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So at what point did you recognise that you were going to need to get a fairly large pharmaceutical company on board too,

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to get the scale up to the scale that it would need to be to provide enough doses to essentially the world?

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Good question. I personally.

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I think we were all figuring out how to do this and just how far the university was would be able to proceed itself.

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And many people would have said that a university couldn't do a pivotal Phase three trial very rapidly and efficiently on its own.

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And it proved that we could in the end and virtually everybody would have said it

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wouldn't be possible to do large scale manufacturing for the university or a,

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you know, a small single purpose spin out from the university, which was something that at least some of us considered.

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It's not it's not just the manufacturing is it's it's you've got regulation to deal with.

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You've got distribution. You've got it's more than just making it.

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Yeah, absolutely. But the the a lot of functions in the global pharma industry are outsourced.

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You know, there are there are consultancies, the regulatory affairs manufacturing is often outsourced to contract manufacturers.

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And indeed, that's what has happened. Most of the manufacturing is not.

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None of the manufacturing virtually has actually been done in AstraZeneca facilities.

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And so one one possibility that some of us entertained, as I said, was the idea of a single post,

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single purpose university spin out company, obviously, with very heavy government backing.

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And I think for some of us who were, you know, interested in global health thought I'd had some attraction.

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And also we there was the question of we were working, we had a memorandum of understanding or something,

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you know, a preliminary agreement with the Serum Institute of India from March 2020.

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And so I think there was a there was a question in my mind,

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and I don't think I was the only one as to whether this could be done without a large, you know, Western pharmaceutical company.

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Paul I think in retrospect, the answer is no, it couldn't have been done.

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So I think the decision to partner was, was right on the, you know, the drive towards the.

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Large part of that came from John Bell. And what the AEC as a partner brought in.

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And that in the end really was the. Massive bandwidth needed to do the coordination of multiple regulatory submissions globally very,

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very quickly, and also to coordinate the very large number of manufacturing sites.

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I don't think anything other than a multinational Western pharma company could have

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managed that and indeed I think it was quite challenging even for AstraZeneca.

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You know, they're not the biggest of the multinational pharma companies and they have only one licensed vaccine product.

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They did a great job. They continue to be through the steps of how how they got to that point.

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Yeah. So March 2020, I don't think there really was a plan.

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You know, we had Adrian had the Hill and set up this memorandum of understanding with the services of India.

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But Top Brass University wasn't really yet engaged in thinking this was, you know, a real Goa that needed a partner rapidly.

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April That changed. And clearly the decision had been taken by John Bell,

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and it was working closely with the Vice Chancellor and, and Gavin Scruton and Oxford University Innovation.

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And a decision had been taken that we did need a large pharma partner.

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And it's in the public domain that I spoke initially with Merck.

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And that came very close to an agreement.

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I mean, one of the. The university had a major priority for the university, and the negotiations was.

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Equitable access.

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Very early on, a public pledge had been made that none of the universities innovations would be licensed exclusive, licensed exclusively.

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And it wasn't possible for university to find a partner that was willing to accept a non-exclusive license for the vaccine.

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And so if we were going to be locked into one partner,

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it was clearly absolutely critical that they were going to do a good job in terms of rapid and efficient submission of,

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you know, regulatory filings and and pulling the clinical data together to, you know,

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actually get the vaccine licensed and alongside the manufacturer related data.

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It was important that they share the university vision on pricing, and there was some discussion about exactly what that should be.

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But the really low pricing was a was a very high priority.

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And then there was a question about the degree of commitment and ambition to large volume manufacturing,

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and in particular manufacturing with a view of supplying low and middle income countries LMI sees.

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And. Mm hmm.

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One of the stumbling blocks with with Merck, really,

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was that they did not appear willing to commit to a manufacturing plan of the scale and ambition that we had in mind.

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And they didn't know, from what I remember, appear enthusiastic about, you know, working with the Serum Institute of India, you know,

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to whom we'd already begun transferring the know how on how to make the vaccine and who were the,

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you know, the world's biggest vaccine manufacturer by volume. So.

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A discussion then started with AstraZeneca and.

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Again, the you know, it had to be global exclusive.

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They would only entertain the idea of a global exclusive license.

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One of the reasons being concern about is possible variability of quality of the

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product if it was made in different places and not under a centralised control.

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But I don't know. I think there was a genuine difference fortitude from A-Z as compared to me,

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but I suspect there was also some increase in understanding on the university

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side of what we what our priorities should be and what we needed to negotiate.

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And by the time of discussions with AstraZeneca, what I was I was not in the room for the discussions,

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but at least I was having discussions with John Bell and Gavin about, you know,

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what, what might be important to negotiate for with respect to manufacturing and.

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And also the fact that commitments on volume of manufacturing at risk ahead of a clinical trial result were potentially,

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you know, the most important thing in terms of active access rather than the price.

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You know, the price doesn't matter if there isn't any vaccine to distribute.

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And ah, I remember that.

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You know, trying to make the case that actually the. You know, this vaccine's major contribution was probably going to be about speed.

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You know, it may not turn out to be the very best vaccine in the long run.

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It would be a bit surprising if it did.

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You know, if everyone if the rest of the world kept on investing and researching and nobody came up with anything better.

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But. It's we were in a position to be ready first or very close to first early on.

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And so not commitment to manufacture very large volumes of the vaccine at financial risk ahead of clinical trial results was really important.

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And so was the willingness to, you know, work with partners that.

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They had the capability to do that and be out of business model,

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which was about supplying Alamo CS and really not mean Serum Institute of India and also that I'd started work with

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which she biologics and in China which had very large volume capability and more more contract manufacturing you know,

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more capacity to bring volume of bioreactors on line.

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But either we she or serum learn either Merck or AstraZeneca had in-house.

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So willingness to partner was really important and things move very rapidly in the AstraZeneca negotiation.

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It was, but I think badly more than a week between initial contact and the being, you know,

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heads of terms which was essentially saying we are going to partner, but who's going to be?

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And that was about April the 30th was had two terms, I think.

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And then there was a two week formal negotiation period which went out the 15th of May.

