In May 2020, a group of scientists at Oxford University loaded three 30ml and five 6ml tubes into a small polystyrene box, and carefully packed them in dry ice.
This box was then given to a courier who specialised in temperature-controlled shipping, and driven to Heathrow. There was no unusual security for this – no outriders, no armed guards. Yet it was almost certainly the most important package on the move in the world at the time.
From Heathrow, the eight tubes, which contained billions of viral particles, the result of months of work by a team led by a scientist called Professor Sarah Gilbert, were flown to Washington Dulles airport in the USA. From Dulles airport, they began the final leg of their journey, to Gaithersburg, Maryland, just across the border from Washington. There, Per Alfredsson was waiting to receive them.
At that point, Oxford University’s role in making their vaccine had ended, and Alfredsson’s had begun. The Oxford scientists had made enough doses of vaccine to carry out the early trials, and to prove it could – in theory – be mass-produced. Now he had to make enough to vaccinate half the world.
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Sometimes, the bottleneck occurs in actual bottle necks.
For a while, rubber stoppers were Per Alfredsson’s nemesis. The AstraZeneca vice-president had everything else he needed, but if he couldn’t find more stoppers to put in vials, he realised, his whole operation was in jeopardy.
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It was a few months after that delivery and he was in charge of the most ambitious vaccine manufacturing operation in the history of his company and – at least until that year – in the history of the world.
It involved a product that used the latest genetic technology, that had the backing of the world’s leading governments, and that was gearing towards a production line that could turn out 80 doses a second from 25-plus factories in more than 15 countries.
Yet the entire operation was threatened because he and his small team couldn’t source little bits of rubber.
That was just that week. Other weeks it was the plastic containers they used as bioreactors, or the little clips they needed to hold tubing together. Filters were a particular problem too. Everyone wanted them. They are needed for all sorts of chemical processes – including the kind of chemical processes suddenly crucial in a pandemic. “You can just imagine the surge in demand.”
We know about the scientists who tweaked the vaccine vectors and used fiendishly clever research to design a vaccine in record time. A vaccine in a laboratory is useless, though.
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Manufacturing fast and at scale requires its own kind of cleverness – and provides challenges that can seem, in their own way, equally insurmountable.
Alfredsson, though, surmounted. So it was that, ultimately, the vaccines kept on coming. It was never guaranteed that they would.
At the end of last month, the billionth stopper was put on the billionth vial, and a company that had previously been a very minor player in vaccines took a big step towards fulfilling its stated mission: to provide a vaccine for the world.
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Sixteen months ago, when the Oxford-AstraZeneca vaccine was still just the Oxford vaccine, the only doses produced had been made ad hoc. Dr Catherine Green, who helped run the university’s manufacturing, described their operation as a bit like a small restaurant. “We were essentially a family-run pizzeria, doing everything ourselves,” she says.
They made nice pizza; people appreciated their pizza. But to make a difference they needed to partner with their own Pizza Express. They needed a pharmaceutical company.
At around that time – the time that half the world was in lockdown – Per Alfredsson was standing in a car park in Maryland when his phone rang.
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It was his boss. “He said, ‘We are looking at this vaccine from Oxford University that we are thinking about partnering with... Could you have a look at it, what do you think?’ ”
Blond, tall and perfectly bilingual, Alfredsson, 51, exudes the sort of effortless Scandinavian competence you would want in a moody detective investigating Arctic Circle murders or, say, in the manager of a vaccine logistics operation.
“My role is a bit like a football coach,” is how Alfredsson puts it. “We have a fantastic team of people. They’re really, really good at what they’re doing. I’m not an expert at all. My role is really to make sure that everyone can do their best.”
In that phone call, he was being asked to take part in his own World Cup final. Did he think they could do it?
