Special Report-How a British COVID-19 vaccine went from pole position to troubled start

By Steve Stecklow, Andrew MacAskill, Ludwig Burger, Kate Kelland and Emilio Parodi
LONDON (Reuters) - On June 5, Oxford University researchers tacitly modified a clinical trial of their late-stage COVID-19 vaccine. A new group of participants has been added to a change request noted in a document marked CONFIDENTIAL.
The adjustment appears to be minor in a large-scale study. However, it masked an error that could have far-reaching consequences: many of the subjects in the UK had accidentally only received about half a dose of the vaccine.
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The new volunteers would now be given the correct dose. The process continued.
Much has been driven on the Oxford vaccine, a UK-led venture that also included UK drug company AstraZeneca. Prime Minister Boris Johnson's administration was desperate for a track record after premature abuse of the pandemic contributed to one of the world's highest death toll from COVID-19 - around 65,000 by mid-December. The government has secured 100 million cans.
On November 23, Oxford and AstraZeneca delivered positive news. They announced that the half-dose regimen followed by a full-dose booster appeared 90% effective in preventing COVID-19. Two full doses scored 62%. Oxford researchers have said they are not sure why half the dose was much more effective.
Johnson called the vaccine team and tweeted his thanks "for their brilliant work." He continued, "These results are incredibly encouraging and an important step forward in our fight against COVID-19."
Oxford and AstraZeneca are now hoping for swift approval from the British regulator. But questions about the trial and the results won't go away.
Some experts say the dosage discrepancy casts doubt on the robustness of the study's results. And they're concerned about another recognized quirk of the study: the half-dose regimen wasn't tested on anyone over 55 - the group at high risk for COVID-19. In contrast, a vaccine made by Pfizer / BioNTech has been tested on thousands of people over 65 with 94% effectiveness.
John Moore, a professor of microbiology and immunology at Weill Cornell Medical College in New York, said there needs to be a better understanding of how the Oxford study went. "When you get business and academic scientists to say different things, there is no impression of confidence in what they are doing," he told Reuters. "Was the dosage a mistake or not?"
Now, a Reuters review of hundreds of pages of clinical trial records, scientist interviews and industry metrics provides the most detailed report yet on what went wrong with dosing in Oxford / AstraZeneca's vaccine study. The review found that Oxford researchers were responsible for what their own clinical trial documents called "potency miscalculations".
For Oxford and AstraZeneca, the stakes couldn't be higher. They hope to produce up to three billion doses of the inexpensive vaccine by the end of next year, enough to vaccinate much of the world, including many of its poorest residents. For months, scientists at Oxford have been promoting the prospect of the experimental vaccine in bullish terms - starting even before the first human test subjects were injected with the experimental vaccine.
In an interview that appeared in The Times on April 11, Sarah Gilbert, one of the lead vaccine researchers at Oxford, said she was 80% certain that her team could potentially produce a successful vaccine as early as September. That was 12 days before a clinical study to test safety began.
Oxford did not answer detailed questions about the story, but made a statement that the trials "were conducted under strict national, ethical and regulatory requirements". It added that "all test protocols and test changes have been reviewed and approved by the relevant authorities. All safety data has been regularly reviewed" by the regulatory authorities.
An AstraZeneca spokesperson referred questions about the UK clinical trial to Oxford, which it sponsored. A spokeswoman for the UK regulator, the Medicines and Health Products Regulator (MHRA), declined to answer questions about Oxford / AstraZeneca's dosage problem. "Our ongoing review is ongoing," she said. "This information is currently commercially confidential."
The UK Department of Health and Welfare declined to comment.
An exact science
Vaccines are the world's best hope of ending a pandemic that killed more than 1.7 million people worldwide. More than 60 COVID-19 vaccine candidates are currently being tested in humans, according to the World Health Organization.
Pfizer / BioNTech and Moderna vaccines have already been approved for use in a number of countries, including the United States. They use a relatively new technology called messenger RNA (mRNA) that tells human cells to produce antigens, a type of protein that stimulates the immune system. Late clinical studies showed that both vaccines were at least 94% effective. Until the UK approved the Pfizer / BioNTech vaccine on December 2, no RNA vaccine had been approved for general use.
Oxford / AstraZeneca's COVID-19 vaccine uses a more established technique called a viral vector. The vaccine uses a bioengineered version of a harmless cold virus found in chimpanzees to instruct human cells to make antigens.
