemic university and the clinical trial capability to to run trials quickly.
You know, if the journal is good at anything, it's good at getting things into people quickly and efficiently.
The general run, the fastest phase one trial in the world for an Ebola vaccine candidate.
Didn't develop like the vaccine in that case, but.
We're quite good at getting things done quickly.
The UK regulators are very effective as well in getting things turned around fast in an emergency like London,
and I thought it would be possible to progress very rapidly from a phase one into thousands of people.
So I thought the technology in the clinical trial actually probably wasn't that problematic.
They were they weren't going to be the rate limiting thing and getting vaccine out into the world,
the right limiting thing and actually potentially a fatal flaw for universities
programme as a whole was the fact that we had no idea how to manufacture a large scale.
You know, we if you'd asked me what's going to happen in, in, in February 2018, if in February 2020 you'd asked me what's going to happen,
I'd have said I thought probably the most likely scenario or quite unlikely
scenario would be that we might find out in summer that the vaccine worked,
but we wouldn't have any of it to give to anyone what happens in normal times?
How would you normally get a vaccine scaled up for something like like no childhood diseases or one of those?
So what would happen normally is that you would do a phase one trial and then you would stop and
you would look at the results from the phase one trial in a few tens or maybe a hundred people.
And if not looked okay, then you'd do a phase two trial, a couple of hundred people.
And often those are done with only small scale manufacturing capability.
And then in industry, you know, phase three trial is relatively unusual for phase three trials to be done in academia,
or at least unusual to be done by academics without an industrial partner.
Typically what happens is that a phase three trial will happen,
that a large scale manufacturing process will be developed to produce the vaccine for the phase three trial by the commercial partner usually, yes.
Yeah.
And it you know, I can't think of an example of a phase three trial, you know, happening with public funding, with academically manufactured vaccine.
When I in it, you know, the Norway's an industrial partner and the idea there is that, you know, a,
you know, phase three trial is going to cost depending on who you believe, at least tens of millions.
And you should, you know, to no point investing in it's not going to be possible to make it at scale.
B, if you do the trial and then you change the manufacturing afterwards, then you have a comparability.
People get very worried about comparability when manufacturing processes change.
How do you know that what's coming out of the new manufacturing process is exactly
the same as the the vaccine that gave the good results in the clinical trial?
So people like to have the final process pinned down for phase three and but then actual investment
in really making millions and millions of doses would only happen after the phase three.
The result? Sometimes people would invite you if they were confident.
A company was confident. I think they might invest in actually building a new factory in parallel with a phase three trial.
But you certainly wouldn't be churning out millions of doses during the phase three trial.
So that's the usual way of things. And.
That clearly wasn't going to work in this case.
On the other, things about the usual way of things is incredibly slow.
So pharmaceutical manufacturing happens on to this GMP, good manufacturing process regulation.
And there's a deeply ingrained culture of quality and quality to you and me might mean,
you know, something as good something as fit for the purpose for which it's intended.
But in that environment, I think this is what a lot of people would rightly expect.
It's a very, very risk averse environment. And.
For me, coming from a clinical background, I sometimes find that quite challenging.
The I, the there's very high value placed on avoiding any potential risk arising from a manufacturing problem and.
Less value placed on the home.
The results if making. The manufacturing so controlled actually makes it so expensive and slow that no drug gets to
patients or it's impossible to develop the drug or it gets to patients years later in it.
In a clinical medical context, you accept that for every everything you prescribe to a patient, all the risks and benefits.
It's not a zero risk culture, but the culture and in biopharmaceutical manufacturing is.
Close to being a zero risk culture. I love that because of a fear of litigation.
Yes.
And I think also, you know, there's a basic feeling people should know, you know, nobody should die because of a defective vaccine, the 21st century.
You know, that is an unacceptable thing. My personal feeling is that the.
Aspects of that culture of quality and risk aversion are.
Far more onerous than is proportionate to the actual true risk.
And that, you know, and that's because the culture is dominated by manufacturing specialists and not not by clinicians who think about,
you know, what is a real risk to a person. So the relevance of this to COVID 19 is that the.
That expectation of.
Extremely controlled,
extremely well understood manufacturing processes and no change in those manufacturing processes between a Phase three trial and.
