Dosing Mix-up Raises Questions About Promising Covid-19 Vaccine

Dosing Mix-up Raises Questions About Promising Covid-19 Vaccine
Vials used by pharmacists to prepare syringes for an experimental vaccine. (Image: Associated Press, AP)

A manufacturing error is raising concerns about a promising covid-19 vaccine being developed by pharmaceutical company AstraZeneca and the University of Oxford.

Less than a week after we learned about the promising new vaccine, the developers have admitted to a manufacturing error that resulted in two different doses being administered during the recently concluded phase III trial, as the Associated Press reports. This promising covid-19 vaccine, developed by AstraZeneca and the University of Oxford, was described as being 70% effective at protecting against the coronavirus, but that number now seems a bit misleading — and not necessarily in a bad way.

The two separate doses used during the trial had a direct bearing on the results, in which participants who were given a lower dose of the vaccine appeared to be better protected (90% efficacy) than those who were given full doses (62% efficacy). That a lower dose group was included in the trial was the result of a manufacturing error, as the developers admitted yesterday. And because different age groups were included in the two versions of trial — one in the United Kingdom and one in Brazil — the results of this trial are clouded even further.

According to Bloomberg, AstraZenica will now likely conduct an additional global trial to evaluate the efficacy of its covid-19 vaccine.

“Now that we’ve found what looks like a better efficacy we have to validate this, so we need to do an additional study,” said AstraZenica CEO Pascal Soriot, as quoted by Bloomberg. The pending trial will probably be another “international study, but this one could be faster because we know the efficacy is high so we need a smaller number of patients.”

This vaccine, known as AZD1222, uses a virus taken from a chimpanzee. The virus, technically an adenovirus, is harmless and incapable of self-replication, but it’s still capable of infecting a cell. And because it’s equipped with genetic instructions for churning out coronavirus surface proteins, it prompts the desired immune response to fight covid-19.

In the wake of the encouraging test results, AstraZeneca said it could produce 3.75 billion doses in 2021. Vaccine AZD1222 is particularly promising in that it’s relatively inexpensive to produce, and it can be stored in a regular refrigerator (unlike two other promising vaccine candidates, one from Moderna and one from Pfizer, that will require extreme cold storage).

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When the AZD1222 phase III trial first began, both the U.K. and Brazil groups were supposed to get a full initial dose, called the prime dose, followed by a booster dose around 30 days later. As the U.K. version of the study unfolded, however, the researchers noticed that the vials were only half full, the result of an unexplained manufacturing error.

This meant that people participating in the U.K. trial had been receiving half of the required dose for the prime shot. Instead of calling it quits or excluding these half-dose people from the trial, the team decided to alter the study protocols, which they did after consulting with regulators. The updated protocol involved a half prime dose and full booster dose for participants in the U.K., and a full prime and full booster for participants in Brazil. In total, 2,741 participants were in the low dose group, and 8,895 were in the full dose group.

Unexpectedly, the vaccine worked better in the low dose group, at 90% efficacy, while the full dose group exhibited 62% efficacy. For some strange reason, however, the developers declared 70% efficacy, which doesn’t make any sense, as that figure now seems completely spurious.

“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,” David Salisbury, an associate fellow at the Chatham House think tank, told the Associated Press.

To further complicate the matter, no one in the low dose group was over the age of 55, which wasn’t the case for the full dose group. This convolutes the results even more, as younger people tend to mount stronger immune responses to covid-19.

There are a bunch of takeaways here, but that’s not to say this vaccine won’t be a major contributor in our fight against the pandemic. It probably will.

We’re all rooting for this vaccine to succeed, but this latest episode reminds us of the challenges involved when trying to develop medicines on accelerated timelines. Relatedly, and as this incident also shows, it’s really tough to get the dosages right. When it comes to facilitating an optimal immune response, more isn’t necessarily better, as this trial has so splendidly revealed, even if it wasn’t deliberate.

Finally, this news, which comes several days after the initial announcement of the test results, comes to us via a press release. As it stands, the AstraZeneca and University of Oxford scientists have yet to publish their results in formal scientific paper for all to see. Until that finally happens, we’re all left guessing about their phase III trial and this apparently promising covid-19 vaccine.