Unrest is growing over the way Oxford University and AstraZeneca have handled the early readout of trials of their coronavirus vaccine, which much of the developing world can rely on to get out of the pandemic.
The results were recognized as success as they showed an average efficacy of 70 percent – a figure achieved by pooling the results of cohorts on two different dosing regimens.
One group of participants received two identical doses one month apart, while the other group received half a dose and then a full dose. The effectiveness for the first larger group was 62 percent. In the second subgroup it was 90 percent.
It turned out that the administration of half the dose started with a mistake. It was then given to a smaller number of participants than those who received two full doses, making the discovery of its greater effectiveness seem like a happy break.
On Tuesday, Moncef Slaoui, head of Operation Warp Speed, the U.S. government's funding program for vaccine development, announced that the second subgroup is also restricted to those under the age of 55, a population group at lower risk of developing severe Covid-19 to get sick.
Oxford and AstraZeneca did not disclose the age distribution on Monday when the results were released.
"There are a number of variables that we need to understand," said Slaoui. It's still possible that the difference in potency was "accidental," he added.
The markets have taken notice. AstraZeneca shares listed in London have lost more than 6 percent since the announcement. By comparison, since their vaccine study results were published earlier this month and show 90 percent effectiveness, Pfizer and BioNTech holdings have increased 6 percent and 14 percent, respectively. Moderna is up 11 percent since vaccine trial data was released, on top of the large gains leading up to the release.
An early reviewer this week, Geoffrey Porges, an analyst at SVB Leerink, said the AstraZeneca push was unlikely to be allowed in the US after the company “tried to beautify” its results by adding greater potency in a "relatively small subset" highlighted by subjects in the study ".
John LaMattina, former president of Pfizer's global research and development unit, wrote on Twitter that it was "hard to believe" that US regulators would give emergency approval for a "vaccine whose optimal dose was only given to 2,300 people."
Much of the confusion is due to the fact that Oxford and AstraZeneca did not fully explain the reason for the two different dosing regimes – which changed unexpectedly as the trials progressed.
In a statement late Wednesday, Oxford admitted that a difference in manufacturing and measurement processes meant that later stages of its clinical trials resulted in half a dose being incorrectly administered instead of a full.
The methods for measuring concentration are now in place and we can ensure that all vaccine lots are now equivalent
Wednesday's statement said this was discussed at the time with regulators, who agreed to use two test schemes. "The methods for measuring concentration are now established and we can ensure that all vaccine lots are now equivalent," it said.
Richard Lawson, a UK study participant who still does not know whether he received the vaccine or a placebo because the study has not yet been unblinded, told the Financial Times that he was informed of the mix-up in July before joining one Received refresher shot.
Typically, vaccinators aim for the lowest dose that is still effective, but the effectiveness of the lower dose is not yet explained.
Pascal Soriot, managing director of AstraZeneca, told Bloomberg News on Thursday that the company would conduct an "additional study" to confirm the different rates of effectiveness.
"Now that we've found better effectiveness, we need to validate this and do an additional study," said Soriot.
In response to a request for comment on the Bloomberg interview, AstraZeneca replied late Thursday, "As we announced earlier this week, it makes a lot of sense to investigate the half-dose / full-dose regimen further."
The company said it will continue to evaluate the data and work with regulators to find the best approach to doing it. This would "complement data from existing studies" currently being prepared for the submission of regulations.
Oxford professor Sarah Gilbert has said that it is possible that a lower starting dose could stimulate the immune system in a way that better mimics a natural infection. However, there is no precedent for other vaccines to be administered this way.
"We just don't have all the information to determine whether these results are reliable," said Natalie Dean, assistant professor of biostatistics at the University of Florida. "We certainly don't have enough information in the public domain to decide whether this half dose really works."
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Prof. Dean compared the information from AstraZeneca with those of other studies. "We had set that precedent through the other vaccines with Moderna and Pfizer / BioNTech, and these were stand-alone studies with a pre-published protocol," she said. “We had the opportunity to look through it. . . It was pretty easy. "
There are also concerns about the differences in how the Oxford vaccine is tested in different countries. In addition to different dosage regimens, there were also differences between the control groups in different countries: in the UK, participants who did not receive the Covid-19 vaccine were given a meningococcal vaccine; In Brazil they were given a table salt placebo.
These discrepancies have led to the suggestion that the data are too sketchy to be combined into a single convincing efficacy result.
An AstraZeneca spokesperson defended the study, saying it was "conducted to the highest standards" and had reached its primary efficacy endpoint. The company announced that more data will continue to accumulate and additional analysis will be conducted to refine the effectiveness indicator and determine how long the vaccine will protect against the virus.
The results are published in a peer-reviewed journal, and regulators have set a 50 percent effectiveness threshold, which means that a sting with 70 percent effectiveness is still going to be approved.
Despite the questions about effectiveness, the Oxford / AstraZeneca vaccine offers some undoubted benefits. It's cheaper than Moderna and Pfizer / BioNTech's mRNA vaccines and can be stored in the refrigerator rather than the freezer.
Oxford University said it "fully" understood the interest in the discovery of the dosing bug and the change in dosing tactics approved by UK regulators.
“As this is a complex scientific area, our scientists would like to wait until the Phase 3 interim results are peer-reviewed in The Lancet [Medical Journal] before discussing this further, which we expect in the next few weeks. "it said.
Additional coverage from Hannah Kuchler in New York and Kiran Stacey in Washington