Eighteen months. Half a billion doses in 178 countries. Thousands of lives saved. The scientists behind the Oxford vaccine, Professor Sarah Gilbert and Dr Catherine Green, tell Tom Whipple how they pulled it off.
February 2020
There is a new virus in China and Sarah Gilbert, an Oxford scientist, is trying out a novel vaccine technique. The epidemic in China may come to nothing, she tells me, but this is a good exercise in proving that vaccines can be made faster.
Number of doses of the Oxford vaccine administered: 0.
November 23, 2020
Sarah Gilbert looks tired. We have spoken a couple of times since, but this is our first Zoom call. The efficacy results of the vaccine are out, and it looks likely to be approved and in general use before Christmas. I ask her if she and her team are planning to have a Zoom party. "We are all having an early night," she says.
Number of doses of the Oxford vaccine administered: fewer than 100,000, in trials in 4 countries.
June 2021
Gilbert still looks tired, but this time she is wearing a mask – we are meetingin person. I ask again if she has had a celebratory party yet. She hasn't.This time she has a colleague with her, geneticist Catherine Green. "We've been exactly the same as everyone else. We've missed the events that would ordinarily be marked by champagne and cake," says Green.
Number of doses of the Oxford vaccine administered: just shy of half a billion, in 178 countries. Lives saved in the UK due to vaccination: 12,000, estimated.
It has been a long 18 months.
They called it a "Disease X" situation. At some point, a completely new pathogen would emerge for which a completely new vaccine was required. And at Oxford's Jenner Institute at the start of 2020, they were ready.
The small problem, says Professor Sarah Gilbert, is that when Disease X arrived, no one had anticipated a very specific scenario. What if they themselves – the people working on that vaccine – ended up being in the same country as the disease? "The idea of having to live through a pandemic while we developed a vaccine to get us out of a pandemic?" says Gilbert. "We hadn't planned for that."
They had always imagined they would swoop in, the vaccine cavalry, to defeat an outbreak in some distant country. In the sort of distant country that has pandemics.
Instead, it turned out that it's not only distant countries that have pandemics. They can also strike cities such as Oxford and affect Oxford academics, who also have children who need schooling, toilet rolls that need replenishing, coughs that need isolating.
By the spring of 2020, with empty shelves, pasta panics and a closed canteen, that flaw in planning was most keenly felt in the office vending machine. "We ate nothing but Mini Cheddars and Bounty bars for two weeks solid," says Dr Catherine Green.
There are many procurement triumphs in the vaccine's story, but the earliest – and most unsung – was when Green bought a jar of £2 coins from an elderly lady after everyone ran out of change for the machine.
This was a period when the Oxford vaccine team, the hope of a nation – the hope of the world – was fuelled by chocolate and cheesy biscuits. "All of us," says Green, "were getting spotty." Then the inevitable happened: the last packet of Mini Cheddars tumbled down to the bottom of the vending machine and even those meagre rations were gone.
It's funny, but food matters. Morale was low; they were doing 18-hour days. If it had gone on much longer, says Gilbert, "I think a lot of people would just have given up."
She had, coincidentally, been approached by two couples, Jonathan and Tracy Turner, and Denise Foderaro and Frank Quattrone. They are philanthropists and they wanted to know how they could help. Her answer? They needed meals. The couples agreed on the condition the meals were healthy. After spending an elderly lady's lifetime savings on Bountys, no one demurred.
This was, in a minor way, a turning point. "It was transformative for the team," says Green. "It felt that someone had noticed them. It felt like an endeavour. It was one of the first times I think we started to feel there's a community willing us to succeed."
Ebola was not a Disease X. When it re-emerged in 2014 it was well known and understood, and the outbreak was depressingly predictable.
Green and Gilbert are speaking to me because, with the help of a ghost writer, they have written a book about their fight against Covid. And it is in West Africa, with a disease that arrives not beneath the cloak of a cough and a sniffle, but with the terrifying sight of people bleeding from the eyes, that they begin their story.
