(Jacqui Wise’s article from the BMJ on April 14, 2021.)
Hailed as a “vaccine for the world” with its low
price and easy storage requirements, AstraZeneca’s vaccine candidate has faced
a string of setbacks in 2021 with questions over effectiveness, possible side
effects, and long running disputes about supplies.
It’s not clear why the Anglo-Swedish company and its vaccine have been singled out for so much criticism, but poor communication seems to be at the heart of the problem.
Martin McKee,
professor of European public health at the London School of Hygiene &
Tropical Medicine, says, “This is a company that has taken an innovative
product to market in record time but has mishandled communications at every
step. Trust and confidence are so important for vaccines—you can’t divorce the
two.”
Clots
AstraZeneca’s
latest crisis is possibly also its biggest so far. Its vaccine has been linked
to thrombosis, as well as a rare type of blood clot in the brain called
cerebral venous sinus thrombosis (CVST), with a number of episodes in younger
women.
The vaccine was
authorised for use in Europe at the end of January and started to be used more
widely in February. On 7 March Austrian authorities announced that they were
investigating a death that was possibly vaccine related. A few days later
Denmark and Norway were investigating reports of blood clots and a death after
vaccination. On 15 March Germany suspended its use of the vaccine, followed
swiftly by several other countries.
The European
Medicines Agency (EMA) and the World Health Organization say that the vaccine’s
benefits outweigh any risks: the EMA undertook an in-depth review of the issue
and, while acknowledging a “possible” link to blood clots that should be listed
as “very rare” side effects, on 7 April it confirmed that the “overall benefit-risk
remains positive” for the vaccine’s continued use.3 The cause of the clots is
still unknown, with research ongoing.
In the UK, which
has ordered 100 million doses of AstraZeneca vaccine, the Joint Committee on
Vaccination and Immunisation (JCVI) advised on 7 April that people aged under
30 should be offered alternative vaccines where available—even though the
Medicines and Healthcare Products Regulatory Agency (MHRA), which conducted the
UK review of the evidence, emphasised that it was “not recommending new age
restrictions in COVID-19 Vaccine AstraZeneca vaccine use.”
The MHRA said
that, up to 31 March, 79 thrombosis events with low platelets had been reported
from over 20 million doses of the vaccine administered. Among these reported
cases, 19 people have died. The overall risk of these blood clots is about four
people in every million who receive the vaccine.
At the time of writing, Australia, Belgium, and
France had restricted the vaccine to people aged over 55, while Italy and Spain
limited its use to over 60s after the EMA’s announcement. Scandinavian
countries had already paused their rollouts of the vaccine, while Canadian
provinces had suspended its use in under 55s on 30 March. Several German states
have also suspended its use in under 60s.
Ines Hassan,
senior policy researcher with the Global Health Governance Programme at the
University of Edinburgh, sees a positive in the way the issue is being
investigated. She says, “The scrutiny from regulators and pharmacovigilance
experts shows that the system and safety monitoring procedures are working as
they should.”
What’s not
helpful is how it’s been communicated. Whether from different regulators,
government officials, academics, or the media, Hassan tells The BMJ, “It is
clear that the mixed messaging from these different stakeholders has caused
confusion among the general public, and it has already led to increased vaccine
hesitancy in some parts of Europe among other regions.”
Martin McKee
says that, although the MHRA and the JCVI have different roles, it’s “extremely
regrettable” that one is advising no age restrictions while the other proposes
that people under 30 should be offered an alternative. Those aged from 30 to,
for example, 50 will wonder why the UK guidance, even if contradictory, differs
from that in other countries. He adds, “ I have previously criticised messaging
about the AstraZeneca vaccine. Sadly, it seems that we have learnt little.”
In the US
Adding salt to
the wound, AstraZeneca had simultaneously but separately faced criticism in the
United States. In a 22 March press release the company announced the long
awaited results of a key US trial, one that it hoped would finally win
emergency use approval for the vaccine from the US Food and Drug
Administration.
The FDA has been
cautious around the AstraZeneca vaccine: it has yet to issue approval for its
use in the US despite approving vaccines from Pfizer, Moderna, and Johnson and
Johnson (Janssen) and nearly four months since the UK approved it.
In the March
announcement AstraZeneca said that the results showed a 79% efficacy in preventing
symptomatic disease. Hours later, however, the US National Institutes of Health
(NIH) took the unusual step of issuing a midnight statement saying that its
Data and Safety Monitoring Board had “expressed concern that AstraZeneca may
have included outdated information from that trial, which may have provided an
incomplete view of the efficacy data.”
AstraZeneca says
that the agreed cut-off point for data was 17 February, as publicised in its
initial release. In response to the NIH, within 48 hours it added more recent
data and revised the efficacy down to 76%. The US chief medical adviser,
Anthony Fauci, called this an “unforced error” on AstraZeneca’s part. Speaking
on Good Morning America, he said, “It was not necessary—if you look at it, the
data really are quite good, but when they put it into the press release it
wasn’t completely accurate.”
