The Oxford vaccine: the trials and tribulations of a world-saving jab
The Oxford vaccine: the trials and tribulations of a world-saving jab
In January 2020, when most of the world slept soundly in ignorance of the pandemic coming its way, a group of scientists at Oxford University got to work on a vaccine to save the planet. They wanted it to be highly effective, cheap, and easy to use in even the poorest countries.Prof Sarah Gilbert, Prof Andrew Pollard and others pulled it off. With speed crucial, they designed it and launched into trials before bringing in a business partner. The giant Anglo-Swedish pharmaceutical company AstraZeneca would manufacture it, license it around the world – and not make a profit until the pandemic was over.It was an inspired, idealistic and philanthropic crusade – yet they have spent the last year being attacked from all sides.As politicians, regulators, the public and the press have all weighed in, it is almost as if the vaccine has gone from hero to zero.So much has gone wrong, and the well-intentioned folk at Oxford and AstraZeneca have taken so many blows, that it is hardly surprising that they wonder whether they have been the victims of a deliberate disinformation campaign.It seems they have. There is clear evidence that the Oxford vaccine, and other jabs, have been targeted by Russians peddling disinformation in order to promote their own version, Sputnik V.At the university and the company, whose partnership has held firm under the extraordinary strain, there is bemusement at the disasters and deluge of criticism. “Everyone is ascribing this dark motive to everything we do,” said one company insider.Sir John Bell, regius professor of medicine at Oxford and the government’s life sciences adviser, who has been involved with the vaccine from the beginning, says they have been singled out.“Of course the vaccine is not perfect … We were very clear that we understand that there are complications from the vaccine, as I think you’ll find there are with all the vaccines to be honest. But ours has had the bloody spotlight, and people just won’t let go.“There’s a long history of trouble with this vaccine. And it’s hard to pin it on any one thing, and I think it would be fair to say maybe we haven’t handled the negative news as well as we might have. But we’re kind of new at this game [and] there was nothing deceitful about what we did. We just perhaps didn’t get in front of the dialogue.”Speaking to experts and insiders, the Guardian has pieced together the inside story of the vaccine’s fall from grace.There has been no single enemy with Oxford/AstraZeneca in its sights. Instead, it is a story of cultural and political differences, of misunderstandings and mistakes. It is a very human story, at heart, featuring people behaving badly, or with naked self-interest, in the midst of a terrifying pandemic.The odd coupleA merger of minds and money, idealism and pragmatism. Photograph: Joel Saget/AFP/GettyThe coupling of Oxford University’s scientific idealists with big pharma was an important contributory factor, and it was this merger of minds and money, idealism and pragmatism that set the Oxford/AstraZeneca vaccine off on the rockiest of roads.“AstraZeneca isn’t really known as a vaccine specialist company,” said Dr Penny Ward, a visiting professor in pharmaceutical medicine at King’s College London, who has spent a lifetime in the industry. “Also, not long before, they had shut down their entire anti-infectives division.” That meant AstraZeneca had hardly any involvement with infectious diseases.A deal had been expected with the US pharmacetical giant Merck & Co, which is known as MSD outside the US and Canada and has a huge vaccine division. But the UK health secretary, Matt Hancock, is said to have torpedoed it because there was no guarantee that Britain would get priority once doses were available.By the time AstraZeneca got involved, Oxford’s scientists had already set up the early trials. That meant, said Ward, that the studies were not tailored to the needs of regulators in the way that big drug companies would have done it.“There are things that you can do as an academic and it all seems perfectly rational to an academic who thinks scientifically, but don’t actually make a great deal of sense in drug development terms,” she said. “There is in fact a difference between academic science and development of a product that you’re going to sell in the marketplace.”Two things happened that would cause serious problems with regulators later on. Oxford had an extremely cautious approach to older people, and chose to recruit mostly under-60s for the earliest trials in the UK.Second, there was a glitch in the production of vaccines for the studies. A contractor accidentally supplied half-doses, according to AstraZeneca’s Sir Mene Pangalos, who headed the research once the company was on board. When they found out, the academic researchers told the Medicines and Healthcare products Regulatory Authority (MHRA) in the UK , and got the go-ahead to continue with two dosing strengths to see what happened.When the trials reported, it turned out that volunteers given a half-dose followed by a full dose got more protection – up to 90%, compared with 62%.Pangalos described it as serendipity. Regulatory bodies such as the Food and Drug Administration in the US don’t like serendipity. They like predictability and no surprises. The oddity of the information sowed doubt at the