"To understand what we now all know intimately as Covid-19 and to explain how my colleagues and I designed a vaccine to protect against it," they write, "we first need to travel 12,500 kilometres west from Wuhan in China to Guinea in West Africa."
When reports emerged of the ebola outbreak, there were vaccines already in development. One was known, snappily, as ChAd3-EBOZ. It was different from the vaccines you would have learnt about at GCSE or O-level.
Edward Jenner, after whom the Oxford institute where Gilbert works is named, began the world's vaccine journey when, so the (apocryphal) story goes, he noticed that milkmaids had lovely smooth complexions, unlike the pockmarked skin of their less cow-orientated compatriots.
They were not, it seems, catching smallpox, a disease that killed a fifth of those infected and left the rest with scars. The reason? They contracted cowpox instead. Their bodies were trained on a similar but milder virus and could then fight off the scary one. This has long been the principle of a vaccine: find a weaker or deactivated version to simulate an infection, and train the immune system on that.
ChAd3 worked nothing like this. It was what is known as an adenoviral-vectored vaccine. It was not a deactivated version of ebola. It was nothing like ebola. It was, in fact, a completely different family of virus.
But inside the adenovirus that formed ChAd3's key innovation was a little snippet of genetic code taken from ebola. When it infected the cells of vaccinated people those cells became vaccine factories, churning out harmless fragments of ebola proteins so that the body was prepared to recognise and fight off the real thing. This was a near-miraculous technology. It was not so much a vaccine as a "platform", ready to be adapted to new diseases as and when they arrived.
And in 2014-15 the process was still too slow. Bottlenecks in manufacturing and testing meant that by the time it was ready to be used, ebola was under control.
When Gilbert and Green heard reports of a new kind of pneumonia appearing in China, they were determined not to repeat the same mistakes. "The dilemma of being a vaccinologist is you don't really ever want a situation where your vaccines need to be used at this kind of scale," says Green. "We decided, if we're going to need it, we're going to need it fast. Let's prove we can do it and how fast we can do it, because then we can learn from that for next time."
Ebola had taught them that designing the vaccine was only the start. They needed trials, pipelines, pharmaceutical companies. They needed to do things concurrently that had previously been done consecutively. At the start of 2020, this was what they resolved to do.
"We had to get everything moving," says Gilbert. "Start the manufacturing, make the starting materials, get the clinical trials off the ground – phase one, phase two, then phase three trials in different countries. There was the immunology, the bloods coming from the clinic back to our labs, getting all the data together, recruitment, volunteers."
"It's massive," Green continues. "You have to buy new freezers. You have to buy inventory control systems. There were hundreds of people working on this campus. The thing that Sarah was doing sounds like logistics, but it's massive logistics."
Gilbert makes a comparison between this time and the months after she had triplets. As then, "There have been times when it's just so totally full-on that all we can do is focus on the next half-hour, and then the half-hour after that. It's been quite traumatic, frankly."
Of everything that could go wrong, the most likely was the early stages of manufacturing. Making the first vaccine, constructed from adenovirus and DNA, was a miracle of biotechnology, but it was also well understood. They had done it for ebola and for other diseases since.
Growing more vaccine from that, using cells and bioreactors to churn out the doses of adenovirus needed, was more temperamental.
This was Green's job. She talks about making the raw ingredients of a vaccine as if it is a little like animal husbandry. She speaks of coaxing cells, finding those that thrive, giving them the environment they need. One batch failed entirely. One was more successful than she could have hoped. Eventually in her lab she had a Coke can's worth of raw material – 600 billion particles of virus – from which every one of the planned 3 billion doses of their vaccine would be descended.
As science editor of The Times, I remember chatting around this time to members of the Oxford team. Gilbert was saying that, in contravention of all known precedent, they could be through trials and into general use in a year. It seemed simultaneously fantastically optimistic and also far too slow. Surely a pandemic would be long over by then?
