LONDON – 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% effective. In the group that got two full doses, the vaccine appeared to be 62% effective. Combined, the drugmakers said the vaccine appeared to be 70% 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 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.
It’s not clear what effect, if any, these results will have on a 30,000-person trial of the same candidate vaccine in the United States.
All 11,000 people who have participated in the U.S. trial so far have received two equal doses of the vaccine, said Moncef Slaoui, co-director of Operation Warp Speed, the Trump administration program to develop, manufacture and distribute COVID-19 vaccines.
Not enough people in the study have come down with COVID-19 to trigger an interim effectiveness analysis, and the company can’t review the results until then.
Slaoui, a career vaccine developer who has been overseeing the AstraZeneca/Oxford trial in the U.S., said via email that he has confidence in the process here, “and we have, I believe, a more controlled situation.”
Did researchers mean to give a half dose?
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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.
In a statement Wednesday, Oxford University said some of the vials used in the trial in the U.K. and Brazil 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.
What about the results themselves?
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% effectiveness, said David Salisbury, an 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.″
Why would a smaller first dose be more effective?
Oxford researchers say they aren’t certain and they 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. 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.”
Will the dosage issue affect FDA approval?
AstraZeneca can use the results of its trial in the U.K. and Brazil in applying for FDA authorization of its vaccine, but it’s pursuing a separate trial in the U.S. as well.
The American trial is expected to be fully enrolled with 30,000 people by the end of the calendar year, with effectiveness results available early in 2021, Slaoui said.
The age range of participants in the U.S. study is wider, he said, including more senior citizens. It also includes many people from different ethnic and racial backgrounds and people in high-risk groups because they have conditions that would predispose them to getting sicker if infected.
Slaoui is working with AstraZeneca to try to understand why the lower initial dose may have triggered a more effective response than two full doses and whether that response can be reproduced.
“If that turns out to be the case, then we will consider whether to use that schedule also in the U.S. trial,” he said.
Vaccine candidates from Pfizer/BioNTech and Moderna were the first to report results, showing they are 95% effective. Many experts anticipated other vaccines that target the same protein, including the AstraZeneca/Oxford one, would have the same effectiveness.
In May, Operation Warp Speed promised AstraZeneca/Oxford $1.2 billion to manufacture 300 million doses of its proposed vaccine, called AZD1222.
The government has pledged just under $2 billion to Pfizer/BioNTech to manufacture 100 million doses of its candidate vaccine, and roughly the same amount to Moderna to develop and manufacture 100 million doses. Both are expected to be authorized next month by the U.S. Food and Drug Administration.
What are the next steps?
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 they will give a more complete picture of how effective the vaccine is.