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But really it was practically a done deal by the time of the heads of terms and so so in in the week between preceding that,

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things move very rapidly and we couldn't get a Z to commit firmly in the period that they would be willing to work with the Serum Institute of India,

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which was fair because, you know, they had no experience of working with them.

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They had no idea, you know, what their quality of operations manufacturing were, were like, whether they could do business with them.

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But we did. The university did manage to get wording in the agreements about making very best efforts to supply analyses and to work with partners,

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including the services of India, to do so.

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But I think the deal we had with ICI had it in.

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It sort of crystallised what by that point was it?

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It was clear in our minds that that partnership was important.

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That ended up represented on paper. It ended up clear to AstraZeneca the.

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Those of us leading the program in the university that was very important to us and for us to be happy and willing to to,

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you know, get you know, can I need you to.

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Exactly, exactly. Exactly. Yeah.

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And I think also, genuinely, AstraZeneca did the senior leadership in AstraZeneca genuinely did have a vision,

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a positive, you know, remarkable willingness to share the vision of a vaccine for the world.

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I think they genuinely did have time. And I I'm not sure that we saw a lot.

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Ethos from from Cohanim. Anyone else?

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So I think the spirit with which they approached it was very positive from the beginning.

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And so we had this idea of terms in place of around about the 30th of April, and things then proceeded very rapidly.

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I think really in in parallel with the negotiations to finalise the deal.

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You know, we were already getting into fairly detailed technical discussions with the AC manufacturing team about what they would need to do.

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And you were still working in parallel with Paul and Paul?

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Yeah. And Oxford Medical and the other companies that you've been talking to that was just in relation to the clinical trial, was it?

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No, no, no, no. So so what happened to Paul was the first proof of concept of manufacturing at a, you know, commercially viable scale.

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Okay. 200 litres. And but that didn't actually get used.

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That wasn't going to get used, right? No. But it was proving that the process could work.

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Yeah. It was the process that was designed for large scale, you know, non clinical trial supply,

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but just executed outside of a clean room, you know, in an experimental lab.

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Yeah. And Cobra Biologics.

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And Alex. And Alex. The Biomedical Biomedica with the promise of the UK government funding,

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which was I don't know to what extent that was tied in because obviously we all were aware of what was going on in the negotiations with Merck and AC.

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But the impression I had was certainly that the funding would have come anyway.

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You know, the fact that actually the task force wanted us to get on with the manufacturing, whoever we were going to partner with.

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So all of that worked as set up for commercial scale manufacturing to supply the UK.

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And similarly the the technology transfer to Russia and China and Serum Institute of India for commercial scale manufacturing.

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That was all happening in parallel with the negotiations and you know, well advanced before AstraZeneca joined us.

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Something quite important.

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Was that we had actually shipped the cells used to make the manufacture to the Serum Institute of India.

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Surely before the agreement with AstraZeneca.

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And that was because growing those cells and making a frozen bank of them with which future batches of vaccine could be made.

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We expected that to be the the rate limiting thing, the slowest step in making the vaccine at large scale.

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So you just needed to start regardless of who, you know, we may or may not end up partnered with, but we'd shipped them before we partnered with AEC.

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So they already happened.

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And we'd also shipped them for, you know, experimental process development work, some research grade virus, not clinical grade virus.

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But is actually that the same thing really that it would be possible to make

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clinical grade virus from the research grade virus if you knew what you were doing.

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And so Serum Institute, you know, had possession of the materials that they needed to proceed.

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Independent of AstraZeneca trying to claim, no, we didn't think they would.

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Although it would be technically possible to make clinical grade virus from research grade virus,

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we didn't think that that was something they were too likely to do.

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And the material transfer agreement that we had with them didn't.

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I think I think that made them from doing that. But.

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There was. A certain amount of momentum and also sort of established facts on the ground and possession being nonsense.

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The law type thing about the circumstances of India, you know, were going to be involved and we very strongly wanted them to be involved.

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And so. Easy.

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You know, I guess it became a priority for easy to negotiate the relationship with,

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you know, high level between Pascal Soriot to the ICC and Adar Poonawalla.

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The serum has changed the you know, it became important for them to negotiate a new arrangement in a way that I suspect it would not.

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That would not have been a priority for any major Western pharma company, possibly including Asia,

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if you know, the facts on the ground had not been established in quite that way.

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So the way the deal was negotiated with was when I a the the amount of preparation we'd done with the Serum Institute and the university research.

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His attitude towards the importance of working with Simmons to.

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A letter, essentially Tracy partnering with Sarah and granting them a sublicense for so easily and sublicense to Sarah.

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The rights to supply the vaccine across a large number of low and middle income countries India.

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But. But also for coming.

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So I think that that in the end, the fact that we ended up with Sarah on board proved to be hugely important.

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They manufactured more than half of the global supply themselves.

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You know, they manufactured more themselves than all these other manufacturing partners put together through 2021.

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Most of most of what they made stayed in India, which was a, you know, problematic for supply to Africa.

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But on the other hand, it was pretty much the only supply that India had.

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So it was very important for India. So I think that the series of events that led to the partnership with Serum Institute,

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trans universities partnership with Simmons transferring into an ABC University serum triangle was really hugely important.

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So once the agreement was was was signed, was in existence, did you then begin to have direct contacts with Haiti?

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Oh, yeah. So I mean, the the first there was one there was one call, which was the university research leaders.

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So I think myself, Adrian and Sarah.

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Don't think South Korean was on. I'm not sure about ties with Pascal Soriot.

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Many Pangloss and their senior manufacturing people as well.

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Senior clinical people. You know, so there was a there was a face to face.

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You know, before anything was signed, before that terms, you know, by the 23rd of April.

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And then after the two terms were signed, that became increasingly technical and detailed.

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And we were.

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We didn't actually transfer any physical cells or all the vaccine virus to Asia until after the law firm deal was signed, which was the 15th of May.

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But we I think we had been talking with them a lot about what they would need to

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do and how how the manufacturing process worked and what our vision was for.

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You know, the five that we have set up, this pattern of franchising,

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essentially the manufacturing to the different contract manufacturing sites and and partners.

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And, you know, it was I think it was apparent to everyone that really that was why they would need to continue to do it,

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because they didn't have the in-house capacity to do that.