And deployment of a vaccine. Makes it incredibly slow.
To develop new products. And actually looking in February 2020 that.
It seemed to me that the speed with which the manufacturing could be scaled up,
both from the point of view of doing it in a regulatory compliant way and from the from a financial perspective,
the fact that, you know, if you want to make a vaccine and you don't have your own factory,
you need to invest millions of pounds in booking a facility upfront.
And we didn't have millions of pounds. And, you know, it takes months and months to prepare the facility to do the first batch.
I use the analogy with people. It you know, it's a little bit like setting up a new branch of McDonald's or something.
You know, it might take months and months to prepare the facility trains, train the staff and,
you know, invent the recipe if you're inventing hamburgers for the first time.
But once you've got it, you can churn out the vaccine very quickly and.
I was concerned that that set up was not going to happen soon and often.
And I hadn't. I felt it had to be done before we knew, before we had evidence whether all the vaccine was going to work.
So really, within a few days of that reading, that New York Times article, having sort of torn my hair out for a battle,
I remember writing to the Guardian neighbours and saying, Do you want it?
Would you be interested in a piece from the vaccine developer about how to regulate?
Quite a lot of pinch, though I felt there was a problem of awareness that actually it would be possible to make a vaccine.
But the challenges were around regulation, manufacturing.
But I wasn't part of the programme here and I thought it was important people understood that.
The Guardian, unsurprisingly, were not interested in what I had to say.
But I realised that actually all of the people in Oxford who might be able to do something about this problem.
Well, really, I was the only person who had worked on scalable manufacturing of this type of vaccine.
And so I started thinking, you know, what can we do?
And with Katrina's result or coroner's results show it was that we could get.
More vaccine from a very simple process than had previously been thought possible.
And with that, it seemed like it would be not that hard in a sort of purely technical sense, but very, very hard.
And that's been in a sort of GMP compliance sense, unheard of in a GMP compliance sense, technically possible, but regulated,
really challenging to take what we had at the scale of, you know, literally two tablespoons, 30 millilitres was the scale.
Kareena had got her original results. It seemed to be possible to turn that into a commercial scale process, which would be 200 litres.
And on what kind of time scale?
Well, in fact, in February 2020, I started putting together a grant proposal in the UK or I had a UK government research funding,
how to do emergency COVID funding. So I put in a grant and got 2 million for the Phase one trial and I missed the first deadline known to exist.
And I wasn't ready. I put but essentially I put together an application for £400,000 to and the pitch was enabling production of the titles,
enabling production of a million doses by the end of 2021 to vaccinate NHS workers.
That was, that was, you know, that seemed like a wildly ambitious, you know,
no one really was thinking, well, a million doses might be available within 2020.
And we knew, we knew we couldn't do that internally.
So to enable putting together the proposal, I had reached out to the Vaccine Manufacturing Innovation Centre directly.
So that was something that at that point, V-neck was no building.
I was six people in an office on the science park with some plans for building, but they had one guy called John Humphrys,
who was the head of process development, who was going to be part of process development side.
And you know, this was their remit, this mobile they were set up to do.
So I got in touch with them and the boss put me in touch with John and he then put me
in touch with a Dutch company called Halix as a contract manufacturing organisation.
They'll take all the people's problems and manufacture them. A commercial is coming.
They very, very new and I don't think they really done anything yet in that facility.
So that was one direction in which I reached out to try and, you know, find some friends, you know, get some help.
The other was Cath Green, who runs the CBA,
said she was on this mailing list for the UK Bio Industry Association and she sent a message to say if anyone on the list would help us.
So she sent out a message on my behalf asking for help and the scale up.
And we got a lot of responses very, very amazingly fast and pull by a tag which is a big sort of equipment that's l p,
I think equipment and materials supplier multinational but with a base in Portsmouth legal all mainly and they said,
well, we'll run it will run a 200 litre barge will will will take your lot process and we'll take it to 200 litre industrial scale and we'll do that.
You know, we'll put in our people's time and, you know, the materials that are up,
you know, pull materials and all the equipment they would supply them.
So it was a big package of in-kind support worth a couple of hundred thousand pounds.
And at that point, you know, really it was an amazing response.