FDA.And the Oxford/AstraZeneca explanation of the 90% efficacy turned out to be wrong. Those who got the lower doses also had a bigger gap between the two shots. That, it turned out, was what improved the outcome. As we know now, a strategy of delaying the second dose paid off in the UK, but it was unorthodox.The FDA looked askance. It had already been perturbed by the side-effects in the trials.Regulators don’t like surprisesA volunteer receives an injection of the Oxford/AstraZeneca vaccine at a hospital in Soweto, Johannesburg. Photograph: Siphiwe Sibeko/APLast September, two people were reported to have suffered transverse myelitis – damage to the myelin sheath that protects the spinal cord. Nobody now thinks these were vaccine-related injuries. But the FDA did not believe it had been alerted soon enough. While other regulators suspended the trials for a few days, in the US they did not restart for two months while the agency demanded more information.News of the setback had been leaked from within the US, where commentators attacked AstraZeneca. Ed Silverman at the influential Stat News wrote an open letter to Pascal Soriot, the CEO of AstraZeneca, in his Pharmalot View column on 9 September. “I have concerns about your commitment to transparency,” he wrote, accusing the company of failing to come clean with the public.“Whatever your reasons, I think you did the wrong thing,” he said. “In the middle of a pandemic – when the whole world, literally, is hoping a useful vaccine is on the horizon – everyone was left to guess what went wrong and what it might mean.”The following day, the more widely read New York Times commented in its coverage that “many details about the trial’s suspension and the event that triggered it remain murky”.At AstraZeneca, they were nonplussed. In all the cancer drug studies they had submitted to the FDA, they had never been called on to account to the public for what they were doing. This wasn’t how the pharmaceutical industry normally operated.When the US trials eventually reported in March, AstraZeneca’s top executives thought they were home and dry. They reported good results: 79% efficacy against symptomatic illness and 100% against deaths. They had hardly had time to pop a champagne cork before the world turned upside down again. They were accused by experts in the US of massaging the data to give a more favourable result.The data safety monitoring boardissued a statement accusing them of putting out “potentially misleading” figures.Vaccine nationalismDr Anthony Fauci: ‘This kind of thing does nothing but really cast some doubt.’ Photograph: Saul Loeb/AFP/Getty ImagesIt was unprecedented. Data safety monitoring boards don’t normally go public. But they had, with no warning.Then the National Institutes of Health, headed by Dr Anthony Fauci, weighed in. “We urge the company to work with the DSMB [Data and Safety Monitoring Board] to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible,” it said in a statement.Fauci appeared on Good Morning America, describing the data issue as “an unforced error … this kind of thing does nothing but really cast some doubt”.Oxford and AstraZeneca’s scientists were astounded by the onslaught. They worked day and night to update the figures. Adding the very latest data pushed the overall efficacy down from 79% to 76%, which was barely a drop, and actually pushed up efficacy in the older age group from 80% to 85%.AstraZeneca’s vaccine is still not licensed in the US.Those close to the fray say nationalism may have played a part in the undermining of the Oxford vaccine.But there’s also a culture gap. The FDA expects the data to be cut and dried. The UK regulator was willing to think outside the box.Production problemsThe EU was unhappy with AstraZeneca reducing the amount of doses it said it was able to provide. Photograph: Dado Ruvić/ReutersWhile the US trials were stalled, the new year did not bring AstraZeneca any better luck in Europe. In January, the company revealed it was having production problems at a factory in Belgium.The European Union had ordered 400m doses, with the first 90m expected by March. AstraZeneca said it could only manage 40m – and then 30m – in the first quarter.As European leaders watched the UK’s steady rollout of vaccines,the problems quickly escalated into a full-blown row.Soriot insisted that they had promised only their “best efforts” to deliver the doses on schedule. But the EU Commission president, Ursula von der Leyen, went to war, insisting Europe had a right to doses made in the UK under its contract with AstraZeneca.Some at Oxford and the pharmaceutical company believe the row was heightened by Brexit tensions and British bragging about its vaccination programme.With anger rising, the commission threatened to block Pfizer/BioNTech vaccines made in Europe from being exported to the UK – and Italian police raided a pharmaceutical plant wrongly suspected of stockpiling vaccines destined for Britain.Bruno Maçães, Portugal’s former Europe minister, called it possibly “the most embarrassing day in EU history”.Efficacy in over-65sA woman in Germany receives a shot of the Oxford vaccine. Photograph: Lennart Preiss/AFP/GettyAnother huge issue had already rocked public confidence. On 25 January, a German-language business newspaper, Handelsblatt, ran a front-page story. “AstraZeneca vaccine apparently hardly effective in seniors,” said the headline. Efficacy in the over-65s, the age group