McKee says that
it is “completely unprecedented that a data monitoring committee would say that
what you said in a press release was not accurate. It’s so basic that you don’t
issue contradictory information. What on earth was going on there that they
didn’t check?”
However, Peter
English, a retired consultant in communicable disease control who is former
editor of Vaccines in Practice magazine and immediate past chair of the BMA’s
Public Health Medicine Committee, has sympathy for the company. “It seems like
it was an attack on the company and not founded on science,” he says.
“AstraZeneca had stated in advance in their protocol the time period, so [they]
couldn’t cherry pick the data. If they had done it other way round they would
rightly have been criticised.”
He tells The
BMJ, “It was incredibly irresponsible of the NIH [to issue that statement], as
it implied there was something terrible going on—which we found out a few days
later wasn’t the case. It brought the vaccine into disrepute based on nothing.
This harms confidence in all covid vaccines and in vaccines overall.”
Early troubles
Part of the
problem may be that AstraZeneca isn’t a traditional vaccine manufacturer. McKee
tells The BMJ, “A number of commentators have raised questions about the
experience of the board in communicating some of the challenging messages
around vaccines.”
Oxford University, which developed the vaccine,
originally intended to partner with the US company Merck, but the UK
government—which had invested £65.5m (€75.7m; $90.1m) in the vaccine’s
development—insisted on a UK based company. (GlaxoSmithKline reportedly turned
down a partnership, as it had its own candidates in development.)
Andrew Pollard,
the Oxford vaccine group’s chief scientist, was delighted that the
Anglo-Swedish company agreed to undertake the drug’s production at cost and at
volume, making it “a vaccine for the world.” But it seems that no good deed
goes unpunished, and AstraZeneca’s learning curve has been steep.
In September
2020, phase III clinical trials of the covid-19 vaccine in Brazil, South
Africa, the UK, and the US were temporarily paused because of unexplained
neurological symptoms in one of the volunteers. After investigating the
incident the MHRA gave the go-ahead to restart UK trials within days, but the
FDA maintained the US suspension for six weeks, apparently unhappy that it
hadn’t been told of the problem quickly enough. This seems to have sparked the
general caution in the FDA’s approach to evaluation.
Then, on 23
November, AstraZeneca was criticised for the way it announced the vaccine’s
efficacy. It had combined the results of different trials and had, critics
said, missed out key details.
Rather than coming up with a single figure for
efficacy like other vaccine manufacturers—Pfizer and Moderna had just a week
earlier announced higher than expected efficacies of 91% and 95%,
respectively—AstraZeneca announced an overall 62% efficacy and another of 90%
in people who had originally received a half dose (this followed a dosing error
in one arm of the phase III trial, which fortuitously led to better results).
The higher number was later reinterpreted as due to a longer gap between doses.
Media reports
criticised how AstraZeneca had communicated the information about its trials.
“There have been contradictions between statements given to investors, press
releases, and internal documents,” says McKee.
A scientific
paper can’t be sent out for peer review if it has market sensitive information
such that a reviewer or editor could potentially exploit the market position.
Preprint publications can face delays, which make it difficult to coordinate
with market communications. McKee says that this may be why AstraZeneca relied
on press releases—“but, that said, they should be consistent [with their
information], and they haven’t always been so.”
Nevertheless, on
30 December 2020 the UK and Argentina became the first countries in the world
to approve the AstraZeneca shot. The year ended with the company marking its
first success in the vaccine field but with the shine somewhat taken off. And
there was more to come.
Annus horribilis?
On 25 January
2021 the German newspaper Handelsblatt claimed that the vaccine had only 8%
efficacy in over 65s.10 The report turned out to be baseless—but not before
damage had been done to public confidence in the vaccine across the continent.
A few days later the EMA approved the AstraZeneca vaccine for all age groups in the EU, but that same day the French president, Emmanuel Macron, claimed that it was “quasi-ineffective” for over 65s. After Macron’s comments Germany and France initially prevented the drug’s use in over 65s.
Confusion over which age groups should have the vaccine has contributed,
unsurprisingly, to a lack of confidence. More than half of people surveyed in
France, Germany, and Spain thought that the shot was unsafe in a YouGov poll published
on 22 March.
The timing
couldn’t have been worse. It came just as AstraZeneca faced a political crisis
with the EU around missing vaccine deliveries. The company had agreed to
deliver as many as 120 million doses to the EU by the end of March 2021, but
yield problems and other issues prompted it to tell the EU that it could supply
only 30 million doses (subsequently increased to 40 million). The EU, in the
grip of a rising third wave of infections, did not take this well.
