Oxford University and AstraZeneca have acknowledged a manufacturing error meant some trial participants received only a partial dose of their experimental Covid-19 vaccine.
The announcement has raised questions about why researchers did not mention the error when they claimed the jab was “highly effective” just days ago.
It has also raised some concerns about the part of the study which showed a 90% success rate. Oxford and AstraZeneca have since addressed these issues and explained the next steps for the jab, to ensure its safety and effectiveness.
AstraZeneca CEO Pascal Soriot told Bloomberg News: “Now that we’ve found what looks like a better efficacy, we have to validate this, so we need to do an additional study.”
Soriot said he did not expect the additional trial to hold up regulatory approvals in the UK and European Union – but it is thought the concerns over the trial could hold up approval in the US.
Here is what we know:
On Monday, Oxford and AstraZeneca announced preliminary results from trials showed an average efficacy of 70% – a figure reached by pooling the results from two different dosing regimens.
One month apart, one set of volunteers received two identical doses while the other received a half-dose, and then a full dose. In the first group, the efficacy was 62%. In the second, 90%.
The results were hailed a success, but it has since been revealed that some volunteers were only given a half dose because some of the vials did not have the right concentration of vaccine.
Mene Pangalos, R&D lead at AstraZeneca, admitted to this dosing error to Reuters on Monday.
The manufacturing error was only caught when some of the people in the study did not show the usual adverse effects. Oxford has said it discussed the problem with regulators and completed the late-stage trial with two groups.
The second subgroup – the one that had a 90% efficacy – was also limited to participants aged 55 and below.
In a statement on Wednesday, Oxford acknowledged a difference in manufacturing and measurement processes meant later phases of its clinical studies resulted in half a dose being administered instead of a full one.
“The methods for measuring the concentration are now established and we can ensure that all batches of vaccine are now equivalent,” it said.
What this could mean
Some parts of the scientific community have responded to the news with confusion and discontent, with Oxford and AstraZeneca coming under fire for lack of transparency.
Experts have said the relatively small number of people in the low dose group – 2,741 compared to the 8,895 people who received two full doses – means it is difficult to know if that average efficacy is accurate.
The fact that the low-dose group were all aged 55 and under has also sent alarm bells ringing. Younger people are generally at a lower risk of developing severe Covid-19, so the results of the group could merely reflect this stronger immune response.
This is a particularly significant problem because many people on the list of groups to be prioritised to receive a Covid-19 vaccine would fall into the category of over the age of 55.
Experts have also highlighted the fact that the results of the Oxford vaccine trials came out of two separate studies: one in the UK and one in Brazil.
In the UK, participants who were not given the vaccine were administered a meningococcal vaccine. In Brazil, the equivalent group was administered a saline placebo.
The variation in “control” injections in volunteers has led to concerns that the data is not standardised and cannot be combined into a single efficacy result.
“We just don’t have all the information we need to tell whether these results are reliable,” Natalie Dean, an assistant professor of biostatistics at the University of Florida, told the Financial Times.
“We certainly don’t have enough information in the public domain to decide whether this half dose is really working.”
Another point of confusion comes from a decision to pool the results to reach an average 70% effectiveness, said David Salisbury, and associate fellow of the global health program at the Chatham House think tank.
“You’ve taken two studies for which different doses were used and come up with a composite that doesn’t represent either of the doses,” he told Associated Press. “I think many people are having trouble with that.”
By combining two separate trials into one combined data, Oxford/AstraZeneca could be indicating results from each were not clear enough to release on their own, Wired magazine reported, calling the incident a “scientific red flag with flashing lights”.
This could also mean the Oxford vaccine might not receive regulatory approval as soon as hoped.
John LaMattina, a former president of Pfizer’s global R&D unit, said it would be hard to believe regulators in the US would issue an emergency-use authorisation for the vaccine.
What have Oxford and AstraZeneca said?
A spokesperson from AstraZeneca said the trials were “conducted to the highest standards” and met their primary efficacy endpoint.
Details of the trial results will be published in peer-reviewed journals and provided to UK regulators. These will provide a more complete picture of how effective the vaccine really is, and help regulators decide whether to authorise its distribution.
When reached for comment, a spokesperson from Oxford University said: “During the phase III trials, our UK study used two dose levels.
“The initial dose selection, which was agreed with regulators, was based on the same measurement of the concentration (using spectrophotometry) used in the phase I study, but, as a result of a difference in the manufacturing process for the later study, this method was subsequently shown to over-estimate the dose on the new batches of vaccine resulting in a half dose of the vaccine being administered as the first dose.
“We have different ways of measuring the concentration of the vaccine and when it was apparent that a lower dose was used, we discussed this with the regulator, and agreed a plan to test both the lower dose/higher dose and higher dose/higher dose, allowing us to include both approaches in the phase III trial.
“The methods for measuring the concentration are now established and we can ensure that all batches of vaccine are now equivalent.”
What about the other vaccines?
The Moderna and Pfizer/BioNTech experimental vaccines only involved single trials and released trial protocols weeks ahead of time for expert scrutiny.
But neither of the jabs have been tested for whether they break transmission of Covid-19, only for whether they stop people from developing Covid-19 symptoms or testing positive.
Despite this recent news, the Oxford vaccine is still the best hope for many countries as it is cheaper than the mRNA vaccines and can be stored in a refrigerator instead of a freezer.
It is also the UK’s best chance for mass vaccination by the end of spring, as the government has already ordered 100 million doses to vaccinate 50 million people.
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