We got via email because at that point the leading UK platform and if you read the papers, the leading UK vaccine programme was, was Imperial.
No one had really heard about as we were. We hadn't nothing, nothing had been put out in the press.
And then one of the other companies that responded that was called Cobra Biologics.
And also I'd made I'd made contact with Oxford Biomedica just down the road.
So I had these conversations.
I remember pacing around the frosty car park in mid-February,
trying to persuade chief scientific officers from these companies I'd never dealt with before,
you know, working at a scale I had no experience of to do this.
Absolutely. What to them was preposterous to take a lab a lab process, couple of tablespoons and turn it into an industrial process with no funding.
Incredibly fast. And Cobra, Biologics and Halix.
The Dutch company came on board for this initial application to UK R.I. and they said they would provide some.
Basically they would prepare to run the process in their facilities, which is a modest investment of that time, but not actually run it.
Oxford, Biomedica at that point decided they weren't able to be involved.
You know, they were much bigger, you know, listed company and they had their own business, you know.
Well, that's out of all the customers needs to me. And they, they weren't able to get involved in the stage, but we kept in touch with them.
And so. Things really how you know what happened very, very fast around the end of February.
Look, you know, within a day or two of speaking to these people,
I put in the application to UK arrived within a day or two of the UK or I phoned back and you know,
they said, you know, we're not we're not officially taking the decisions on these grounds for a while,
but we're going to we're going to fund get on with that. So by the end of February 2020, we were like, well,
we're scaling up as fast as we possibly can towards a but what's called an engineer and basically a process run,
not a clinical grade, but industrially, industrially relevant scale.
And that was going to be done in Paul's facility in Portsmouth. In my lab.
We were all we hadn't done the sort of purification with this, you know, with with vaccine that come from this new media.
All we'd done was we knew we could get a loan from the upstream process.
So in my lab we were frantically checking, well, can we actually still purify the stuff in the way that we had done it before?
How do you in simple terms, how do you purify the product that you want from a very simple time?
And so it's a series of filters, slightly less simple terms of what's called chromatography step, where the virus sticks onto a filter.
Another thing was pass through. So when you say the virus, I think we need to keep clear all the time.
Are we talking about the hot new virus or the spike protein? We're talking about getting the virus for the good question.
Whenever I say the virus in a manufacturing context, I mean the vaccine.
Yeah. Yeah. In the last. Around.
About that time I remember setting up a WhatsApp group with Garth Green and Adam Ritchie, the project manager.
It was called The Coronavirus versus Corona Virus Growth Rate.
Growth Rates Club, you know, and I'd do the logo for the group first set up was to feel a bit of a geeky joke was barely a joke.
It was two intersecting exponential curves. You know, at that point, the corona virus was growing faster.
But what we had to do was try and find a way to make our virus in the virus grow faster, and that should be possible.
You know, I thought the what should be possible. Technically, it was possible.
It was a question of dying in a way that was regulated, fully compliant and financially practical.
So. Three, three Feb 2021.
A plan for getting the manufacturing to, you know, roughly million dollar scale.
I put that together and it looks increasingly like time to plan all the people support in parallel with I was.
Involved in trying it out of us, trying to, you know, motivate.
I felt like I was trying to motivate colleagues within the university to treat this as a real, real emergency.
I remember writing a briefing note for that at an apartment.
In which I said I. Foods. This was potentially the worst emergency for the country since World War Two.
And something that's. It was highly plausible that tens of millions of people would die.
And in February 2020, look, I don't know the case in the UK and a lot of people are still thinking this thing would be contained in China somehow,
despite the big outbreaks in Italy and Iran saw it, the sort of parallel stream of stuff I was doing, which was really trying to.
Persuade people to treat it as a real threat in an emergency.
And I find it quite distressing, to be honest, that there was no.
The prevalent attitude. I was also, you know, at the same time involved in.
Trying to. Well proposals for what we would want, how our clinical development program would work.
So I was speaking with Sara Gilbert and Cascarino.
Adrian Hill was overseas by. Listening to him on the pod wasn't.
Originally involved. A plans to run a paediatric triathlon and later in the summer.
And I put forward this I and the original plan was going to have the first batch of the vaccine made and.
In Italy and a CBF our own manufacturing facility was manufacturing and other products.
