(Repeats story published late on Thursday)
* Astra research chief: Successful half dose 'serendipity'
* Oxford scientist: Dosing was a deliberate decision
* Confusion raises questions on robustness of data - experts
* Rare public dissonance between collaborators on a big
project
By Ludwig Burger, Kate Kelland and Abhirup Roy
LONDON, Dec 3 (Reuters) - AstraZeneca and Oxford
University have given conflicting accounts of how they came upon
the most effective dosing pattern for their COVID-19 vaccine, a
rare instance of public dissension between major institutions
collaborating on a pivotal project.
The discrepancy, reported for the first time by Reuters,
centres on the regimen administered to a smaller group of
volunteers in the late-stage trials, of half a dose followed by
a full dose. This diverged from the original plan of two full
doses, given to the majority of participants.
The half-dose pattern was found to be 90% effective, versus
the 62% success rate of the two-full-dose main study, based on
interim data.
AstraZeneca's research chief told Reuters 10 days ago, when
interim trial data was released, the half-dose was given
inadvertently as a first shot to some trial participants, and
emerged as a stroke of fortune - "serendipity" - that scientists
expertly harnessed.
This narrative was refuted by a leading Oxford University
scientist, however, who told Reuters on Monday that the
half-dose shot was given deliberately after thorough
consultations.
Uncertainty over how the dosing regimen came about raises
questions about the robustness of the data, according to some
experts who said it risked slowing down the process of gaining
regulatory approval for the shot and denting public confidence.
"These differing accounts are worrying," Eleanor Riley, a
professor of immunology and infectious disease at the University
of Edinburgh, told Reuters.
"Trust is at a premium when it comes to vaccines and we must
not do anything that might in any way undermine it."
There is also the potential impact on AstraZeneca, whose
shares have underperformed rival vaccine developers that have
also announced successful results, partly due to concerns from
scientists about the relatively small sample size for the
half-dose sub-group that led to the 90% efficacy finding.
AstraZeneca declined to comment about the conflicting
accounts.
An Oxford University spokesman said that a media briefing
would be held once the detailed interim trial results are
peer-reviewed and published in a scientific journal.
"This will be the appropriate time to discuss the
complicated intricacies of the global trial design," he said.
OXFORD SCIENTIST: 'THAT'S NOT TRUE'
More than 20 countries, including many poorer nations, have
ordered the vaccine, which costs less than some rival shots and
is easier to distribute.
The trial data was released on Nov. 23, when developers
hailed "a vaccine for the world". Hours later, AstraZeneca's
head of non-oncology research and development, Mene Pangalos,
told Reuters the half-dose schedule had been a case of
miscalculated dosing given to some volunteers.
It came to light, he said, after side effects in some
participants turned out to be surprisingly mild.
"The reason we had the half dose is serendipity," he said.
However, professor Adrian Hill, director of the Jenner
Institute at the University of Oxford which co-developed the
COVID-19 shot with AstraZeneca and led the UK trials, told
Reuters in a phone interview on Monday that it was a conscious
decision by researchers to administer a lower dose.
"There had been some confusion suggesting that we didn't
know we were giving a half dose when we gave it - that is really
not true," he said.
"What we were aware of was that we were using a different
batch of a vaccine from a different manufacturer. We knew the
measurements on it and we had been in discussions with
regulators about how to move forward."
"The dosing that we started with that new batch, was a half
dosing compared to what we had used previously," he added,
without giving details about the different manufacturer.
Both AstraZeneca and Oxford University scientists said they
had consulted health regulators and were given the go-ahead to
continue with the half-dose among a limited group of volunteers
in Britain, and to follow up with the full-dose booster shot at
the scheduled time.
Britain's Medicines and Healthcare products Regulatory
Agency (MHRA) said its rolling review of the vaccine is ongoing
and that any vaccine must undergo robust clinical trials in line
with international standards.
"No vaccine would be authorised for supply in the UK unless
the expected standards of safety, quality and efficacy are met,"
a spokeswoman said. She did not comment on when the regulator
was consulted about the half-dose regimen.
The European Medicines Agency did not respond to repeated
requests for comment.
'NEED TO BE CLARIFIED SWIFTLY'
For Oxford's vaccinologists, the confusion is a far cry from
last week's euphoria when interim data appeared to vindicate
almost three decades of work.
But the conflicting versions of events are the latest twist
for the vaccine data, which has drawn scrutiny from scientists
and investors since its release.
"Whether or not they are accurate, and whether or not they
affect the validity of the data released last week, they need to
be clarified swiftly," Riley of the University of Edinburgh said
of the contradictory accounts.
While U.S. regulators have said a minimum of 50% efficacy
for a COVID-19 vaccine to be considered for approval, Moderna
and Pfizer-BioNTech have set a high bar, reporting
efficacy data above 90% for their shots.
Independent scientists have expressed concerns that the
AstraZeneca-Oxford half-dose group - with just over 2,700
participants - was too small to yield a robust efficacy result.
That's a fraction of the tens of thousands of participants
in trials that resulted in the high efficacy data from
Pfizer-BioNTech's and Moderna's vaccines.
"All we have to go on is a limited data release," Peter
Openshaw, a professor of experimental medicine at Imperial
College London, said last week. "We have to wait for the full
data and to see how the regulators view the results," he said,
adding that U.S. and European watchdogs "might possibly take a
different view" from each other.
AstraZeneca has lost almost 7 billion pounds ($9.35 billion)
in value since the interim trial results amid such worries.
It has said it hopes that more trial data gathered over time
in that group will solidify the interim findings. It is also
considering a new global trial based on the dosing pattern for
added clarity.
Oxford and AstraZeneca say they have submitted their
read-out to regulators across the world to seek marketing
approval. They say the dosing pattern is also subject to
discussions with regulators.
The university said last Friday it supported the idea of
further and ongoing trials, but added that the interim analysis
had already "shown the vaccine is highly effective in a global
study of 24,000".
(Reporting by Ludwig Burger in Frankfurt, Kate Kelland in
London and Abhirup Roy in Pune; Additional reporting by Euan
Rocha in Mumbai; Editing by Josephine Mason and Pravin Char)
Astrazeneca (AZN)