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So you'd actually saved them quite a bit of time by doing all that ahead of time.

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Oh, those partnerships. Oh, and all. Yeah. Yeah.

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I mean, I.

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I. I mean, I don't think there would have been a way of getting that time back if we hadn't done it.

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I don't really know whether a large pharma company would have.

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I can't really see how a large pharma company could have signed on to the vision of.

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Global scale, manufacturing and financial risk.

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If there haven't been proof of concept that the vaccine could be made at commercial scale, which was what we'd provided Paul in March and April.

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So we might have got a partner, but I think it would have been a partner with a view to, okay, we'll keep going.

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Going on the clinical trials will develop a manufacturing process,

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a normal commercial pace, you know, perhaps slightly accelerated because of the pandemic.

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But I don't really we we were starting from the point it is possible to make this vaccine.

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It is possible to transfer the manufacturing to lots of different places.

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Let's transfer it to as many places as possible.

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And I think that was very, very different from how well radio is, different from how any vaccine manufacturer had ever worked.

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I think at that stage when we were still in phase one clinical trial in mid-May.

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So, yes, I think we should say some time, but also I think the the model that we had developed,

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the proof of concept we provided and the model we had developed.

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And just the idea that, you know, we would try and commit to making billions of doses before there was a clinical trial results.

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I think that probably contributed a bit more than just saving time.

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I think it actually shaped Daisy's level of ambition.

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So yeah, after the firm deal was signed on the 15th of my, you know, things became concrete, you know, we started shipping things to to the, you know,

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everything they would need to actually do, um, both sort of manufacturing, you know,

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continuing the manufacturing process development and optimisation in their labs and also actually.

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Making more cells, making more virus with which to to seed manufacturing is at the contract manufacturing sites.

202
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What's their scope for much improvement to that stage? Do you think you can make that the big leap with Kareena's work?

203
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Yeah. So there were two significant things that were changed.

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One of them. Related to the way in which the virus was grown in the cells.

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This is a bit technical but basically hazy.

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Were concerned about how much seed virus they would need to make.

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As an input to the manufacturing.

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And so they change the manufacturing process from one which used a single viral lifecycle and needed quite a lot of input seed virus,

209
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which was on our original two one which used to viral lifecycle and used much less in, let's say, virus.

210
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Personally, I'm not. I remain unsure whether that was.

211
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I hope for all, whether it actually created problems downstream.

212
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I think that make making enough seed virus would have been a real challenge.

213
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But personally, I think it may have been possible.

214
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But anyway, that that change was made and then and driven by as a the other was something that we had started working on in,

215
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in April here ahead of the A-Z partnership which was.

216
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Trying to simplify the purification process. So what would you do in that proof of concept?

217
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Run it to hundred litres. Gallup poll was really just linearly scale scaled up.

218
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It was a, you know, just a bigger copy of what we had done, a very small scale in the lab and some of the components, some of the filters.

219
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Were bigger than they needed to be. I knew.

220
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Oh. And bigger than would be practical to use, as you know, repeatedly a very large scale bigger.

221
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You know, they were too big to allow it to scale another ten times from 200 litres to 2000 litres.

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And so we you know, we were conscious of this, you know, the whole the Hollyoaks and Oxford,

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Biomedica and Cobra and Paul and everyone was in agreement that this would be challenging with a

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particular problem as well as the first tangential flow filtration or one step and to the purification.

225
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And so we'd started it, you know, tiny scale, you know, ten tens of millilitres,

226
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seeing whether we could eliminate that by basically skipping it and instead of doing that filtration stuff.

227
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Moving straight on to the next step in the process.

228
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And it wasn't very good bedtime football with a lot of good work, but at small scale it did seem to work and.

229
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I think we've got lots a couple of litres Gayle working in my lap and everyone agreed that it had to be done.

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That was the only real option for a 2000 metre scale.

231
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So sort of that changed. And what came out of it, the vaccine that came out of it was the, you know, entirely acceptable purity and and quality.

232
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Removing the stuff, the filtration stuff didn't didn't seem to be a problem.

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It just made things simpler. So, yeah,

234
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everyone was sort of moving us one towards thinking that thought a simplified purification process would want to be done for the commercial scale.

235
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So those were the two technical changes that were made, the two lifecycle processes less see and a simplification of the purification process.

236
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But the the backbone of the process remained the same, you know, same same cells,

237
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same medium, same purification process with with the exception of the removal of hot last.

238
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So didn't change all that much. And and really actually it was remarkable how.

239
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You know how how effectively it did scale of you know, there weren't huge surprises or problems long along the way.

240
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So did AstraZeneca actually stop making. Lots of doses while the clinical trial was still underway?

241
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Or did it just set itself up so that it could?

242
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The setting up is much more difficult than the the preparation is is the time consuming part, both in terms of developing the method.

243
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In characterising the method in depth. You know, we, we, we gave them the method with the exception of the to life cycle growth of the virus.

244
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But to use it commercially, you have to do a whole lot of experimental work, you know, in depth characterisation, you know, exactly.

245
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You know, if I tweak this, what happens, you know, really in-depth understanding the, you know,

246
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it was beyond what we could do ourselves and so needed that you need to prepare a huge amount of documentation.

247
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You need to prepare plans for testing, and you need to procure all the equipment.

248
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You need to procure all the materials. So they.

249
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So for much of the period of, you know, sort of May through to about October, what they were doing was that preparation.

250
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But just doing the preparation was very committing the whole bit.

251
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Yeah. So the fact that they weren't actually churning out huge amounts of vaccine in that period doesn't reflect them not having been committed.

252
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Um, the, um, and what was happening was that the, the manufacturing sites that we had gone a bit further along with the,

253
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you know, were the, we had started before A-Z and you know, it had a head start on getting the equipment and, and so on.

254
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They actually were making vaccine.

255
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So Cobra biologics and stuff which they did a first run, a 200 litre scale using exactly the methods the poll had used.

256
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So without without the tweaks that we introduced to allow it to get to 2000 leagues a scale.

257
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And that batch was made in June, July.

258
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So that was incredibly quick to have gone from, you know, our lab in February poll in March,

259
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April to actual GMP production and to release the scale in June, July.

260
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And you know, a lot of people's.