Making a vaccine is not like making cans of Coke. You can’t just take, for example, your Fanta processing plant, switch the ingredients and get going. Different vaccines have very different requirements and the process has lots of stages, each of which can go wrong. At points in this process, such as when you are coaxing cells and trying to, in Alfredsson’s words, make them “happy”, it is closer to animal husbandry than manufacturing.
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He went through what would be required. AstraZeneca isn’t big on vaccines, but there are other drugs it makes that have similarities in terms of manufacturing to the one Oxford was producing. “I was looking at it and thinking, ‘Can we scale the process? What do we need to do in this process? Do we have the materials and equipment we need? Is it feasible to get hold of enough capacity? How strange is this process really? How strange are the things that we need?’ ”
He said yes.
Ten days after the phone call, the company had signed with Oxford. “From there on, we have never stopped.”
“I was number two, three – maybe four – on the programme. It took us just two months to get to at least 700. It was very much begging, stealing, borrowing people.”
It wasn’t hard though.
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“It was so great to see everyone rallying to this cause. I’ve never worked in an environment where if you ask for something people say, ‘Of course. And, by the way, I have someone else that could help you too.’ ”
The Oxford vaccine is what is known as an adenoviral vectored vaccine. Vaccines work by presenting your body’s immune system with something that looks like a pathogen or part of a pathogen, but which isn’t. The first smallpox vaccine, for instance, was cowpox – a related virus, relatively benign. Cowpox had enough similarities to smallpox that, if you learnt to fight it off, then afterwards you were protected from both.
Adenovirus vaccines are part of a new generation of “platform” technologies that are a bit different. Unlike cowpox, the adenovirus that gives the vaccine its name does not itself look anything at all like the coronavirus. It is as evolutionarily distant from it, in fact, as you are from a halibut.
Instead, it holds the genetic instructions to make something that does look like the coronavirus. When the vaccine is injected, the adenovirus does what viruses tend to do, and infects your cells. Once inside, it does what viruses tend not to do – it doesn’t replicate. Rather than hijacking your own cells to copy itself, it has been genetically engineered to instruct the cells to make copies of the coronavirus spike protein, churning them out.
The principle is ingenious. So too, though, must be the manufacturing.
After signing, Oxford sent over everything AstraZeneca needed, in those eight tubes. It wasn’t much. “They were small bars, like small protein bars,” he says, holding up two fingers to demonstrate the size.
Some of the frozen bars were the “viral seed”, the adenovirus whose descendants would end up in their billions in each of the billion doses made so far. Some of them were a very specific line of cryogenically frozen cells.
A key problem facing Alfredsson was that he had to make trillions of copies of an adenovirus that had been specifically designed so that it would not make copies of itself.
The entire claim to safety for the vaccine was that the virus it used was “benign”, that it had been deactivated in such a way that it could not reproduce. This meant there was no risk of it causing its own infection.
Now he had to reactivate it. How? This was where the cells came in. The virus had been genetically engineered no longer to have the tools required for replication. The cells in those frozen bars had been engineered to contain the missing tools. Together, they were a lock and a key. These were the only cells in the world in which it could infect and spread.
Alfredsson likes Green’s pizza analogy. “It’s a very complex pizza with a lot of ingredients on.” He had a method from them for growing the human cells, infecting them, then harvesting the adenovirus. But it was too fiddly. “It was a small-scale, artisanal setting – and what we need to do is think, how can we do millions and billions of pizzas? We needed to take it to an industrial scale.”
Yet while doing so, they also had to maintain the kind of flexibility that you don’t associate with industry. “This is a biologics process… We need to really treat the cells so they are happy, and make sure they are happy.” The happiness of cells is the reason that, still, there is huge variation in what some manufacturing plants can produce. “It’s important to understand it’s not, ‘A + B always becomes C’.”
In the end, what he had was a recipe to tell each of the factories they were working with how to make the vaccine. The difference between it and a pizza recipe is that this one is 1,000 pages long.
