Enlarge /. Vials in front of the logo of UK biopharmaceutical company AstraZeneca can be seen in this creative photo taken on November 18, 2020.
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Pharmaceutical company AstraZeneca and Oxford University made an exciting announcement on Monday: The jointly developed COVID-19 vaccine appeared to be up to 90 percent effective at preventing disease. But in the days since, that exciting news merged into a pool of confusion after it became clear that the 90 percent figure came from a complete accident. Now experts are scratching their heads about what actually happened in the study and what that means for the future of the vaccine.
The questions all revolve around the vaccine dosage regimen. In initial press releases, AstraZeneca and Oxford stated that researchers had used two different dosage regimens to test their experimental AZD1222 vaccine. In one regimen, the study participants received two “full” doses of the vaccine 28 days apart. In the other, participants received half a dose of vaccine followed by a full dose 28 days later.
The researchers pooled the results of studies in the UK and another in Brazil and found that the two-full-dose regimen was 62 percent effective against COVID-19 – a good but not great result. The half-dose / full-dose regimen, on the other hand, appeared to be 90 percent effective – a pretty impressive result.
The problem is that none of the studies should have half-dose-full-dose therapy.
"The reason we got half the dose is coincidence," said Mene Pangalos, head of non-oncology research and development at AstraZeneca, in an interview with Reuters on Monday.
Pangalos explained that at the start of the UK study, the Oxford researchers gave patients their first round of shooting and found that the vaccine side effects – fatigue, headache, arm pain – were milder than expected.
"So we went back and checked … and found that they underestimated the dose of the vaccine by half," Pangalos said. The researchers then decided to continue the study and give the relatively small number of incorrectly dosed patients the correct dose for their second shot.
In the pooled trial analysis, 2,741 participants were recruited while the incorrect half-dose / full-dose regimen was being used and 8,895 participants were involved in the analysis of the two-full-dose regimen.
AstraZeneca and Oxford put some thought into how exactly this error occurred. In the meantime, external experts have expressed doubts as to whether the 90 percent effectiveness of the half / full dose is even real, given the smaller number of participants.
Another wrinkle is that the dosing error occurred at the start of the study when researchers were only recruiting people between the ages of 18 and 55 – with the exception of the elderly, who were more prone to disease. The analysis with the two full doses, on the other hand, included older age groups.
"There are a number of variables that we need to understand and what role each of them played in making the difference in effectiveness," Moncef Slaoui, chief scientist for the US government's Operation Warp Speed, told a news conference on Tuesday .
Operation Warp Speed has invested in AZD1222 and is supporting an ongoing study of the vaccine in the US. Slaoui noted at the press conference that they knew about the dosing error at the time of the incident. "When they found there was a mistake – or a change in approach, technique used – they corrected it," he said.
After the results were released, Slaoui said it was important to look into what went on between the two regimes. On the one hand, researchers should examine whether there are different immune responses that are induced by the different dosage regimens. Some researchers have speculated that increasing the vaccine dose between the first and second shots might have helped build better immune responses against the pandemic coronavirus SARS-CoV-2.
Others have speculated that starting with a heavy dose – as in the two-full-dose regimen – due to the way AZD1222 was developed, may have thwarted effectiveness. The vaccine uses a weakened adenovirus as packaging to provide the immune system with the genetic code for the SARS-CoV-2 spike protein. However, starting off with a strong first dose may cause the immune system to focus on attacking the adenovirus rather than the packaged coronavirus component, some think.
Once the researchers have a better understanding of what is going on, they can make decisions about changing the ongoing studies, Slaoui said. In the US, approximately 11,000 out of a planned 40,000 participants were recruited for a Phase III study with AZD1222. So it could still be changed to include the half-dose regimen as new information comes in. Salaoui noted, however, that given the speed at which the pandemic is advancing in the U.S., such information needs to be received quickly.
In conclusion, Slaoui reiterated that the difference in effectiveness and the dosage error could be meaningless overall: “The 90 percent effectiveness group and the 62 percent effectiveness group statistically overlap, so it is still possible that this difference exists random difference, ”he said. "It's unlikely, but it's still possible that the difference was accidental."