AstraZeneca’s best COVID vaccine result was a fluke. Experts have questions

Pharmaceutical giant AstraZeneca and the University of Oxford made an exciting announcement on Monday: The COVID-19 vaccine they developed together appears to be up to 90% effective in preventing disease. But in the days that followed, this exciting news turned into a pool of confusion after it became clear that the 90% figure was from a complete accident. Now, experts are scratching their heads over what actually happened in the trial and what that means for the future of the vaccine.

The questions all revolve around the dosing schedule of the vaccine. In early press releases, AstraZeneca and Oxford explained that the researchers used two different dosing regimens to test their investigational vaccine, AZD1222. In one scheme, trial participants received two “full” doses of the vaccine, 28 days apart. In the other, participants received a half dose of the vaccine followed by a full dose 28 days later.

Combining the results of trials in the UK and another in Brazil, researchers found the full two-dose regimen to be 62% effective in preventing COVID-19 – a good result, but not so good. . The half-dose / full-dose regimen, on the other hand, appears to be 90% effective – a rather impressive result.

The problem is, there was never meant to be a full half-dose-dose regimen in any of the trials.

Serendipity?

“The reason we got the half-dose was coincidence,” Mene Pangalos, head of non-oncology research and development at AstraZeneca, told Reuters on Monday.

Pangalos explained that when the UK trial began, researchers at Oxford were giving patients their first round of vaccines and noticed that the side effects of the vaccine – fatigue, headache, pain in the arms – were more lighter than expected.

“So we went back and checked … and found out that they had underestimated the dose of the vaccine by half,” Pangalos said. The researchers then decided to continue the trial and give the relatively small number of incorrectly dosed patients the appropriate dose for their second injection.

In the analysis of pooled trials, 2,741 participants were recruited while the incorrect half-dose / full-dose regimen was used and 8,895 participants were involved in the analysis of the two-full-dose regimen.

AstraZeneca and Oxford are not sure exactly how this error occurred. Meanwhile, outside experts have raised doubts about 90% effectiveness with the half dose / full dose, given the smaller number of participants.

Another difficulty is that the dosing error occurred at the start of the trial, when researchers were only recruiting people between the ages of 18 and 55, excluding older people more vulnerable to the disease. The analysis with the two full doses, in contrast, included older age groups.

Persistent questions

“There are a number of variables that we need to understand and what was the role of each of them in making the difference in efficiency,” said Moncef Slaoui, Chief Scientist of Operation Warp Speed. From the US government, during a press briefing Tuesday. .

Operation Warp Speed ​​has invested in AZD1222 and is supporting an ongoing trial of the vaccine in the United States. Slaoui noted during the press conference that they were aware of the dosing error at the time it happened. “When they realized there was a mistake – or a change in the approach, the technique used – they corrected it,” he says.

Now that the results are out, Slaoui says it’s important to dig into what was going on between the two regimes. On the one hand, researchers should look to see if there are different immune responses induced by different dosing regimens. Some researchers have speculated that increasing the dose of the vaccine between the first and second vaccines might have helped develop better immune responses against the pandemic coronavirus, SARS-CoV-2.

Others have speculated that starting with a high dose – as in the two full dose regimen – might have foiled effectiveness because of the way AZD1222 is designed. The vaccine uses a weakened adenovirus as a packaging to deliver the genetic code for the SARS-CoV-2 spike protein to the immune system. But starting with a strong first dose may cause the immune system to focus on attacking the adenovirus, rather than the packaged coronavirus component, some believe.

Once the researchers have a better understanding of what was going on, they can then make decisions about modifying the ongoing trials, Slaoui said. In the United States, approximately 11,000 of the planned 40,000 participants have been enrolled in a phase III trial of AZD1222. Thus, it could be further modified to include the half-dose regimen if new information comes in. However, Salaoui noted that this information should come quickly, given the pace of progression of the pandemic in the United States.

On a final note, Slaoui again pointed out that the difference in efficacy and the dosing error as a whole might be meaningless in the end: “The 90% efficacy group and the 62 efficacy group % overlap statistically, so it’s always possible that this difference is a random difference, ”he says. “It’s unlikely, but it’s always possible that it’s a random difference.”