most at risk of dying from Covid, was only 8%, the article claimed..Handelsblatt’s sources were not in the German government. Its journalists had been speaking to regulators and vaccine advisers. The figure turned out to be inaccurate – and taken out of context.There were too few elderly people in the early trials, because the Oxford academics did not want to expose them to risks. And if you have too few people in a trial, the results you get are not reliable. There was simply not enough evidence to prove how well the vaccine worked in the over-65s.Handelsblatt acknowledged that there was too little data, but that was lost in the ensuing row.Within days, Stiko, Germany’s vaccination advisory panel, said it would not recommend the vaccine for the over-65s because of the lack of evidence that it worked for them. In France, President Macron said the jab was “quasi-ineffective” in the over-65s.Within weeks, Macron was forced to say publicly that he would have the jab himself – and by early March it had been approved by France for the over-65s. But the damage had been done.Bell says you can get only limited data from vaccine trials – you have to see what happens “in the real world. The studies are different, the clinical trial populations are different, the type of virus that people are being exposed to is different. The outcomes are all different”.“And yet throughout Europe we had lots of these little so-called expert committees saying: ‘Oh God, you can’t use it in the over-50s, oh God, you can’t use it in the under-50s. You can’t use it at all. Well, maybe you could use it if you’re upside down, drinking a milkshake.’ It was unbelievable.”Real-world data eventually proved that the vaccine worked very well in older people. But it also revealed a serious problem in a tiny minority of younger people. On 7 March, Austria suspended the use of a batch of the vaccine aftera woman of 49 died and another aged 35 became seriously ill with blood disorders shortly after inoculation.As Covid cases continued to surge,the European Medicines Agency (EMA) said the benefits outweighed the risks, but launched an investigation.Prof Marie Scully’s first case was admitted to University College hospital, London, in the UK on the weekend of 6-7 March. A young, healthy woman in her 30s had blood clots on the brain and low platelets. “It was most unusual,” said Scully, a consultant haematologist. “We use vaccines all our life. Why would the AZ vaccine suddenly cause this situation?”But it did, the EMA and MHRA eventually ruled, albeit in only four in a million cases. It was enough for many European countries to restrict the vaccine’s use.Russia wades in onlineRussia was keen to promote its own Sputnik V vaccine. Photograph: Anadolu Agency/Getty ImagesThe real-world problems were compounded by misinformation in the virtual world – seeded by pro-Russian state interests who had a vaccine of their own to promote.Sputnik V was designed by the Gamaleya Research Institute, part of the health ministry and funded by the Russian Direct Investment Fund, a sovereign wealth fund, which is headed by Kirill Dmitriev.Dmitriev christened the AstraZeneca product “the monkey vaccine” because it uses a chimpanzee virus as its delivery mechanism. Last October, memes, videos and pictures of King Kong injecting a screaming woman and Boris Johnson as part of the cast of Planet of the Apes were posted from anonymous online accounts and went viral.A report by the EU watchdog, the external action service, found that between December and April, the disinformation intensified. “Russia and China, in particular, continue to intensively promote their own state-produced vaccines around the world.”It accused them of pursuing “a zero-sum game logic” designed to undermine trust in western-made vaccines, EU institutions and western vaccination strategies.AstraZeneca was not the only target, but the catalogue of disasters provided Russian interests and their proxies with new opportunities to promote Sputnik V – and stoke social divisions. There are suggestions that Kremlin interests hoped to sow dissension across Europe, destabilising Germany and France in particular. Certainly, those behind Sputnik and RT, the Russian state television channel, have amplified the anti-vaccine and anti-mask voices in Europe and the US, gaining particular traction in France.For the scientists at Oxford and AstraZeneca, seeking to make sense of all the troubles that have afflicted them, it feels personal.Most critics and defenders of the vaccine agree on one thing: the developers, manufacturers and for that matter the British government should have come out fighting. Thinking they were saving the world, it didn’t occur to Oxford or AstraZeneca that they needed to be proactive.They also agree that the world – particularly the developing world – needs this vaccine.Dr Peter Hotez, co-director of the Texas Children’s Center for Vaccine Development, cited three issues that had gone badly wrong. “AstraZeneca is not a vaccine company. That’s probably one. Two, they’re trying to accelerate this in a public health emergency. Three, there is this rare complication, the cerebral thrombosis, happening in an environment of intense anti-vaccine aggression. And you’ve now got reports from the Russian government trying to discredit their competitors’ Covid vaccines.“It’s been a perfect storm … They’ve got to figure out a way to communicate this to walk it back so we can get this fixed.”