261
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I think most people in the industry would have thought that that was unrealistically fast, but they did it a very good job and they used,

262
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you know, in order to do that, we'd had to prepare a bunch of cells so it could burn a bank virus, seed oil, which was done in the Netherlands.

263
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So there was a lot and all the documentation, materials, equipment, and so a lot came together in that first batch from COBRA.

264
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We were very nervous. Everyone was very nervous about whether it would work or was it.

265
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It was largely, largely a repeat of what had been done, a poll and how it worked.

266
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But we'd made some tweaks, you know. To essentially try and, you know, some learning from what happened to Paul.

267
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So it was the first time had been run in exactly that way and.

268
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To cut a long story short that that first batch from Cobra through three June and July,

269
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we would run out of vaccine basically late June and July would run out of vaccine for clinical trials.

270
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We'd used up all the vaccine had been made in clinical biomanufacturing facilities

271
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and we'd used up all the vaccine from the box that came from from Italy,

272
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from our funds. They'd all gone into giving people the first doses in a clinical trial.

273
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We didn't have enough to boost people. And so that first bunch from from Cobra using what was a, you know,

274
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a precursor to the commercial scale process that ended up being used to boost people in clinical trials.

275
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So a lot of things are happening in parallel. And and the fact that the fact that we had run out of vaccine, you know,

276
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originally the clinical trial was was designed, you know, the original plan was for it to be a single dose vaccine.

277
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And a handful of people were given two doses and then immune responses after the second dose looked better.

278
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But. We'd prioritise.

279
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You know, we've given as many people as possible the first dose.

280
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And you know, because we would be thinking, well, if there's a wave of infection in the summer,

281
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then, you know, maybe we'll get a clinical trial result from that.

282
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But we hadn't that we'd ended up with no vaccine to boost people in clinical trials.

283
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And so the you know,

284
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the plan had been a for we you know went well what we what we thought was going

285
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to be the way of using two doses was to have a four week gap between them.

286
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But by the time that batch from COBRA became available,

287
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a lot of the people who'd had their first dose early on in the clinical trial should have been much more than four weeks.

288
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Some of them had out it later. It was less then, you know, it was about four weeks.

289
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And so what we ended up with was this very unusual variation in the in the dosing interval between the first and second doses in a clinical trial.

290
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That was that was entirely because the original design had been to do a single dose trial.

291
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And then one of the deaths of both the given two doses, the, you know, the vaccine wasn't available.

292
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So getting that and getting that batch from from COBRA.

293
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I'm unlocked, you know, essentially doing a two dose clinical trial, which meant getting ethics and other kinds of approval, presumably.

294
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Oh, yeah. I mean, the trial had the chance to be amended in order to give everyone the second doses.

295
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And the second shot is the the.

296
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But no, it doesn't seem to be possible to turn it off.

297
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I don't remember. I'm sorry. Yeah.

298
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So the trial had the protocol not to be amended to give everyone a second dose.

299
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We had to give the order by this point.

300
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It was a they had to prepare the documentation about the manufacturing process that had been done at COBRA in order to supply that to the regulators,

301
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in order to use that material in the trials. We it was very, very, very close.

302
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We we didn't get as much from the first batch of Cobra as we'd hoped.

303
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And it was, it was very, very close to being too diluted to use.

304
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We, you know, it was. I mean, at one point it looked like we weren't going to be able to use us, which would have been an absolute disaster.

305
00:41:17,960 --> 00:41:21,010
Um, I would have.

306
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Yeah, I'd have felt pretty terrible, but, you know, it would have been really a failure of hope,

307
00:41:27,730 --> 00:41:32,140
you know, that that was the most important job from what my team had been doing up to that point.

308
00:41:36,320 --> 00:41:42,320
So that was pretty nerve wracking. And also that batch, I think Glenn ended up supplying the US phase three.

309
00:41:42,660 --> 00:41:48,410
I think the US phase three trial was done entirely and material from that first batch from COBRA.

310
00:41:52,700 --> 00:42:04,210
Yeah. So you, you, you were asking whether AC were just preparing to, to manufacture vaccine or whether they were actually doing it.

311
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And I was saying so in short, the preparation was a major investment and a major commitment,

312
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and that had to be started and took a certain amount of time before large scale manufacturing could happen.

313
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But also, COBRA had starts manufacturing in 200 to scale ahead of everyone else.

314
00:42:24,410 --> 00:42:34,340
Alex also and Serum also had done runs a large scale as well during summer 2020.

315
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So that was the beginning of large scale manufacturing.

316
00:42:38,960 --> 00:42:46,760
I can I think I think I don't know when serum did that first.

317
00:42:46,880 --> 00:42:53,940
I can't remember when Serum did that first. Ultimately, they ended up operating at 4000 leaves a scale.

318
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I can't remember when they did their first run in large scale.

319
00:42:57,260 --> 00:43:09,680
You know, the final commercial scale, I don't think I don't think a GMP clinical grade on a thousand litre scale at Oxford,

320
00:43:09,680 --> 00:43:19,940
Biomedica happened until about October. There's just a little this is just dotting and I'm crossing a T, but there's a step called fit and finish.

321
00:43:21,250 --> 00:43:25,030
Is that something you were concerned with at all with other people? Yeah.

322
00:43:25,070 --> 00:43:30,940
And we knew it was a concern because it just means putting the thing in a vial and labelling it.

323
00:43:30,940 --> 00:43:37,569
Is that right? Yeah. Yeah. Which on the surface seems relatively simple,

324
00:43:37,570 --> 00:43:45,520
but is clearly a heavily regulated process to make sure there's no contamination introduced at that stage,

325
00:43:45,520 --> 00:43:48,610
to make sure it doesn't damage the vaccine during that process.

326
00:43:49,420 --> 00:43:57,360
And there's quite a finite number of facilities and capacity for doing that and so on.

327
00:43:57,470 --> 00:44:07,050
I remember back in March 2020 when I was on in these sort of initial discussions with Chuck from the World Bank saying,

328
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you know, everyone's going to be wanting the fill and finish capacity.