On December 8th, Oxford published an interim analysis of its test results and more than 1,100 pages of supplementary documents in The Lancet. These show that measuring the concentration of viral materials can be difficult, and they provide information about the chain of events leading to the dosage discrepancy.
Viral vectors are typically produced in bioreactors with a capacity of up to 2,000 liters, which are then filtered and purified into a concentrated batch of active ingredient of just a few liters.
"This is not about measuring pens, pens, bricks or solid objects of a certain size," said Lucio Rovati, managing director of Rottapharm, an Italian biotech company that is trying to develop another type of vaccine using a genetic fragment . "It's about living biological products."
According to the Oxford documents, in May the researchers received a shipment of vaccine from Italy's IRBM / Advent - one of the contract manufacturers, Oxford, which was supposed to complement its own vaccine production. The late stage of the Oxford vaccine was about to begin.
The consignment, batch K.0011, underwent quality control by the Italian company using an established genetic test - quantitative PCR or qPCR - to determine the viral substance per milliliter.
Oxford carried out its own analysis. The university had used a different method known as spectrophotometry. It measures viral material in fluids based on how much ultraviolet light the viral substance absorbs.
The measurement in Oxford showed that the batch was more effective than the Italian manufacturer, as the documents show. Oxford trusted its own result and wanted to be consistent with a measuring instrument it had used in an earlier stage of the experiment. She therefore asked the UK Medicines Agency for permission to reduce the volume of the vaccine injected into the subjects from the K.0011 batch. Permission was given.
"Dosage decisions were all made in consultation with the regulatory agency. When we started the study, we had some inconsistencies in measuring the virus levels in the vaccine," Andrew Pollard, chief investigator for the Oxford study, told Reuters.
A regulator spokeswoman declined to discuss when she first became aware of the dosage issue.
Study participants who received recordings from the Italian batch showed milder than normally expected side effects such as fever and fatigue. Mene Pangalos, executive vice president of AstraZeneca, said the dose was measured incorrectly. "It was half the dose," he told Reuters. He named the bug "serendipity" because data analysis later found that half the dose followed by a full dose booster shot was much more effective than two full doses.
He recently told the BBC, "I think we would have done the study a little differently if we had done it from scratch, no doubt. But ultimately, that's what it is."
IRBM / Advent informed Reuters that there was no manufacturing problem with the batch. The company said in a written statement that the measurement gap was "the result of a change in testing method" that confirmed the effectiveness of the dose "after the material was shipped."
The documents published in The Lancet confirm that the error was with the Oxford researchers. A common emulsifier, polysorbate 80, used in vaccines to facilitate mixing, had interfered with the ultraviolet light meter, which measures the amount of viral material, according to the documents. As a result, the vaccine virus concentration was overrated and Oxford ended up giving half doses of the vaccine, believing it to be full doses.
The documents do not contain a detailed schedule, nor do they show that Oxford informed AstraZeneca at this point. However, they show that Oxford has re-contacted the UK regulator to get approval to change the measurement method to that used by the Italians and to find out how to proceed with a late stage where participants got the wrong dose . The documents do not contain full details of the communication between Oxford and the regulator.
In early June, regulators gave the go-ahead to continue injecting people with half the dose in an attempt to keep the study as large as possible and speed up results, according to the analysis published in The Lancet. The regulator also decided that Oxford would need to add another test group in order to receive the full dose, as per its original plan to test the safety and effectiveness of the full doses.
"We went back and discussed it again with the regulators and agreed with them," said Pollard, the chief investigator for the Oxford study.
Ultimately, 1,367 study participants - none of them over 55 - received the half-dose / full-dose therapy. 4,440 adult participants from all age groups were given two full doses.
The MHRA, the UK regulatory agency, is expected to decide soon whether the vaccine will be approved. The agency is run by June Raine, a doctor who trained in general medicine at Oxford. The university's website shows that she made donations, lectured and volunteered for the university's Somerville College, which she attended.
The MHRA said before a decision is made on the Oxford / AstraZeneca vaccine, Raine will "ensure full transparency" that her interactions with Oxford as an alumnus are explained. It added that "none of these attachments are of a nature that could lead to a conflict that requires rejection."