It was busy. And I.
Felt quite strongly that the. Manufacturing should stop.
And the quickest way we could make get a clinical trial started was to make it in our own facility, and that could be done within a matter of weeks.
So and I also felt that it was possible to progress the clinical trial plan quite rapidly.
So. On. The first discussion I'm aware of of a continuous phase one, phase two, phase three clinical trial was a.
An email thread started on the 25th of.
February 2020. And things came together for a.
If it felt like critical mass to me, critical mass was achieved.
And this is not. I think it's important to be very clear.
Sarah. Sarah And tests have been working on this from, from January.
Tom Fantastic. Look.
The critical mass around the plan of real emergency clinical development coupled to emergency
manufacturing development to actually get meaningful quantities of it into the real world.
And actually, the connection between the manufacturing and clinical trials was really very important.
You know, we could only do the clinical trials quickly as we can manufacture the vaccine.
So the idea of, you know, really just in time supply, first of all, apart from trial,
kind of go by manufacturing facility building very fast till phase one and then accelerating the
batch from Italy and then maybe whatever we could do it 200 leads scale using one new process the.
The idea we could make that happen and it could feed into a continuous phase one,
two or three trial, and that would then be an industrial scale process.
Ready? And this would be a program that would involve both the General Institute and the Department
of Medicine and also the vaccine group and the Division of Paediatrics that coalesced in a.
For me in a slide presentation to the group of principal investigators from the Department on the 26th February 2020.
And I'm Adrian Holloway.
I asked Richard Cole if we could have the opportunity to present this as the vaccine development team at the start of the meeting.
And Adrian Dalton from Massachusetts Forum in the morning where he was antipolo and came along for the first time,
I think, and they had come to a Department of Medicine meeting relating to the pandemic and.
But all these slides basically said we thought we could open efficacy results and millions of doses of vaccine by the end of the year.
Well, the timeline on the slide was a bit over optimistic.
I think I was leaving for August, but. It was on the call of a figure law.
Amazing. And I remember having a conversation with Crystal Fraser, who's a eminent infectious disease epidemiologist who was in the room.
And he said. Well.
If what you're saying is right, it is possible to make meaningful quantities of vaccine a lot of times.
You know, that sort of timescale, then all the assumptions on which policy is being made.
You know, the decision to not lock down early. Which was, you know, influence my philosophy tone for the most convenient function or any time soon.
He said, Well, you know, people people haven't understood that I could be long seen or be seen on.
If what you're saying is right, then the policy decisions that are being made a roll.
I was. Pretty profound.
Mm hmm. And surely within within the week after that was the first the first meeting of the COVID vaccine programme,
Joint General and Perpetrator Vaccine Group, then planning a phase one trial, you know, huge.
You know, it's absolutely not to an elbow. We were not at all in the frame of infection control.
You know, people were not thinking about how do we, you know, the idea that the virus itself might be a threat to the programme.
Was not there to begin with. It was we were crammed and, you know, 50, 60 people in a tiny room.
And that was quite a discussion about, you know, a phase one that might produce an efficacy result was going on.
I remember saying, you know something someone reminded me in the pub recently that I had said something about everyday.
The everyday slower that we developed a vaccine could be that thousands of people died, which just, you know, it's like great.
You know, sounds grandiose. But I felt it was true.
I thought we had a very serious responsibility to try and move as fast as we possibly could.
I didn't think, you know, early on I thought I vaccine had a good chance of being efficacious.
I didn't I didn't think it would likely turn out to be the best vaccine against COVID 19 in five years time.
But I thought it might be that we were we were able to do it faster.
So for me, speed was the the critical thing.
So yeah, that's the that's the sort of I've been talking for quite a long time.
I've only really brought it up to the end of February 2020. When how is this?
Is this the sort of thing? Yes, yes, absolutely. Absolutely.
It's very much giving us what what it was like to live through it.
I can see it kind of watching it. You are living through it again.
Yeah. So. So once you'd, um. Got that group together.
I mean, you still needed funding, didn't you? Yeah, I know.
But it was a couple of it was a couple of months till before the vaccine taskforce was set up, wasn't it?
Yeah. So for me, February and March 2020 were.
Without a doubt the most intense and distressing. Traumatic.
