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On March 15, consultant haematologist Sue Pavord saw a patient who had recently received the Oxford/AstraZeneca Covid-19 vaccine.
The young man presented with serious and almost contradictory symptoms: a severe blood clot coupled with very low platelets, fragments of cells that help the blood clot.
“It’s common to have those things separately but as a linked combination it’s very unusual,” said Pavord, who is also a lecturer at Oxford university.
Pavord had spent time in Canada in the 1990s researching a rare clotting condition called Heparin-induced thrombocytopenia (HIT), which tends to occur about five days after receiving the drug Heparin. She and four colleagues noted strong similarities with the symptoms in a handful of patients who had received the AstraZeneca vaccine.
When she got home that day, the doctor received a WhatsApp message from her 25-year-old son saying he had just received the same vaccine. “I thought, ‘Oh my God! I have five days to work out what’s going on.’”
“If you’re responsible for a 21-year-old who’s losing their life, that’s a lot on your shoulders,” Pavord said of the intense pressure she has felt while investigating the cases over the past 10 weeks.
While acknowledging the vaccine had saved a lot of lives, she said there were times when, “I would want to stand on a rooftop and shout, ‘Stop the vaccine rollout!’”
The vaccine developed by Oxford university and produced by AstraZeneca had once looked like the silver bullet in the fight against Covid-19: cheap, effective and easy to transport.
For AstraZeneca, it had also appeared to be a fine way to enter a new market. Although the UK pharma group had promised to provide doses on a non-profit basis for the duration of the pandemic, it was a possible springboard to enter the vaccine business.
In the UK, India and many other countries, the vaccine has helped save many thousands of lives. But in Europe, AstraZeneca is battling an EU lawsuit over big delivery shortfalls. In the US, the vaccine is still waiting for regulatory approval, months after its rivals began successful rollouts.
Meanwhile, there are doubts over the vaccine itself, with rare fatal side-effects and, relative to competitors, lower efficacy against new variants from India and South Africa.
Springboard to a vaccine business
“Our goal initially was really to come in and help,” said Pascal Soriot, chief executive of AstraZeneca, in an interview with the Financial Times last week. “That was it. And so one option for us was to come in and help, deliver this vaccine, and then go back to our core business. And we haven’t decided, really, what we’re going to do, long-term with vaccines.”
Before the setbacks, however, AstraZeneca’s mindset was “play to win”, said one of its former employees, repeating a company motto. It kept intellectual property rights in potentially lucrative western markets, while partnering with companies such as the Serum Institute in India to provide for developing countries.
“They didn’t take on the vaccine so it would be non-profit in perpetuity. There was always a sense that this would be a market at some point,” said the former employee.
Early on, the company created a small team devoted to looking at how to commercialise the vaccine, bringing in expertise from other departments as needed, she said.
“This is a vaccine that, yes, we could possibly make money out of,” said Soriot. “But this is in the future. We’ve said that as long as the pandemic is raging, we’ll continue doing it at no profit.”
AstraZeneca does not own the ChAdOx1 platform behind the vaccine, which belongs to Oxford spinout Vaccitech. But it has rapidly built expertise that it could use to build a vaccines business.
Even as Soriot says he remains undecided, AstraZeneca is advertising for a global medical affairs leader for vaccines, a role in which the applicant will be responsible for strategy, launching products and communicating with healthcare providers, and three other regional positions.
John Bell, Regius professor of medicine at Oxford, who helped engineer the deal with AstraZeneca, said he hoped the company would carry on in the market, and is confident the Covid-19 shot has a future in the developed and developing worlds because repeated booster doses are likely to be required.
“The booster thing is real,” he said. “You’re probably going to want your boosters to be AstraZeneca too once you’ve had the original.” Researchers believe that mixing vaccines could increase efficacy, but a recent study suggested there was also a bigger risk of short-term side-effects.
If supply is plentiful, AstraZeneca could be forced to compete on price. Rival vaccines from Pfizer and Moderna are already four to six times more expensive, and they have told investors they will be able to raise prices after the pandemic.
AstraZeneca might also consider offering more convenient ways of delivering the vaccine to gain an edge over rivals. The company is funding a phase 1 trial of a nasal spray vaccine with Oxford.
Even if AstraZeneca decides the Covid-19 market is too crowded, it could still use the expertise it has gained during the pandemic. Soriot said its new knowhow could also be useful in the development of anti-infectives, or antibody treatments, which tend to fetch higher prices than vaccines.
Oxford’s Bell said the way the Covid-19 shot is delivered, using an inactivated cold virus called an adenovirus vector, could also help with oncology medicines that harness the immune system’s T-cells.
There is a hard-nosed counter-argument. Dan Mahony, an investor at Polar Capital who has shares in AstraZeneca, said the company should consider where it might better invest its cash “rather than suddenly throwing money at vaccines”.
Shareholders may prefer the company to invest in its pipeline of innovative cancer drugs, or to expand further in China, where it is one of the largest western pharmaceutical companies.
“If they serenely exited stage left after the last 18 months . . . I would not be unhappy,” Mahony said.
International relations
There was not much serenity in a Brussels courtroom this week when Hakim Boularbah, legal counsel for AstraZeneca, dismissed complaints from the EU about slow deliveries.
“This is not a contract for the delivery of shoes or T-shirts,” he said, insisting that the unprecedented effort to scale up production of billions of doses of the vaccine was a complicated task.