329
00:44:10,930 --> 00:44:19,690
And for that was one of the brilliant things of our service sheet of India was that they had the massive capacity and it

330
00:44:19,690 --> 00:44:28,929
was on site and they were able to very efficiently move from manufacturing the bulk vaccine to putting it into vials.

331
00:44:28,930 --> 00:44:32,499
And, you know, they make more doses of vaccine than anyone else in the world.

332
00:44:32,500 --> 00:44:39,880
They had the biggest filling lines in the UK.

333
00:44:40,660 --> 00:44:50,990
It was we had started working with a German company called IGT in March 2020 and they were going to be all fill finish partners.

334
00:44:51,010 --> 00:44:56,169
So, you know, that was it was part of the plan from actually from February.

335
00:44:56,170 --> 00:45:02,470
I think when my very early discussions with John Humphrys of V-neck, we, we were trying to find places to do, fill and finish.

336
00:45:03,700 --> 00:45:12,100
I'll admit I didn't see it as being I saw it as being a capacity challenge, but not a not a huge technical challenge.

337
00:45:13,000 --> 00:45:16,239
So it was scientifically it wasn't really where my focus was on.

338
00:45:16,240 --> 00:45:21,040
But we we the was work going on to make sure that the you know,

339
00:45:21,550 --> 00:45:31,870
to make sure we could do it initially led by John Humphrys and then that was something that the to be

340
00:45:32,080 --> 00:45:39,280
a vaccine manufacturing task force led by Ian McCubbin one of their work groups was was felt finish

341
00:45:39,910 --> 00:45:50,110
so that we gratefully on the part off to them really in April and they secured for UK supply they

342
00:45:50,110 --> 00:45:57,920
basically I think they read I think their reef first refitted and then bought out a filling line,

343
00:45:58,350 --> 00:46:01,600
a company called Walk Hard in Wrexham.

344
00:46:01,690 --> 00:46:07,600
How do you spell that? w0ckhardt Thank you.

345
00:46:10,360 --> 00:46:17,950
So that's where some of the majority of the UK's supply of this vaccine was was filled and finished.

346
00:46:17,950 --> 00:46:22,750
In the end was why Boris Johnson won for his photo opportunities and so on.

347
00:46:27,310 --> 00:46:33,700
Yeah. So the next landmark is the landmark the for the outcome of the.

348
00:46:34,300 --> 00:46:38,790
Phase three trial. The next thing that you were waiting for?

349
00:46:40,170 --> 00:46:44,880
Oh, I think I think that I think that probably was the next the next landmark.

350
00:46:45,840 --> 00:46:50,940
So I think by the time the that result came along, which was.

351
00:46:52,950 --> 00:46:59,340
I think very early December on Pfizer Moderna's results had been mid-November and also a couple of weeks after.

352
00:47:02,340 --> 00:47:17,010
By that time, large scale manufacturing was actually on way uneasy, you know, underway at Oxford, Biomedica and Halix for the for the UK and A-Z.

353
00:47:17,010 --> 00:47:25,110
By that point a have this network of. A dozen or so manufacturing sites globally.

354
00:47:25,320 --> 00:47:29,760
I'm not sure exactly how many of them were actually up and running and manufacturing at that point.

355
00:47:29,760 --> 00:47:33,300
But in order to have vaccine released.

356
00:47:35,200 --> 00:47:45,010
In, you know, around the time the turn of the year is actually is it's nearly 100 day process from

357
00:47:45,130 --> 00:47:50,620
the first in the forms to make a batch of the vaccine which is thawing the cells.

358
00:47:51,520 --> 00:47:56,530
You doesn't need to spend basically a month growing the cells to have enough cells.

359
00:47:57,700 --> 00:48:07,749
It takes about a a week to from adding the seed virus to grow the vaccine virus and then to purify it.

360
00:48:07,750 --> 00:48:11,530
That's only about a week. But then there's another.

361
00:48:14,490 --> 00:48:20,880
It takes, you know, 30, 40 or 50 days from there to get the product into vials,

362
00:48:21,960 --> 00:48:27,390
especially if that's happening at a different site from where the bulk vaccine is being made,

363
00:48:27,390 --> 00:48:31,740
which was the case for most of the manufacturer with the exception of the same industry to India.

364
00:48:33,510 --> 00:48:38,190
It takes about another 50 days to get it put into vials and then to get it tested.

365
00:48:38,340 --> 00:48:42,390
You need all the test results before the vaccine can be released to be given to people.

366
00:48:43,200 --> 00:48:47,969
And that includes testing that was done by the manufacturer,

367
00:48:47,970 --> 00:49:04,100
also includes the testing was done by a national centralised laboratory in the in the it was called Aqaba OCA.

368
00:49:04,110 --> 00:49:10,230
B.R., I can't remember exactly what that stands for, but the.

369
00:49:12,660 --> 00:49:17,910
So there's this long process of testing even after the vaccine is in the vials.

370
00:49:18,870 --> 00:49:23,680
So. The.

371
00:49:24,570 --> 00:49:33,750
The first batches of vaccine that actually went into people had started being made quite a bit of time before, you know, physically being made.

372
00:49:33,750 --> 00:49:38,520
And they got quite a bit of time before the clinical trial result came.

373
00:49:39,390 --> 00:49:45,630
It was reasonably possible to predict when the clinical trial was going to report yes or no,

374
00:49:45,930 --> 00:49:55,170
because the timing of reporting of the clinical trial was dependent upon how many cases of, of course, COVID came along.

375
00:49:55,830 --> 00:50:02,670
And so you could forecast forward, but it was dependent upon what was happening with a wave of COVID.

376
00:50:02,730 --> 00:50:04,980
Yes. You know, so for a long time,

377
00:50:04,980 --> 00:50:12,510
there were very few cases in the clinical trial being more complicated because there were people vaccinated in Brazil and South Africa.

378
00:50:12,510 --> 00:50:19,290
So it was it was a it was a function of how much COVID there was in Brazil and South Africa and the UK.

379
00:50:19,980 --> 00:50:22,860
But for a long time with a lot of people vaccinated and not much happening.

380
00:50:24,450 --> 00:50:33,240
And then suddenly there was a wave of infection in the in the autumn of 2020 and things happened very quickly.

381
00:50:35,100 --> 00:50:41,669
So, you know, I didn't have sort of access to the trial database.

