AstraZeneca meets threshold for approval despite dosing error

A top executive at AstraZeneca PLC on Wednesday rejected criticism that the company failed to disclose enough data from a clinical trial of its COVID-19 vaccine, and acknowledged scepticism about the vaccine’s 90% effectiveness in a group of patients who were accidentally given a lower dose than intended.

“I’m not going to pretend it’s not an interesting result, because it is—but I definitely don’t understand it and I don’t think any of us do,” said Mene Pangalos, AstraZeneca’s executive vice president for biopharmaceuticals research and development. “It was surprising to us.”


AstraZeneca on Monday said in interviews with news media that the half-dose regimen was the result of a manufacturing error, which neither the company nor Oxford initially mentioned in their press releases announcing the results. The dosing error was identified after a trial investigator noticed that volunteers weren’t having as much of an inflammatory response to the shot, prompting the researchers to analyze their vaccine supply and find that they had miscalculated the dose, Dr Pangalos said.

AstraZeneca and Oxford informed regulators in the U.K., U.S., and European Union and amended the study design to include the half-dose group in their analysis.

“The mistake is actually irrelevant,” said Dr Pangalos. “Whichever way you cut the data—even if you only believe the full-dose, full-dose data….We still have efficacy that meets the thresholds for approval with a vaccine that’s over 60% effective.”

Oxford researchers said on Monday that the lower dose may have been more effective because it more accurately reflects the natural immune response to viruses, but that they would have to investigate the findings further to know for sure.

Other factors could also be at play. The half-dose was only given to volunteers 55 and younger, whereas the full-dose group also included older patients, said Dr Moncef Slaoui, chief scientific adviser to the U.S. government’s Operation Warp Speed initiative, on a call with reporters on Tuesday, the first disclosure of the lack of older participants in the half-dose group. It is also possible that the difference between the groups was a statistical fluke and the result of chance, he said.

“There are a number of variables that we need to understand,” said Dr Slaoui. “It’s unlikely but it’s still possible that it’s a random difference.”

The U.K. company said on Monday that the vaccine it is codeveloping with the University of Oxford was on average about 90% effective in preventing Covid-19 when volunteers were given a half-dose shot followed by a full dose a month or more later, but only 62% effective when two full doses were given. The data pooled trial results from the U.K. and Brazil.

U.S. regulators have set the bar for authorizing vaccines at 50% effectiveness, but vaccines in development by Moderna Inc. and partners Pfizer Inc. and Germany’s BioNTech SE have made the study results greater than 90% effectiveness. Those vaccines use a new gene-based technology that, despite its impressive clinical results thus far, requires the shots to be stored at subzero temperatures. AstraZeneca’s vaccine can be stored in a more standard refrigerator, which could make it attractive to low- and middle-income nations.

Independent scientists and U.S. government officials said the data is further proof that vaccines can prevent COVID-19, but they also cautioned that the 90% effectiveness rate might not hold up under further analysis.

AstraZeneca plans to test the half-dose regimen in a large, ongoing U.S. study expected to enrol more than 30,000 volunteers, Dr Pangalos said. The study has enrolled more than 11,000 volunteers and could have results soon given the progression of the pandemic, Dr Slaoui said.

Dr Pangalos said there is a theoretical rationale for why a lower first dose might work, but that he wouldn’t speculate until the researchers investigate the data further. “I’m not going to handwave with the immunologists,” he said. “Until I see some data that gives me some science behind it, I’m going to say ‘I don’t know.’”

Some scientists have criticized AstraZeneca for not revealing key data from the trial results, such as how the number of infections that occurred across patient groups and broken down by age and severity of disease—though the company did say that no patients receiving the vaccine developed severe disease or required hospitalization.

“AstraZeneca provided very little real information for one to independently assess how their vaccine trials are doing,” said Shane Crotty, a vaccine and infectious diseases researcher at La Jolla Institute for Immunology. “It’s quite reasonable for people to be sceptical.”

Dr Pangalos said the researchers only received the data last weekend and are working to quickly release the full data in a peer-reviewed journal. “The right way of publishing and documenting the results is in a scientific journal, and these data will all be published within the next week or so,” he said.