Others clearly shared my view, not yet convinced of the practical merits of this technology. While Green was whispering sweet nothings to her bioreactors, Gilbert was performing the role that our scientific system appears to have decided is the best use of senior scientists' time: scrabbling around for laboratory space, begging equipment, applying for funding.
Eventually they would get the full backing of the British state, but even then that was not always enough. She remembers a call with Matt Hancock, the health secretary, in March 2020. "He said, 'What can I do to help? What do you need?' " She needed to get the vaccine clinics up and running and replied, "PPE."
"You could see he was thinking, 'Not you as well,' " she says.
As the first wave came to an end, Britain needed heroes. We had put NHS rainbows in our windows and clapped for carers. But carers were to the pandemic what the small boats of Dunkirk were to the Second World War. It was time for the big guns. The nation wanted not pluck in defeat but hope for victory: they wanted Spitfires and Bletchley code breakers. Gilbert and her colleagues provided that.
So it was that something entirely unexpected happened, at least to Gilbert and Green. People started getting in touch, interested not in adenoviruses but in the scientists behind them. Sixth-formers would email them asking who their role models were. TV channels would call. Journalists like me would bother them with interview requests. Schools asked them to speak – Gilbert will visit one after our interview.
"I have mixed feelings about it," says Gilbert. "It's all about personalities. We don't want to be science personalities."
But this is what they'd become. There were appearances on The Andrew Marr Show, there was a profile on Radio 4. "There was," Green reminds Gilbert, "that kid who dressed up as you." A nursery had a superheroes day and one child went as Gilbert. Her parents sent over the pictures. "She's wearing a white shirt that looks like a lab coat, with big glasses and a string of pearls," says Gilbert. ("I've never seen Sarah in pearls," adds Green.)
Is it flattering? Gilbert doesn't like the "role models stuff". "People ask me, 'Who were your role models growing up?' " she says. She finds the question mystifying. "Science isn't about people," she says. "I didn't have time for heroes."
You don't get passionate about viral vectored vaccines by being a people person.
"I was interested in doing the science, finding out how things work and how to use what we know to make something happen, or create something that's more interesting.
"I had an email from a parent of an eight-year-old girl who said she'd seen me on television and didn't realise that women could be scientists, and now she wants to think about being a scientist."
So far, so inspiring? Not quite. Gilbert thought, "Well, what on earth have you been teaching her? For heaven's sake."
Three days after our meeting on the site of Oxford's Churchill Hospital, where much of the development was done, the Queen's birthday honours will be announced. Green will get an OBE, Gilbert a damehood.
Scientists often say they are not interested in being personalities or in press approval. Despite writing a book, which she justifies on the basis that Edward Jenner also worked to publicise his vaccine, I've never doubted the sincerity of these sentiments with Gilbert.
Speaking to journalists she has always been scrupulously polite, but has never invited follow-ups. For much of the past year, if you sent her an email you received an out-of-office that roughly translated as, "I'm very busy. Leave me alone and go to the press office."
In the book she talks about that press office scheduling back-to-back interviews with people like me on key days. The encounters in the book are described with the vague air of a duty ticked off: a task that's slightly unpleasant, mildly regrettable, but probably worth it on balance, much like filling in a grant application.
It feels oddly in character that Gilbert had triplets, as if she had planned the most efficient and rational way to create a family. All, naturally, are now studying biochemistry.
By the time Gilbert was frantically adjusting the blinds in the Jenner Institute for a visit from the Duke of Cambridge last June, she had accepted she was the figurehead of something that was no longer merely scientific.
The first wave had come and gone. The preliminary trials had been successful. Larger trials had begun – too late, alas, to gather enough infections before the summer lull.
AstraZeneca had been brought in to take the vaccine to scale. ("We were essentially a family-run pizzeria, doing everything ourselves," writes Green. "They were Pizza Express.") And now she had a meeting with a prince.