382
00:50:41,670 --> 00:50:44,760
I didn't think it was a it was a very closely guarded secret.

383
00:50:44,760 --> 00:50:59,520
How many cases there were. In fact, I'm not sure, even though I think it might have just been the trial statistician Narain who knew that it was.

384
00:51:00,120 --> 00:51:11,190
Yeah, I think we. But by late November, early December, those of us who didn't have access to that data,

385
00:51:11,700 --> 00:51:15,500
I think we were able to figure out that it must be pretty soon that there would be resolved.

386
00:51:16,140 --> 00:51:19,920
And I think we yeah, if you take a step back,

387
00:51:19,920 --> 00:51:28,530
I think we would most people would have expected from from October also most people would have expected a result before the end of the year.

388
00:51:31,110 --> 00:51:44,260
So everything was being lined up to get the regulatory submissions done and so on for for that,

389
00:51:44,280 --> 00:51:47,680
for it to be possible to release vaccine for around the end of the year.

390
00:51:49,410 --> 00:51:57,930
You know, and it all did come together, you know, almost to the day, really.

391
00:51:58,770 --> 00:52:13,500
The regulatory approval and the release of the first batch of vaccine has been fit for use in the week between Christmas and New Year.

392
00:52:16,780 --> 00:52:21,009
And how did your responsibilities change after that?

393
00:52:21,010 --> 00:52:25,030
And then eventually handed off the manufacturing to AC.

394
00:52:25,840 --> 00:52:31,120
And yeah, the trial was over. So did you have a break?

395
00:52:36,570 --> 00:52:43,170
So I had really largely handed off my responsibilities by the time the first part came from Cobra.

396
00:52:43,680 --> 00:52:53,430
You know, I think it was the end of July or early August that we finally confirmed that I was going to be okay,

397
00:52:53,430 --> 00:52:59,160
two years and my father died on the 23rd of August.

398
00:53:00,730 --> 00:53:06,630
So, um. It was like stepping in.

399
00:53:06,870 --> 00:53:14,880
I think I think I spent quite a bit of time in Scotland with my, with my mother around then.

400
00:53:18,780 --> 00:53:30,930
And yeah, I had less or less responsibility for the manufacturer from from that point, but remained in very close contact with Daisy.

401
00:53:31,440 --> 00:53:37,049
And the main, main thing are things I did on my on the manufacturing.

402
00:53:37,050 --> 00:53:43,830
From there, I guess were like a bit of a nuisance of myself in terms of telling them to.

403
00:53:46,360 --> 00:53:57,680
How about ambition in terms of how much that make? Although really the pattern of law had been set in 19 2020.

404
00:53:59,110 --> 00:54:06,670
And we also started working on, you know, basically improving the manufacturing process so that it could make more.

405
00:54:08,740 --> 00:54:12,250
And in your lab. In my life. Yeah. Yeah.

406
00:54:13,810 --> 00:54:23,560
Um, and we do, you know, we were able to improve it very significantly, but unfortunately,

407
00:54:24,100 --> 00:54:28,690
it's very, very hard to change the manufacturing process once it's got regulatory approval.

408
00:54:30,640 --> 00:54:41,140
And I see and in the end, never, um, but they basically stuck to the original, the original process.

409
00:54:42,120 --> 00:54:47,560
Um, I think if we'd had another, you know.

410
00:54:48,850 --> 00:54:52,390
Six months or so before things had gone life.

411
00:54:53,530 --> 00:54:59,760
We, you know, might have been able to make vaccine more than twice as efficiently.

412
00:54:59,800 --> 00:55:04,870
But it did require it was significant changes to the to the process to do the.

413
00:55:06,700 --> 00:55:11,980
But all the way along, you've had this tension between trying to do things well and trying to do things quickly.

414
00:55:14,500 --> 00:55:20,110
It sounds to me, from what you've said so far, that your priority was always, did you do things well enough but do it quickly?

415
00:55:21,040 --> 00:55:27,149
Yeah. I mean, I guess the. I guess.

416
00:55:27,150 --> 00:55:40,830
Well well, as a I think it's important to stress that, you know, at no point did we compromise on the quality of the product, but we did, you know,

417
00:55:40,950 --> 00:55:45,629
have to take decisions about whether to, you know,

418
00:55:45,630 --> 00:55:50,880
it clearly would not have been the right thing to do to invest six months in fine tuning the process,

419
00:55:50,880 --> 00:55:56,970
to get as much financing out of it as possible or or indeed to say, well,

420
00:55:57,210 --> 00:56:05,280
we're not going to set up the process in the original way because we think this new way of doing it,

421
00:56:05,280 --> 00:56:12,960
which in the end required, you know, some different equipment and so on, might prove to be better, but it might not.

422
00:56:14,250 --> 00:56:18,870
You know, the decision just had to be taken to to to get on go ahead.

423
00:56:20,280 --> 00:56:30,750
And, you know, we were. Reasonably clear from the mouth so that you know the yield of the original process.

424
00:56:32,040 --> 00:56:35,460
That it could make a lot of vaccine.

425
00:56:42,640 --> 00:56:46,120
And I you know, if you have a process which is commercially viable.

426
00:56:49,220 --> 00:56:56,000
You know, in the sense that it is capable of making enough vaccine, that, you know, the vaccine doesn't cost £200 a dose or something,

427
00:56:56,900 --> 00:57:05,389
then actually, even if it's not a perfect process, you know, even if you are arguably improving the yield of it doesn't matter that much.

428
00:57:05,390 --> 00:57:10,070
You just book more manufacturing facilities and. But.

429
00:57:12,820 --> 00:57:18,459
The counterargument to that, of course, is that in reality there is a finite number of individual facilities,

430
00:57:18,460 --> 00:57:20,920
and there's also a finite supply of raw materials.

431
00:57:23,090 --> 00:57:29,510
So for a period of time, the outpost was constrained by availability, you know, global supply of raw materials.

432
00:57:32,930 --> 00:57:42,230
But yeah, there's no question that the decision had to be taken to proceed with, you know, a version of one process very, very, very rapidly.

