Concerns over Oxford's COVID-19 vaccine with some wondering if high efficacy was a chance finding

Multiple concerns have been raised over the accuracy of the latest trial results for the University of Oxford-AstraZeneca coronavirus vaccine candidate.

An effective jab has long been hailed as a route back to life as we knew it, however, the scale of the pandemic means no single pharmaceutical company can roll out enough doses to stem the outbreak.

With Pfizer’s and Moderna’s candidates already demonstrating up to 95% efficacy, it appeared another jab had been added to the immunisation arsenal after the Oxford-AstraZeneca scientists announced their vaccine was overall 70% effective at warding off the infection.

Although only preliminary data, the scientists were surprised to find the two-dose regimen was up to 90% effective if the first jab was given at a half dose, followed by a full dose vaccine. When both jabs were full dose, efficacy was reported at 62%.

Boris Johnson and medical experts hailed the results as “fantastic”, “tremendously exciting” and a “Herculean achievement”, however, not everyone is as optimistic.

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Among other concerns, many are perplexed the 62% and 90% figures may have been combined to create an overall efficacy outcome of 70%, despite different doses being administered to achieve these percentages.

Others have noted less than 3,000 volunteers received the low-dose, high-dose regimen; a relatively small number of participants for a novel vaccine chasing widespread approval.

With full data yet to be released, it is unclear whether this 90% efficacy outcome achieved statistical significance, effectively proving its value. Critics worry the small volunteer sample size may mean it was just a chance finding.

AstraZeneca announced on 26 November it will specifically test the low-dose, high-dose regimen in a separate study.

Off the back of the Oxford-AstraZeneca announcement, some pointed out the vaccine candidate did not appear to be as effective as the jabs being developed by Pfizer and Moderna, which have demonstrated 90% and 95% efficacy, respectively.

Enthusiasm was therefore boosted when the scientists revealed up to 90% efficacy was achieved with the low-dose, high-dose regimen.

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Variations in how the various vaccines were developed also means the Oxford-AstraZeneca candidate can be stored in a domestic fridge, while the Pfizer and Moderna jabs require temperatures of around -80C (-112F) and -20C (-4F), respectively.

Many have flagged this as being a logistical set back for the Pfizer and Moderna vaccines, particularly when it comes to immunising rural residents in less developed countries.

Muddled dosing

The ongoing Oxford-AstraZeneca trial is made up of more than 20,000 volunteers.

Preliminary data released on 23 November revealed 30 coronavirus cases arose among those who had two doses of the jab, compared to 101 incidences in the participants in the control arm of the trial.

In the UK, the control volunteers were given a saline injection, while in Brazil, these participants were vaccinated against bacteria that commonly cause meningitis – a discrepancy that is also a source of contention.

Regulatory approval tends to be granted off the back of a single large trial with a consistent dosing regimen, as was the case for the Pfizer and Moderna studies.

In the Oxford-AstraZeneca trial, all the volunteers were given two injections 28 days apart.

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Surprised to find the low-dose, high-dose regimen brought about more promising results, the scientists wondered if the initial low dose “primed the immune system”, allowing it to launch a better response down the line.

It has since come to light some of the vaccine vials used in the trial did not contain the full concentration of the jab due to a manufacturing error, which was only identified when some of the participants experienced milder side effects than expected.

This explains why 2,741 of the volunteers were given a half dose initially, despite the trial protocol released ahead of time making no mention of this unusual dosing regimen.

The Oxford-AstraZeneca team claim they discussed the dosing error with vaccine regulators, who gave the green light for some of the participants to receive one half dose and the remainder to have two full doses as planned.

The manufacturing error has been corrected, added the scientists.

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‘Possible it’s a random difference’

The overall 70% efficacy result is thought to have been reached by pooling the 62% outcome among the double high-dose participants with the 90% result achieved by those who had a half dose to start off with.

“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,” said David Salisbury from the Chatham House think-tank, according to AP News.

“I think many people are having trouble with that.”

Dr Moncef Slaoui, head of Operation Warp Speed – the US government’s funding programme for vaccine development – has voiced similar concerns.

“The 90% efficacy group and the 62% efficacy group are overlapping statistically, so it is still possible that difference is a random difference,” he said, according to Ars Technica.

“It’s unlikely but it’s still possible it’s a random difference.”

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With information only coming from press releases to date, many are tempering their enthusiasm until the full data are published.

“We just don’t have all the information we need to tell whether these results are reliable,” said Natalie Dean, from the University of Florida, according to the Financial Times.

“We certainly don’t have enough information in the public domain to decide whether this half dose is really working.”

While the 2,741 people who received the low-dose, high-dose regimen may sound like a large sample size, it is relatively small in the context of testing a novel vaccine in a clinical trial. Some 8,895 participants received the double full vaccine dose.

The small number of low-dose, high-dose participants makes it difficult to gauge whether this regimen is as effective as it appears or if the outcome was just a chance finding.

Dr Anthony Costello, from University College London, told his more than 64,000 Twitter followers: “I don’t want to be a killjoy but there are serious concerns about the design and analysis of the Oxford Astra trial(s).”

The medic, who is also a member of the Independent Scientific Advisory Group for Emergencies (Sage), added the Pfizer and Moderna results have also been reported “way too early”.

The Oxford-AstraZeneca team also did not break down the effectiveness of the different doses according to the participants’ age.

Statistics have repeatedly shown elderly people are significantly more likely to develop coronavirus complications, with these individuals also having a worse response to vaccines in general.

An earlier stage Oxford-AstraZeneca coronavirus vaccine trial suggested the jab brought about a robust immune response in people of all ages.

Dr Slaoui has since announced no one in the recent trial’s low-dose group was over 55, while the double full-dose regimen was given to participants of a range of ages.

It has therefore been suggested the low-dose, high-dose regimen may appear to be more effective due to the participants’ youth, rather than this being the optimal immunisation plan.

‘Embellished results’

With the pandemic a pressing issue, many scientists have released preliminary results of their vaccine trials, before they have been published in a peer-reviewed medical journal.

The Oxford-AstraZeneca vaccine candidate continues to be monitored in ongoing trials in the UK, Brazil and South Africa to help the scientists calculate its optimal dose, as well as gaining more insight into its safety and efficacy.

Full data will later be provided to regulators, who will decide whether to approve the jab for public use.

Geoffrey Porges – an analyst at SVB Leerink – has expressed doubt over whether the Oxford-AstraZeneca vaccine will be approved in the US, claiming the scientists “tried to embellish their results” by suggesting higher efficacy in a “relatively small subset of subjects”.

John LaMattina, a former president of Pfizer’s global research and development unit, tweeted it was “hard to believe” US regulators would grant emergency-use authorisation for a “vaccine whose optimal dose has only been given to 2,300 people”.

Regulators have set the efficacy threshold for a coronavirus jab at 50%, in line with flu vaccines. A jab demonstrating 70% efficacy would therefore be approved.

In the US, a phase III trial – the final step before requesting approval – has recruited around 11,000 volunteers out of a planned 40,000.

Dr Slaoui has said dosing could be altered if the half-dose, full-dose regimen is shown to be effective. Given how pressing the pandemic is – particularly in the hard-hit US – this information will have to arrive quickly, he added.

An AstraZeneca spokesman told the Financial Times the trial was “conducted to the highest standards” and met its primary efficacy endpoint; the main result that is measured at the end of a study to see if a given treatment worked.

He added the release and analysis of more data is pending, which will better reveal how effective the vaccine regimen is and how long any protection may last.

Yahoo UK has also contacted AstraZeneca for a comment.

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