Period of my life. Because it felt like watching a slow motion train crash on and it was completely avoidable.
Or it felt like it was should be avoidable to a large extent. And you mean in terms of the government not implementing mitigation strategies earlier?
Well, in terms of how the actual work on the vaccine was going.
I think. Partly a bit.
A bit of both. Yeah. I might ask you about it. Not part of the bit that goes online immediately.
I said, well, both of those fell on the vaccine development program, not not just ours, but globally.
Wasn't getting the level of investment. You know, it was.
You know, if you looked at some cost modelling of pandemics, you know, like premiums,
you know what people have done, modelling the cost of a flu pandemic. It was obvious this was going to cost trillions of dollars.
And it was obvious that an effective vaccine would save many billions of dollars.
And we were making decisions for one of lack of 50 or £100,000,
or we were not taking decisions because they would put at risk that sort of money that we did not have.
That could delay things by a couple of weeks. And, you know, I've mentioned in terms of monetary values, but it was also obvious that,
you know, global death rates were probably going to have been thousands of deaths a day.
So. It was terrible and obviously terrible and my own.
I didn't really feel I think a lot of people thought personally I was mad because I was so agitated about it.
I think my own family were worried about me. My father.
Hunt's. Terminal lung cancer.
And he was on chemotherapy. And in February, in February 2020, he decided to go to you know, he's always wanted to see the Sistine Chapel.
He liked art. So I had this, you know, terrible conversation with my parents, first of all, while they were literally on the tarmac at Heathrow.
And then when they'd arrived at the hotel in Rome saying it was a man was immunosuppressed with lung cancer, you should not be in Italy.
I'm really sorry. I know you want to see the Sistine Chapel. But you've got to come home.
And I thought I was mum, but I did come home in the end.
But, you know.
You know, it was a very difficult time. But coming back to the the voting problems, you know, we did not the level of investment we needed.
And, you know, in February, March 2020, the games that the were in town, as it were, for funding was UK RMI,
which had coughed up a couple of million pounds to 2.3 million, I think was a 400,000 for 4 million on the Fox role.
And that was enough to see us through a phase one trial.
There was. Cepi, the Coalition for Epidemic Preparedness Initiatives Innovation, who had previously given Sarah £10 million to work on a mars vaccine.
Yeah.
And Cepi it proved quite challenging to actually get commitment from them to, to very large scale, you know, the scale of funding that was needed.
So we went, we didn't have any funding of the scale needed to do large scale manufacturing and the whole way through March.
You know, it felt like the world wasn't a week gone by by that point.
We assembled a consortium to scale the manufacturing of, I think about nine organisations.
So in February, Vaccine Manufacturing Innovation Centre Halix Cobra.
Oxford Biomedica who took a while to actually commence.
But they were we were talking with them and informally they were, you know,
participating in a phone calls, I think, and then a couple of sort of suppliers.
And then in March the Serum Institute of India and I'd spoken to Ruchi Biologics,
which is the Chinese contract manufacturer, and they said W you excite correct you.
And. I'm sure I'm forgetting other.
Paul. Paul? Yeah. So, but in, in March, you know, we had this with we were having calls, multiple calls over every week,
coordinated by, by me and Adam, one project manager while Karina was doing a lot of work, essentially.
You know, one part of it was how do we do this 200 later on?
Paul You know, the mechanics of how to go in the cells, how do we get the materials to pull fast and enough?
And, you know, we we compressed and compressed the timescale.
So instead of like doing a wrong by August, we decided, you know, the urgency was increasing.
And we, we decided we'd try and get the 200 metre run done in in April.
So that was one strand of work. And then the other was, well, Kobra and Alex had said that they would prepare for what's called inward tech transfer,
taking the manufacturing process and really running it to GMP standards and increasingly turning towards doing that.
And, you know, and saying, well, we actually we really want to do this for real as soon as we possibly can.
And, you know, can we actually really make a batch for the NHS, you know, within, within summer 2020 maybe and.
We had no money. And so, you know, every week I was on this phone call with CEOs of these different contract manufacturers saying,
oh, we're talking to such and such a fund. We'll have some money next week.
It was like magnanimous, you know? John tomorrow.
But it was never John today. And you know, please, guys, please stick with us.
