Half-dose finding ‘a useful mistake’ says Mene Pangalos, amid scrutiny of AstraZeneca and Oxford’s Covid-19 vaccine trial
AstraZeneca’s Sir Mene Pangalos has described the finding that a half dose of its Covid-19 vaccine followed by a full dose was 90 per cent effective as “a useful mistake”.
His comments came amid growing international scrutiny about the readout of data from the Cambridge-based biopharmaceutical company and Oxford University concerning their vaccine trial results.
They announced on Monday that overall efficacy from two different dosing regimes in a Phase III trial was 70 per cent.
A half dose followed by a full dose was found to be 90 per cent effective, according to a subset of data involving 2,741 participants, but the efficacy was 62 per cent among the 8,895 people given two full doses.
Earlier this week, Moncef Slaoui, the scientific head of the US’s Operation Warp Speed – the programme to supply America with vaccines – confirmed that the half-dose regime was only given to people aged 55 and under.
Older people are, however, most at risk from Covid-19.
Results from an earlier Phase II study published in The Lancet medical journal did show though that the vaccine produced a strong response in all age groups.
A new peer-reviewed study of the latest data is expected in The Lancet this weekend.
Meanwhile, AstraZeneca has said it expects to carry out a further global clinical trial using the half-dose regime, but does not expect that to hold up regulatory approval of the vaccine in countries, including the UK, which has purchased 100 million doses.
There has been disquiet, however, that the reason for the half-dose regime was not initially disclosed.
It has emerged that as university researchers were distributing the vaccine candidate at the end of April, they noticed that there were milder side effects - such as fatigue, headaches and sore arms - than expected.
Cambridge-based Dr Pangalos, AstraZeneca’s executive vice president, biopharmaceuticals R&D, said they found they had “underpredicted the dose of the vaccine by half” - leading to a result he described as “serendipity”.
Dr Pangalos told the New York Times: “The reality is, it could end up being quite a useful mistake. It wasn’t putting anyone in danger. It was a dosing error. Everyone was moving very fast.
“We corrected the mistake and continued on with the study, with no changes to the study, and agreed with the regulator to include those patients in the analysis of the study as well.
“What is there to disclose? It actually doesn’t matter whether it was done on purpose or not.”
A spokesman for AstraZeneca said on Thursday: “As the development of the vaccine was scaled up into the Oxford-sponsored Phase II/III trial, the measurement used for earlier trials was shown to over-estimate the strength of dose in the new larger batches, resulting in a half dose of the vaccine being administered.
“This was reviewed by the independent Data Safety Monitoring Board and the UK regulator, both of whom approved the continuation of this dosing regimen and the regulator publicly confirmed that there was ‘no concern’.
“All other regulatory authorities were informed that we would continue to monitor and study this cohort.
“Given the high efficacy we have now seen with the different dosing regimens, there is strong merit in continuing to further investigate these findings in order to establish the most effective dosing regimen.
“We are in discussions with regulators around the world to evaluate these findings and we look forward to the publication of the peer-reviewed results, which has now been submitted to the journal.”
Professor Andrew Pollard, director of the Oxford Vaccine Group, told a press briefing that the 90 per cent effectiveness finding had already met the “necessary statistical evidence as required by regulators”.
He said further evidence will probably be available next month but it is “a highly significant result even with the numbers that we have”.
Some experts have also raised questions about the use of two differently designed clinical trials in Britain and Brazil, and pooling analysis from both.
They suggested it is unclear how many coronavirus cases were found in each group of the trial.
John Moore, a professor of microbiology and immunology at Weill Cornell Medical College, told the New York Times: “The press release raised more questions than it answered.”
Two other vaccines - from Pfizer/BioNTech and Moderna - have shown very high efficacy.
But they require very cold temperatures for storage, which makes them more expensive, logistically more challenging and less suited to less developed parts of the world.
By contrast, the Oxford/AstraZeneca vaccine is expected to cost only £2 to £3 per dose and can be stored in the fridge.
The jab is being assessed by the Medicines and Healthcare products Regulatory Agency (MHRA) for use in the UK.
Tom Keith-Roach, president of AstraZeneca UK, has said there had been “highly statistically significant efficacy results in all subgroups… so I think the regulators will look at it on that basis”.
As analysts raised questions in the US, British scientists have leapt to the defence of AstraZeneca and Oxford.
Helen Fletcher, professor of immunology at London School of Hygiene and Tropical Medicine (LSHTM), said: “What’s remarkable is that Oxford University and AstraZeneca have gone from square one to 100 million doses in less than a year.
“It’s not surprising if some manufacturing issues were still being ironed out when they started clinical trials but early stage trials are all about safety and the safety data we have seen has been very robust.”
She said it was important to wait for the full dataset to be published.
“I also think it’s possible that a lower initial vaccine dose could result in higher vaccine efficacy,” she said.
“More is not necessarily better when it comes to vaccines and immunotherapies. You need to stimulate an immune response but if you push too hard you can hit a negative feedback loop where the immune system seeks to control and dampen down the response.
“It’s also possible that a strong immune response to the first vaccine could effectively block an immune response to the second shot of the same vaccine – but we should be able to see evidence of that when the data is published.”
Stephen Evans, professor of pharmacoepidemiology at LSHTM, said “the idea that no protocol has been published (by Oxford and AstraZeneca) is simply not true”.
He added: “The variety of age groups and dosing regimes is a feature of a number of the vaccine trials and not just the Oxford/AstraZeneca vaccine.
“The way the data are put together will have been specified in the protocol and scrutinised very carefully by regulators to ensure that there is no ‘cherry picking’ of the results.”
But Joy Leahy, of the Royal Statistical Society, said the scientific community was “rightly seeking more data in the form of a peer-reviewed paper”, but a press release was put out because of the risk to financial markets from too many people knowing the results while awaiting peer-review publication.
She said the “dosing error does throw up some problems” and the 90 per cent result found may be due to random statistical variation.
“There are also some other complications in looking at this subgroup given that they were all in one location and apparently not representative of the full age profile in the trial,” she added.
Paul Hunter, professor of medicine at the University of East Anglia, said: “Given that many vaccines are less effective in older people, we have to be even more cautious about taking this 90 per cent efficacy at face value, at least for older people.”
Oxford University said it would not comment ahead of the data appearing in a peer-reviewed publication.
Additional reporting: PA
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