Oxford University and AstraZeneca 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 did not receive as much vaccine in the first of two shots as expected.
In a surprise finding, 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.
The partial results announced on Monday are from large ongoing studies in the UK 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, and 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 analyse the results. Any deviation from that protocol can put the results in question.
In a statement on Wednesday, Oxford University said some of the vials used in the trial did not have the right concentration of vaccine, meaning some volunteers got a half dose. The university said 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 said 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 is that 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, rather than the size of the dose, is why it looked more effective.
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, an associate fellow of the global health programme 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 said they are not certain why a smaller does would be more effective and are working to uncover the reason.
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," she said. "Too much could give you a poor quality response as well. 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 UK regulators so they can decide whether to authorise 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 will give a more complete picture of how effective the vaccine is.
Moncef Slaoui, who leads the US coronavirus vaccine program Operation Warp Speed, said on Tuesday in a call with reporters that US officials are trying to determine what immune response the vaccine produced and may decide to modify the AstraZeneca study in the US to include a half dose."But we want it to be based on data and science," he said.