Please don't give away your manufacturing capacity to someone else who's got the money now.
You know, they were they were saying, well, we're going to have to give them you know, we can't commit to do this for you haven't got any money.
And it's you know, ultimately they've all done very well financially out of it.
It was a good business. You know, there was this unique confluence of the right thing to do altruistically.
And also actually there was a very good business case for coming on board with our vaccine programme in the early days.
All the companies that did have done very well, but we needed real money.
And that only changed in April.
And. A couple of other things that happened during during March which.
I'm maybe worth just touching on in terms of my personal experience.
So. I.
I was. You know, I've become increasingly convinced that it was possible to make a vaccine and that
manufacturing and supply was going to be the limiting factor in actually getting it to people.
And it's increasingly public that there wasn't enough funding harmonising and
the government governments were not engaged with the scale of the problem.
And my. My partner is an economist in the School of Government.
Her boss is the former chief economist for different Department for International Development.
And I sent him an email explaining the situation at the end of February and saying that
I saw a lot of middle income countries were going to be in the back of the queue to get.
A real deal. And he put me in touch with a guy called David Kindler is the UK's number two in the world punk too,
between myself and Kate, my partner with a bit of input, a review from Stefan, her boss and Adrian Hill.
We put together a discussion, you know, essentially a briefing note that said.
If the world invested some of basically it was arguing that it was an incredibly
good investment for governments to put in hundreds of millions of pounds,
like then in March 2020.
I'm told I'm told that and then that there was a need for, you know, market commitments to buy the vaccine before the clinical trial results.
I'm told the briefing note had some influence on. COVAX subsequently being set up.
And. And. This is the international organisation principally to supply you to other middle income countries.
That's right. Yeah. Um, but yeah, that was, you know,
all part of this surreal experience is that all of this kind of the World Bank about spending hundreds of millions or billions of pounds.
And we still have short of tens of thousands of pounds.
But there was this sort of track of, you know, I was having those conversations on people on a believe was talking to Chris Whitty and Patrick
Vallance by the end of March 22 I'd sent a message to I think we had a call with Jonathan Van-tam.
I know one or two emails involving Patrick Vallance and Jonathan Van-tam in March 2020, you know,
basis and look, we can do this but you know the manufacturing problem but we can do it.
We can do it in the UK in parallel with the UK Bio Industry Association and set up a vaccine manufacturing what they
call the Vaccine Manufacturing Task Force and subsequently became an arm of the Government's Vaccine Task Force.
But the manufacturing line was set up first and it was it was led by a guy called Ian McKellen,
and he was a former vice president of manufacturing for GSK.
And I think he contacted me on March the 30th email in a phone call.
And basically they had a. In the first couple of calls we had with them, you know, a massive zoom call and dozens of, you know,
well-intentioned and generous people from all the UK bio industry association member companies,
you know, willing to help one out of groups at all to help without Novartis manufacturing.
We had a group set up to help with money, which was basically to help Imperial.
They had a group set up to do will fill and finish putting the vaccines into vials and a group set up to do a deal with supply chain.
Very, very sensible. Very important. And.
To start with. I think they thought that they were you. If the assumption was that we wouldn't have a a large scale manufacturing plant.
And they said that they were going to take over.
So the first couple of meetings were a bit weird. It was like, you know, what do I actually owe for the plant, you know?
And the. But it turned into a very, very productive and very supportive relationship.
And within a week of, I think, April 7th.
He had asked me to put put together a plan.
Well, what would it take to buy the capacity? You know, I said,
I think we need to buy a capacity in the three of three contract manufacturers we had that were potentially for supplying the kind of three,
three sites that might supply the U.K., like COBRA to buy American to internationally etc. maybe talk about into non-European.
But later up the. The task force was interested in UK supply primarily.
And you know, I had been thinking well by this point, well we just need to book the mine, you know, hire the facilities for the rest of the year.
And. I said this to me and I said, Well, you know, what's it what would it cost?
You know, write a plan. And I wrote a few slides.
It's like it needs to be simpler.
And I ended up basically boiling it down to a single slide where said, you know, we could do this for £65 million for the year.
And I was at pains to say, but we don't you know, you don't need to put all that money at risk to begin with.