Deep in the more than 1,100 pages of the supplementary appendices published in The Lancet appeared a description of the dosage discrepancy - "a miscalculation of potency". This approval is included in an Oxford and AstraZeneca Statistical Analysis Plan dated November 17th.
Six days later, Oxford and AstraZeneca announced the interim results of their clinical trials in the UK and Brazil. "Oxford University breakthrough in global COVID-19 vaccine," read the headline of an Oxford press release.
The AstraZeneca press release was more subdued. "Two different dosage regimens have shown effectiveness, with one showing a better profile," it said.
In interviews about the results with Reuters and the New York Times, AstraZeneca's Pangalos spoke of "serendipity," a "useful mistake" and a "dosage error".
But the company's executive director, Pascal Soriot, told Bloomberg, "People call it a mistake - it wasn't a mistake." A spokesman for AstraZeneca declined to comment on the statements.
Meanwhile, the two scientists who led development of the vaccine at Oxford - Sarah Gilbert and Adrian Hill - suggested that half the dose wasn't accidentally given. You didn't provide any evidence. Gilbert, an Oxford vaccination professor, said it was normal for researchers to look at different dosages during vaccination trials. "There was no mix-up on the dosage," she told the Financial Times in an article published Nov. 27.
A few days later, Hill told Reuters that it was a conscious decision by the researchers to give a lower dose. "There was some confusion that we didn't know we were giving half a dose when we were giving it - that's really not true," he said.
Gilbert and Hill have a roughly 10% stake in a private biotech company called Vaccitech, which was spun off from Oxford University. This is according to a notification to Companies House, the UK business register dated October 29th. According to a spokeswoman for Vaccitech, the company transferred its rights to the vaccine to Oxford University's research commercialization division for part of its sales. "If the vaccine is successful, all shareholders and investors in the company could potentially benefit indirectly from it," she wrote in an email.
Hill and Gilbert did not respond to detailed questions about this article.
The conflicting explanations of what went wrong have been criticized by some experts. "Personally, I can say that I think your vaccine is way better than your communication," said Guido Rasi, who until last month was Executive Director of the European Medicines Agency, the European Union's regulator. He said the agency will eventually evaluate the trial data.
For months, the Oxford / AstraZeneca vaccine was described by officials and the media as a front runner in the global race to manufacture a COVID-19 vaccine.
UK Health Secretary Matt Hancock said at a press conference in April that the UK was "at the forefront of global efforts" to find a vaccine.
On June 26, World Health Organization chief scientist Soumya Swaminathan said at a press conference that Oxford's vaccine is likely the world's leading candidate.
Five days later, then-head of the UK's vaccine procurement program, Kate Bingham, told a parliamentary committee: "Oxford is ahead of the world because it is the most advanced vaccine ever."
Some Oxford scholars have done little to dampen the buzz. Gilbert was asked on July 1 in the same parliamentary committee on science and technology whether the world would have to get through the coming winter without a vaccine. "I hope we can improve these schedules and come to your rescue."
In late July, she alluded to competing vaccination efforts. In an interview on the Royal Society of Biology website, she said of the Oxford / AstraZeneca vaccine, "If this doesn't work, I think nothing will."
Your main partner on the project, Hill, was just as optimistic. On May 15, he told Reuters that the Oxford / AstraZeneca candidate was "almost certainly the best single-dose, fast-dose vaccine". He dismissed vaccines using mRNA technology such as Pfizer / BioNTech and Moderna, which have since published results showing that both were at least 94% effective against COVID-19, as "completely unknown" and as a "wild card". The Pfizer / BioNTech vaccine is already sold millions of times in the US and UK.
"Why should you choose a vaccine technology that is new, unproven, maybe quick to make, but expensive to manufacture - that has never been expanded or shown to protect against anything in humans, in a global emergency prioritize? " "" he asked. "It's very strange."
Ian Jones, a professor of virology at the University of Reading, UK, told Reuters that the plethora of optimistic statements had not benefited the Oxford / AstraZeneca vaccine candidate.
"I don't want to deter that everyone has worked very hard and that (the vaccine) is generally safe and healthy," he said. "But the reporting always had a slightly nationalistic tone, which I don't think is helpful."
(Steve Stecklow, Andrew MacAskill and Kate Kelland reported from London; Ludwig Burger from Frankfurt and Emilio Parodi from Milan; additional reporting by Alistair Smout in London and Zeba Siddiqui in Mumbai; editing by Janet McBride)

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