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Alfredsson, as you might have guessed, is not originally from the USA. When we speak, he is in his home country of Sweden. He returned for the midnight sun of the midsummer festivities. He also returned to see his family.
They had moved with him to the USA, but when the pandemic began they left for the more laissez-faire coronavirus policies of Sweden, where his teenaged daughter could continue her schooling.
He is far from the only member of the AstraZeneca team to have made such sacrifices.
There have been hard moments. There have been fires, floods and national strikes. There have been rubber stoppers.
Each time the supply chain was threatened, he and his team hit the phones – or, just as likely, Zoom. That was when something astonishing, for him at least, happened. “If you look at our supply partners, they are normally competitors.” This year, they haven’t behaved like it. “We reached out to companies and they would say, ‘No, we can’t do it, but we know this company and I have contacts with this one.’ ”
Alfredsson is senior vice-president of Global Biologics Operations at AstraZeneca, with 24 years’ experience in Big Pharma, but he had never experienced this. “I’ve never seen it in the industry before, everyone coming together. Everyone wants to do the right thing.”
The hardest moments, though, have been not acts of God but acts of governments – and journalists.
It has been when Emmanuel Macron, the French president, was saying it didn’t work; when the German press was claiming, incorrectly, the vaccine had minimal efficacy in older people; when the company itself, which was producing the vaccine at cost, was being criticised for its trials.
“From time to time, you know, you feel a bit sad. You know that everyone has done their part, that hundreds and hundreds and hundreds of people are sacrificing their family lives and may not see their kids at all. And then you read things in the paper. It can be really, really tough for people.”
That was the bad. There has been more than enough good to counteract it. “It’s been everything from small, handwritten notes saying, ‘Thank you, thank you, for allowing me to meet my grandkids again.’ There was a really nice video from a trust in Africa, where they were vaccinating with our doses and saying, ‘You’re helping us. Thank you.’ ”
He saw the video of Gilbert, creator of the Oxford vaccine, getting a standing ovation at Wimbledon. “That was so good. I was so happy.”
For all his pride, the antibodies currently swilling round Alfredsson’s body are not branded Oxon. Because he lives and works in the USA, he received a different jab – Moderna. People sometimes ask him if he minds this, but he really doesn’t.
His is one story of many, in a pandemic that has seen the best of humanity. He is one of a team that manufactured the vaccine, itself part of an operation of scientists, trialists and regulators that has compressed ten years of development into one. And that’s just their vaccine.
There are other Per Alfredssons for Moderna and Pfizer. There are other Per Alfredssons too for Merck and the Pasteur Institute – although we don’t hear much about them these days.
It is difficult to remember now, but the success of the AstraZeneca vaccine was never assured. Throughout last summer and autumn, Alfredsson and his team did not allow themselves to think about what would happen had it failed.
“We needed to drive as hard as we could, because if it works, we just needed to have as much vaccine there as early as possible. There was no discussion about what we should do if it doesn’t work. It was like, ‘Go, go, go, go, go.’ Because the opposite would not have been the right thing to do.”
For other vaccines, that was also the case. That some of them, such as Merck and Pasteur’s, failed is not their fault; most do. The world needed many vaccines so that some could succeed, and it needed people going full tilt at manufacturing even when all they had was hope – and the knowledge, at the back of their mind, that they were one lottery ticket of many for the world.
So, in that sense, Alfredsson is lucky to still be taking calls from four continents and many more time zones, to still be working as hard as he has ever worked before. He is also, though, looking forward to a return to normality. That time is, he thinks, coming. Mind you, he has thought that for a while.
“I’m always an optimist. My wife tells me I say, ‘No, don’t worry. After summer everything will be back to normal.’ And then, after the summer, of course it is not back to normal. I continue on that three to six-month cycle.
“I think it will be hard work. We have so much more to do, so many more countries to support. When I look back on this, I feel very proud of what we have achieved as a team. It is a once in a career thing to do. Hopefully... I hope we don’t get another pandemic.”