You know, you could bail out if the trial results in May or this point, you know.
So actually, all we're really asking for is £12 billion upfront.
It wasn't even though it was a huge amount of money for me, I'd never asked for that much money for anything before.
But it's like, no, you just need to ask for £65 million and a week after that.
We want to, you know, ride in.
And his task force will help you with a plan and play set up a cause.
Harsh on business Secretary Huntoon, sir, we're talking about the clinical trial and the phone and all these presentations on your functional side.
And very soon after that, we had a, you know, commitments of of.
£65 million. But by that time, the government vaccine taskforce had been established.
It was formally only established, I think, on the 1st of May. Oh, right.
Or at least that's when Kate Bingham came on board.
But certainly through April, there was you know,
we were in contact with government through through this being a vaccine manufacturing taskforce and was connected into government.
And, you know, the there were clearly people in the civil service who had been briefed.
You know, it's your job now to make this happen. You know, there was someone to pick up the phone to and go on from.
Do you feel when you heard you've got 65 million? I know.
Please. Obviously, I mean it. But to be honest, there was still there was so much other stuff going on.
I was like, okay, well, what's got those one problem solved? But, you know, you know, I thought the whole thing felt so real.
It was like a one line email pretty much, and then we didn't actually have a contract.
So still it's gone back to going back to all our partners and saying, Well, look,
we've got this promise of the money, but we still can't give you a contract or the actual money.
But believe us, so everything run on trust.
And by that point, civil servants, you know, would have already been some scandal about PPE contracts.
The government was worried about due process in the contracts and so on.
Things took a little bit of time to finally sort out, but by that point,
the negotiation with AstraZeneca was on and prior to that Mark was just like a lot going on and it was a whole nother parallel track of,
you know, something that £65 million was to fund manufacturing at 200 litre scale for the UK primarily and.
I done some months, so I've got a spreadsheet for the 3rd of March, I think.
Got something on Lauren's calls. I didn't show it to anyone at the time.
It was too, you know, felt too preposterous. A lot of people think, oh,
was that's called that is a spreadsheet called billion those scale essentially doing the as well how would
we do this if we wanted to make a billion doses and it was apparent we couldn't do that on 200 metres scale.
I couldn't do it in the UK. And so how many doses? There's 200 litres.
When you say do you want a little scale, that's just the size of the best. Yeah, that's right.
Yes, right. Yeah. That's an important that's an important question.
So 200 litres originally our original calculations were that would make a million doses and that turned out we didn't,
we weren't able to get quite that much, but a few hundred thousand doses.
Yeah, that's right. So, yeah, there was this one was one truck of work that was technically doing as a too early to scale a pole.
It was another track of work, which was, well, how do we, you know, essentially the business side of it and and the business side of UK supply,
you know, how do we make it, you know, come to a deal that will allow it to be actually made for real for UK supply.
And there was another truck which was well actually covered bigger and can we do something that was globally relevant because like,
you know, I remember so how many of us, 65 is all there in India and there's quite a lot, you know, and.
You know, it looked like. What might be needed would be billions of doses.
But that was just not the, you know, the idea, you know,
and thinking of making a billion doses before any patient had been injected with a product in a trial.
So I'd have been laughed out of town, but. And there was another, you know, another strand of work on how to do that.
And essentially, as soon as the 65 million for the UK was agreed, as soon as the 200 leads a scale plan was agreed,
we'd already have begun staff who had begun talking about well, well we privately called stream two for the UK.
I say we I mean me and Ian McCubbin on the contract manufacturers which was thousand leads a scale within the economy
various people were on the record a lot of points in the UK couldn't manufacture vaccines in the relevant scale.
There was no weather at 1008 to scale for this sort of product in the UK.
But we figured either physically you could fit the thousand Lisa scale thing, you know, equipment in talks for biomedical clean rooms.
And we figured out the equipment actually didn't cost costs of some million.
But, you know, in the scheme of things, it was not done.
At the same time that we were asking for the 200 litres, you know,
we already knew that really what we wanted was 2000 litres, but we didn't think we could make the ask quite.
Yeah. So how did I feel when we got the 65 million?
Great. But it was just so much a little stuff to do. I think perhaps we better stop because you've got something else to stop.
Because you've.