AstraZeneca manufacturing error raises questions about vaccine study results
Some vials used in trial didn't have right concentration of vaccine
AstraZeneca and Oxford University on Wednesday acknowledged a manufacturing error that is raising questions about preliminary results of their experimental COVID-19 vaccine.
A statement describing the error came days after the company and the university described the shots as "highly effective" and made no mention of why some study participants didn't receive as much vaccine in the first of two shots as expected.
In a surprise, the group of volunteers that got a lower dose seemed to be much better protected than the volunteers who got two full doses. In the low-dose group, AstraZeneca said, the vaccine appeared to be 90 per cent effective. In the group that got two full doses, the vaccine appeared to be 62 per cent effective. Combined, the drugmakers said the vaccine appeared to be 70 per cent effective.
But the way in which the results were arrived at and reported by the companies has led to pointed questions from experts.
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The partial results announced Monday are from large ongoing studies in the U.K. and Brazil designed to determine the optimal dose of vaccine, as well as examine safety and effectiveness. Multiple combinations and doses were tried in the volunteers. They were compared to others who were given a meningitis vaccine or a saline shot.
Before they begin their research, scientists spell out all the steps they are taking and how they will analyze the results. Any deviation from that protocol can put the results in question.
Real or quirk?
In a statement Wednesday, Oxford University said some of the vials used in the trial didn't have the right concentration of vaccine so some volunteers got a half dose. The university said that it discussed the problem with regulators, and agreed to complete the late-stage trial with two groups. The manufacturing problem has been corrected, according to the statement.
Experts say the relatively small number of people in the low-dose group makes it difficult to know if the effectiveness seen in the group is real or a statistical quirk. Some 2,741 people received a half dose of the vaccine followed by a full dose, AstraZeneca said. A total of 8,895 people received two full doses.
Another factor: none of the people in the low-dose group were over 55 years old. Younger people tend to mount a stronger immune response than older people, so it could be that the youth of the participants in the low-dose group is why it looked more effective, not the size of the dose.
Another point of confusion comes from a decision to pool results from two groups of participants who received different dosing levels to reach an average 70 per cent 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 said of the figure. "I think many people are having trouble with that."
Oxford researchers say they aren't certain and they are working to uncover the reason.
'The Goldilocks amount'
Sarah Gilbert, one of the Oxford scientists leading the research, said the answer is probably related to providing exactly the right amount of vaccine to trigger the best immune response.
"It's the Goldilocks amount that you want, I think, not too little and not too much. Too much could give you a poor quality response as well," she said. "So you want just the right amount and it's a bit hit and miss when you're trying to go quickly to get that perfect first time."
Details of the trial results will be published in medical journals and provided to U.K. regulators so they can decide whether to authorize distribution of the vaccine. Those reports will include a detailed breakdown that includes demographic and other information about who got sick in each group, and give a more complete picture of how effective the vaccine is.
At the heart of concerns is that the trial's most promising result of 90 per cent comes from a sub-group analysis — a technique many scientists say can produce spurious readings.
"Sub-group analyses in randomized controlled trials are always fraught with difficulties," said Paul Hunter, a professor of medicine at Britain's University of East Anglia.
He said, in particular, such analyses increase the risk of "type 1 errors" — in other words, where an intervention is considered to be effective when it is not.
This is in part because the number of participants is greatly reduced in a sub-group — making it harder to be confident that a finding is not just down to chance differences or similarities among participants.
Moncef Slaoui, who leads the U.S. coronavirus vaccine program Operation Warp Speed, said Tuesday in a call with reporters that U.S. officials are trying to determine what immune response the vaccine produced, and may decide to modify the AstraZeneca study in the U.S. to include a half dose.
"But we want it to be based on data and science," he said.
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Dr. Matthew Oughton, an attending physician at Jewish General Hospital in Montreal, said he thinks there will be ongoing discussions to find out as much as possible about how effective and safe the vaccine is.
"I think if we wait until the companies are completely done their trials before discussing then perhaps we will have missed opportunities," Oughton said Thursday on CBC News Network.
For example, additional trials could help to address questions as they come up to provide better answers, he said.
AstraZeneca said the administering of the half dose was reviewed and approved by independent data safety monitors and the U.K. regulator, adding that the regulator publicly confirmed there was "no concern."
With files from CBC News and Reuters