433
00:57:47,390 --> 00:57:58,370
I think just sort of thinking a little bit more widely about what was going on around that time in early 2021,

434
00:57:58,370 --> 00:58:01,550
when large scale supply of vaccine started.

435
00:58:04,510 --> 00:58:13,450
Those facilities that, you know, we'd started working with very early, especially Oxford Biomedica were able to.

436
00:58:15,520 --> 00:58:26,630
Begin to produce the vaccine quite efficiently. Some of the facilities that AstraZeneca had set up subsequently were not quite on the same stage.

437
00:58:28,340 --> 00:58:40,280
Everyone was still on a learning curve in terms of, you know, how do we make this run as smoothly as as possible.

438
00:58:41,660 --> 00:58:44,900
And so the the rate of output.

439
00:58:46,610 --> 00:58:52,069
Both in terms of the sort of total global input and output from each of the individual

440
00:58:52,070 --> 00:59:04,910
facilities was not maximal at the beginning and also for the output from Oxford,

441
00:59:04,910 --> 00:59:08,120
Biomedica and Horlicks and Cobra.

442
00:59:09,990 --> 00:59:16,400
Was, you know, it had been sold to the UK government as part of the original £65 billion.

443
00:59:17,640 --> 00:59:26,040
And the wasn't. So that just wasn't. And that was before there was any interaction with the.

444
00:59:27,880 --> 00:59:33,100
So. In January and February 21.

445
00:59:33,100 --> 00:59:37,870
There was there was global scarcity of vaccine and.

446
00:59:42,300 --> 00:59:48,380
What vaccine was being made from that original network of Cobra and Horlicks and and also Biomedica.

447
00:59:50,400 --> 00:59:54,750
The priority was to supply the UK and I think personally I think that was right,

448
00:59:54,750 --> 01:00:00,110
it was the UK that had made the investment in making it possible and easy.

449
01:00:01,710 --> 01:00:07,650
I don't I don't know what lawyers might have been able to achieve, but on a very simplistic level,

450
01:00:07,650 --> 01:00:12,180
I don't think they could have sold the initial product to the EU even if they wanted to.

451
01:00:12,180 --> 01:00:19,860
When the EU, you know, started trying to buy vaccine in late May or June, they were a month, a month or two late.

452
01:00:20,700 --> 01:00:23,940
So ease the EU.

453
01:00:26,270 --> 01:00:35,629
You know, really last night, because it was I haven't been the initial funder and there was a period of the

454
01:00:35,630 --> 01:00:41,690
production ramping up of the sites that were meant to supply the and elsewhere.

455
01:00:43,040 --> 01:00:46,040
And so there was this very, very difficult period of scarcity.

456
01:00:46,040 --> 01:00:53,360
And, you know, really, I think ABC being made a scapegoat, which was, I think, quite something for everyone.

457
01:00:54,980 --> 01:01:04,130
You know, it I think it was purely political, you know, mccrone needed or needed a scapegoat.

458
01:01:04,340 --> 01:01:09,470
And they were at that point.

459
01:01:11,770 --> 01:01:20,670
You know, fire fighter. But, uh, how you see change?

460
01:01:20,680 --> 01:01:31,660
I had licensed products. Several companies that had contracts with the EU to supply were not supplying anything.

461
01:01:31,960 --> 01:01:36,280
GSK and Gil Vodka and so on. They didn't get the political heat.

462
01:01:41,860 --> 01:01:50,050
But AC and made a contract to supply large quantities with best efforts the EU had, I think.

463
01:01:51,750 --> 01:01:59,700
Made a mess of its procurement by comparison to the UK and as he became a scapegoat and

464
01:01:59,700 --> 01:02:04,319
the decision to make the interval 12 weeks rather than fall was not to do the scarcity.

465
01:02:04,320 --> 01:02:11,250
It was that genuinely from data from the trial, showing that a longer tool gave you a better protection.

466
01:02:12,380 --> 01:02:19,760
Both. But I think I mean, I, I wasn't involved, you know, that that decision would have been made by the, the JCPOA.

467
01:02:19,760 --> 01:02:25,640
But I, I wholly supported a, you know, the,

468
01:02:27,620 --> 01:02:35,740
the initial discussion around the data from the trial was suggesting that it might be that giving people a lower,

469
01:02:35,960 --> 01:02:42,320
you know, the people the people who had a lower dose of vaccine first seem to have better protection.

470
01:02:45,380 --> 01:02:51,590
And to be honest, really, from the really from the moment the result appeared,

471
01:02:51,590 --> 01:02:56,600
I, I personally didn't believe that that was at all likely to be the case.

472
01:02:57,530 --> 01:03:03,620
Uh, and I knew that those people who'd had a lower dose, they were the people who'd been given the first dose first.

473
01:03:04,880 --> 01:03:10,550
And so they'd had a longer wait before the, the batch from Cobra that was used to these people came along.

474
01:03:10,550 --> 01:03:15,050
And I knew that those people were likely to hold a longer interval I thought.

475
01:03:15,120 --> 01:03:22,400
And it's immunologically it's entirely, you know, it's known that a longer interval gives you a better response.

476
01:03:23,600 --> 01:03:29,209
It made, it made much more sense that a longer interval should give better protection than that.

477
01:03:29,210 --> 01:03:32,210
A small first dose should give better protection.

478
01:03:35,030 --> 01:03:48,510
So. I think it did make sense to to to spread the interval and also the early data supported the fact that a single dose was protective.

479
01:03:48,540 --> 01:03:57,060
You know, it did give a significant degree of protection over, um, over the, you know, 12 week period.

480
01:03:57,260 --> 01:04:02,510
So, and there was scarcity. So it all made perfect sense.

481
01:04:02,520 --> 01:04:07,110
If the data had been the other way that a shorter interval was better, then it would have been a much more difficult decision.

482
01:04:10,900 --> 01:04:20,740
So I mean, one of the fallout, if you like, of of the the vaccine program was that it was obviously extremely high profile.

483
01:04:21,400 --> 01:04:26,380
Was that something that that you encountered directly when you called upon to give interviews?

484
01:04:28,340 --> 01:04:31,630
Yeah, I I've given some interviews.

485
01:04:35,010 --> 01:04:48,750
The I mean I've clearly not had the media profile of Articulate or Sara Gilbert or Tice or counsel Adrian.