She and Andrew Pollard, the director of the Oxford Vaccine Group and the man running the trials, were due to sit down with Prince William and be filmed having a conversation. "It was a bit odd – the three of us in a row." She realised, though, that the backdrop was a mess. "Andy had to go to meet the entourage and I was left there, so I had to fix the blinds."
The Oxford vaccine, as it was now called, had become a patriotic emblem to be lauded at Downing Street press conferences and, perhaps, used as a shield by the government when confronted with other failings.
When something is this big – enough that its success or failure could move percentage points in the global economy – it is not just scientific or patriotic, it is also geopolitical.
This has been hard, say Green and Gilbert. Throughout the book they talk about press and political attention, much of which they perceive as unfair. Misinformation began almost from the start, when there were internet rumours that the first recipient had died.
There were the accusations, which stung, that the trial had made an "error" in giving a subgroup a half-dose of the vaccine: the wrinkle that led to two efficacy statistics being reported on the day their results were at last released. It wasn't planned, but to call it a mistake was also to elide a lot of nuance. And it deflated their achievement.
The nadir, though, probably coincided with that of the nation: the midst of the winter wave, when hospitals were full and, on the continent, politicians were briefing against the Oxford vaccine. The Germans were questioning whether to give it to the elderly. Emmanuel Macron was openly suggesting it was worthless.
"The whole country," says Green, "gave a Gallic shrug at that point."
Then came the fear about blood clots. One of the odd things about vaccine development is that at some point the results are out of your hands. The reason politicians had relative confidence that we could get a vaccine was not because they had faith in any particular team – it was because there were so many teams.
And many have, indeed, failed. That they have done so is not somehow a reflection of their lesser skill, but simply of the sheer complexity of a human body and what happens when you tweak its immune system. One vaccine stopped trials because it caused people wrongly to test positive for HIV. The vaccine interfered with the tests – astonishing bad luck.
So too were the clots. It was a side effect so rare that there was no way of knowing about it except by vaccinating at scale. We still don't understand the mechanism. "Of course we don't want a vaccine that we've been involved in to have these rare serious adverse events," says Gilbert. "There was no way anybody could have known that was going to happen."
Green said her motivation for writing the book was, in part, because of the conspiracy theories: the belief there was some malevolent force behind the vaccine team when, in fact, it was people like her just trying to work out how to home school her daughter in a pandemic.
"We are normal people doing our job to the absolute best of our ability. All the challenges – no pasta in Tesco, no toilet roll, not being able to see your mum and dad – we were experiencing them too." She was also trying to get key worker status so that her daughter could stay at primary school. "So this concept that the vaccine manufacturers are 'them'? We're not them. We are us." It's been hard. "What has been especially tough is the inability to mark what we've done as a team."
They know, though, that they're appreciated. When Green went for her vaccine she couldn't resist telling the nurse. "I said, 'I made that.' She took a selfie and put it on Twitter."
Gilbert gets recognised these days.
"I've had people say to me they've had their vaccine, their parents have had the vaccine, and they're so grateful. And I don't think they expect it, but they get very emotional. They kind of break down into tears. I find that quite difficult." I can imagine. Gilbert does not strike me as a natural with public displays of affection. In the book she talks about how she hopes that a lasting legacy of the pandemic will be the end of the handshake.
But I am being unfair. She finds it difficult, she says, because, "Then I start empathising with them too." It is hard to tell – in our bland meeting room in her offices where we are all wearing masks – but it looks like there is just the hint of emotion there, that she has, like the unexpectedly teary people approaching her in the street, become briefly overwhelmed by the magnitude of it all.
But the interview is over. Green is off to pick up her daughter from school. Gilbert is off to her next engagement. We head out together into the bright Oxford sun. "Right," says Gilbert, with all the forced briskness of someone jollying themselves to go for a Boxing Day swim. "I'm off to inspire a school."
Vaxxers: The Inside Story of the Oxford AstraZeneca Vaccine and the Race Against the Virus by Sarah Gilbert and Catherine Green is published on July 9.
Written by: Tom Whipple
© The Times of London