Although other
vaccines have also had supply problems, AstraZeneca seems to have become a
political football between the EU and the recently Brexit-ed UK. The European
Commission’s president, Ursula von der Leyen, threatened to block AstraZeneca
from exporting doses of vaccine to the UK, and the Belgian MEP Philippe
Lamberts accused the company of dishonesty and arrogance, saying that it had
“over-promised and under-delivered.” At the time of writing the dispute is
ongoing, alongside the new blood clot issue.
To cap it all,
AstraZeneca suffered another blow in February when South Africa—grappling with
rising infections and a worrying new variant of the virus accounting for 90% of
the cases in the country—halted the rollout of the AstraZeneca vaccine after a
study showed disappointing results against the 501 variant. With countries now
looking over their shoulders at new variants and the effectiveness of existing
vaccines against them, the decision was another disappointment for the company.
Fallen heroes
Kate Bingham,
former head of the UK’s Vaccine Taskforce, calls AstraZeneca “heroes” for the
way the company picked up the vaccine and worked out how to test, manufacture,
and distribute it at low cost around the world. Speaking to the Financial
Times, she said that the company had become caught up in geopolitics.
Ines Hassan
emphasises that AstraZeneca has not fallen short on meeting regulatory
requirements: it submitted the necessary data as expected, including when it
recently submitted interim analysis findings to the FDA. However, communication
about trial design early in development, and later about the number of patients
with covid-19 symptoms from its primary analysis, could perhaps have been
handled better, she says.
“One big lesson
is that transparency is essential, especially with regulators and the general
public,” says Hassan, while acknowledging that overcommunicating without
causing unnecessary alarm is a tricky balance to strike. She adds that the
responsibility to communicate safety issues is not the manufacturer’s
alone—it’s the responsibility of regulators, policy makers, public health
academics, and the media, among others.
Peter English questions why the one vaccine being
sold at cost price is the one that’s been the most vilified. “The amount of bad
press they have got is not based on the science,” he says. “It seems completely
disproportionate or unfounded. It looks like a lot of them are attacks on
AstraZeneca itself and seem to have an ulterior motive. It almost feels like
there is a deliberate misinformation campaign.”
But the
consequences of AstraZeneca’s problems go far beyond one company’s reputation
and profits. Its vaccine is an indispensable part of WHO’s plan to roll out two
billion doses to 92 nations by the end of 2021, through the Covax initiative.
The UK’s order of 100 million doses places AstraZeneca at the heart of its
vaccination programme.
And many
commentators worry that crumbling confidence in AstraZeneca’s vaccine may spill
over to others, as the world is already grappling with vaccine hesitancy as an
obstacle to wider coverage and an end to the pandemic. As McKee says, “When you
lose trust it’s really difficult to regain it.”
AstraZeneca’s six month nightmare
2020
9 Sep Phase III
trials are paused after a single event of unexplained illness
30 Dec Argentina
and UK approve AstraZeneca vaccine for emergency use
2021
25 Jan German
newspaper Handelsblatt claims that the vaccine has only 8% efficacy in elderly
people
29 Jan European
Medicines Agency (EMA) approves AstraZeneca vaccine. President Macron of France
claims that it is “quasi-ineffective” in over 65s
9 Feb South
Africa halts rollout of AstraZeneca vaccine after study shows disappointing
results against the 501 variant
7 Mar Austrian
authorities announce investigation of a potentially vaccine related death
10 Mar EMA press
release suggests no specific issue with batch used in Austria
15 Mar Germany
suspends use of AstraZeneca vaccine, pending investigation of three deaths and
four other incidents
18 Mar EMA says
that benefits still outweigh risks
22 Mar
AstraZeneca announces US trial results claiming 79% efficacy
23 Mar US
National Institutes of Health’s Data and Safety Monitoring Board expresses
concern that AstraZeneca may have included outdated information from the trial.
AstraZeneca issues new data and revises the figure to 76% on 25 March
30 Mar Canada
suspends use of AstraZeneca vaccine in under 55s
31 Mar German
states suspend use of AstraZeneca vaccine in under 60s
6 Apr UK
Medicines and Healthcare Products Regulatory Agency (MHRA) pauses a trial of
the vaccine in children and teenagers pending investigation of the blood clot
link. Marco Cavaleri, EMA head of vaccines, tells an Italian newspaper that “it
is clear there is a link with the vaccine [and blood clots] . . . but we still
do not know what causes this reaction.” EMA distances itself from the comments
7 Apr EMA
investigation concludes that “unusual blood clots with low blood platelets
should be listed as very rare side effects” for the vaccine but that “overall
benefits of the vaccine in preventing covid-19 outweigh the risks of side
effects.” MHRA advises that alternative vaccines should be offered to under 30s
where available
8 Apr Australia, Belgium, France, and Italy announce restrictions on use of the vaccine