486
01:04:53,630 --> 01:05:00,500
But I've done I've done some I like some some of the media work I've done has been actually around the intranasal vaccination trial,

487
01:05:00,500 --> 01:05:04,010
which I led later in 2021.

488
01:05:04,070 --> 01:05:09,770
Oh, sorry. We should talk about that before we start. Uh huh.

489
01:05:11,150 --> 01:05:15,840
Um. Yeah, I've talked to some media.

490
01:05:16,190 --> 01:05:22,240
Um. Well, let's pick up on the intranasal drugs that had it.

491
01:05:22,290 --> 01:05:26,580
How did that come about? That there might be an alternative way of delivering the vaccine?

492
01:05:27,540 --> 01:05:30,239
So I think about January 21,

493
01:05:30,240 --> 01:05:41,880
I read a paper that Haslam and colleagues that published a preprint of showing that getting the vaccine intranasally was effective in animals.

494
01:05:43,470 --> 01:05:47,190
Exactly the same vaccine. Exactly. Exactly the same vaccine formulation.

495
01:05:47,230 --> 01:05:55,470
Exactly the same way. And it looked as though giving it intranasal might actually be more more effective in.

496
01:05:57,950 --> 01:06:04,700
Reducing shedding of the virus from the nose than giving it intramuscularly.

497
01:06:05,420 --> 01:06:10,230
And by that point, it was becoming apparent that, you know,

498
01:06:10,550 --> 01:06:17,990
preventing mild infection and transmission of the virus with intramuscular vaccine is actually quite difficult.

499
01:06:21,080 --> 01:06:28,580
And it was quite a good fit with AstraZeneca because their only previous vaccine product was called FluMist, which is an intranasal flu vaccine.

500
01:06:32,030 --> 01:06:38,660
And also there was, you know, debates starting about, well, you know, these vaccines do have some.

501
01:06:39,470 --> 01:06:44,070
Side effects in the sense of making people feel that flu in the day after they've had it.

502
01:06:45,180 --> 01:06:52,280
Covid's very mild in children. You know, all these intramuscular vaccines going to be the right thing to get into children.

503
01:06:53,510 --> 01:07:02,459
So we thought an intranasal vaccine might be one might have fewer of those.

504
01:07:02,460 --> 01:07:03,590
So, you know,

505
01:07:03,920 --> 01:07:15,140
mild but noticeable reactions compared to injected vaccines and might also be more attractive and acceptable for for some people as a sort of option.

506
01:07:16,460 --> 01:07:20,960
So there are a whole variety of reasons that it made sense to try and.

507
01:07:22,420 --> 01:07:26,190
The the difficulties they have it.

508
01:07:26,560 --> 01:07:32,200
The original idea we had was to move very rapidly from a small trial to a large trial and

509
01:07:32,200 --> 01:07:37,810
actually go for an efficacy result in the same way as we'd done for the intramuscular vaccine.

510
01:07:39,010 --> 01:07:44,920
That didn't work out for all for for a series of reasons.

511
01:07:46,120 --> 01:07:51,729
You know, the hope had been that, you know, if we could get the early safety data and move forward,

512
01:07:51,730 --> 01:07:56,889
then it seemed quite likely there was going to be a large wave of infection in summer 21.

513
01:07:56,890 --> 01:08:01,060
As you know, the lockdown eased and indeed the walls.

514
01:08:03,110 --> 01:08:08,300
But it took us a few weeks longer to get the trial started than we'd hoped.

515
01:08:08,480 --> 01:08:15,170
Ironically, because we couldn't actually get supply of all the vaccine that exist,

516
01:08:15,170 --> 01:08:18,620
you know, the commercial vaccine was actually in the sort of government supply chain,

517
01:08:18,620 --> 01:08:24,950
and getting it outside to do a clinical trial was actually quite hard, even with AstraZeneca, and AstraZeneca couldn't do it.

518
01:08:24,980 --> 01:08:30,180
There were a bunch of regulatory and sort of contractual hoops to jump through and it was quite

519
01:08:30,190 --> 01:08:38,720
as it was sort of mundane things that we needed to change the labels on the vials and so on.

520
01:08:39,110 --> 01:08:46,040
It was quite difficult getting a supply of vaccine for a trial. We didn't have a university owned supply just sitting in the freezer at that point.

521
01:08:50,750 --> 01:09:02,809
So it took us a few weeks to get started. We gave it to the first volunteer on the 1st of April and then very, you know,

522
01:09:02,810 --> 01:09:09,080
within the week after that with the first reports of blood clots related to intramuscular administration.

523
01:09:10,610 --> 01:09:17,900
So everything went on hold for a number of weeks while we figured out whether it might affect getting intranasal given the vaccine intranasal,

524
01:09:22,010 --> 01:09:31,280
we didn't think it would. But just, you know, when you've got very little clinical data on something, we have to be very cautious.

525
01:09:32,570 --> 01:09:36,469
So it took us a few weeks to be able to start restart vaccination.

526
01:09:36,470 --> 01:09:40,640
By that point it was mid-May and then by that point,

527
01:09:40,650 --> 01:09:50,270
the rollout of intramuscular vaccination was going so rapidly that actually very rapidly we ran out of people who had

528
01:09:50,270 --> 01:10:08,570
not had a vaccine before in the UK and then we had to amend the trial to we we gave some people who had had vaccines,

529
01:10:08,690 --> 01:10:16,460
intramuscular vaccines before we gave them nasal spray vaccines as a booster to see if I could be a factor in a small number of people.

530
01:10:19,400 --> 01:10:33,410
But yeah, for all those reasons, it's it wasn't really until September or October that we'd, you know, got data on an appreciable number of people.

531
01:10:33,770 --> 01:10:37,580
And by that point, the ship itself with respect, a very rapid progression.

532
01:10:38,570 --> 01:10:49,020
Um, we haven't. We haven't published today yet, but the immune responses we've seen have actually been a bit disappointing.

533
01:10:50,880 --> 01:10:57,800
So yeah, I think it was an important thing to have explored.

534
01:10:59,410 --> 01:11:03,670
But it is not in the end in something that's going to be taken forward.