The court is expected to rule within weeks on whether AstraZeneca must urgently supply at least 20m more doses than its currently forecast 70m for the second quarter, down from the 180m originally scheduled. The EU believes AstraZeneca should divert supply from the UK, the US or elsewhere to fulfil its contract and — if it fails again — to pay daily damages that could amount to billions of euros.
But the EU action also suggests that it does not see AstraZeneca as the vaccine of the future. Earlier this month, it signed a huge deal for up to 1.8bn doses of the Pfizer jab from the end of this year to 2023.
Some countries are cautious about using the AstraZeneca jab because of the rare serious side-effects. Denmark, for instance, which pushed in January for early deliveries of the vaccine before the EU regulator had approved it, has now stopped giving it altogether.
In France, after politicians initially damaged the vaccine’s prospects by giving a false impression of its efficacy, they have switched to urging older French citizens to take it, as 2m unwanted doses have built up.
“It’s undeniably slowing down the campaign in France,” Alain Fischer, the government’s top vaccine adviser told BFM TV last week. “The fears that some in the public have about the vaccine are not justified . . . We must reiterate that this vaccine is very effective, as much as the mRNA ones, to protect against the serious cases of Covid-19,” he said.
While the EU pushes for more doses, the US Food and Drug Administration appears to be in no rush to approve the AstraZeneca vaccine. Stocking up for booster shots this spring, the Biden administration ordered 100m more doses from BioNTech/Pfizer, Moderna and Johnson & Johnson. The US has not ordered any more AstraZeneca doses and it has exported some of its existing supply to Canada and Mexico.
“I doubt it’s ever going to be used in the US, at least in the foreseeable future,” said Peter Hotez, a vaccine specialist at Baylor College of Medicine in Texas. But he added that the FDA endorsement would make it easier to export the remaining supplies.
Soriot said there was “no reason” that the vaccine would not win FDA approval, explaining that the delay is due to the time it takes to collate data from several trials and real-world studies. Yet he acknowledged “the urgency in the US is not as high as it was before for the FDA because they are in a different phase of the vaccination programme”.
In the UK, the Oxford/AstraZeneca shot was initially embraced as a national champion, with early investment guaranteeing supply and AstraZeneca vaccines making up more than 60 per cent of the total given. But confidence in the vaccine slipped slightly after the connection was made with the rare blood-clotting side-effect and the government is allowing people under 40, at greater risk for the reaction, to choose alternatives if they prefer.
Clive Dix, who recently stepped down as head of the UK vaccines task force, said the shot would continue to play a role in the government’s mass immunisation programme.
“The Oxford/AstraZeneca vaccine is still an important part of [tackling] the global threat and it is going to save a lot more lives. AstraZeneca has done an amazing job, they’ve got it available in multiple countries, they’ve got 20 manufacturing sites and are going to be making millions of doses,” he added.
But the UK does have many other options for booster shots, including an order of 30m doses from J&J, which was approved on Friday, another 60m from Novavax, which has finished its clinical trials, an order of 100m from French vaccine maker Valneva, which is in phase 3 trials, and a contract for 60m from Sanofi and GlaxoSmithKline, which entered phase 3 this week.
Oxford noted the vaccine had been “supplied to more countries than by any other developer — currently over 170 countries”.
In Morocco, for example, the most vaccinated country in Africa, the shot is likely to become a permanent part of its plan to protect against a resurgence of Covid-19. The north African country has received 7.5m AstraZeneca vaccines so far, on top of 10m of the China-made Sinopharm vaccine. It has a contract for 25.5m AstraZeneca vaccines.
Mortada Othmane, director of the Institut Pasteur in Tangier, said the country was “wise” to rely on the vaccine — and dismissed the concerns in Europe as political.
“There is a political and economic conflict between the countries that banned the use of the AstraZeneca vaccine, so they did not make the decisions because it is ineffective,” he said.
A hunt for answers
The side-effects, however, are real — though rare. The latest estimates in the UK put the incidence of the sometimes fatal blood-clotting condition at about one in 77,000 recipients.
It is the fear of a fatal reaction that is sending people in the west on the hunt for alternatives.
Pavord described how upset she had been by one case of a 21-year-old woman with no underlying health conditions who died of a massive brain haemorrhage. “We were discussing whether we would be able to use her organs because they had been so damaged by the clots,” Pavord recalled.
On March 19, she called Andrew Pollard, chief investigator for the Oxford vaccine trials. A meeting was convened with Pavord, Pollard, and the UK’s two top medical officers, Chris Whitty and Jonathan Van Tam, she said.
Pavord and Pollard agreed that blood samples from individuals who had received the AstraZeneca vaccine during the trial should be tested to see whether they had particular antibodies associated with HIT, and what has now been dubbed VITT (Vaccine-induced immune thrombotic thrombocytopenia). None of the individuals was found to have these antibodies, suggesting the side-effect was a very specific reaction in a small group of recipients.
Though Pavord said Pollard has been consistently helpful in hunting for the cause of the reaction, at times she felt a resistance from other colleagues at Oxford to investigate. “I was saying, ‘Let’s get all the big brains in Oxford on this’, and sometimes I have felt a bit of pushing back.”
She is the first to admit she had a particular view of the impact of the vaccine, having seen young people suffering first hand but having had little direct contact with people affected by Covid-19 itself.
Pavord said she still thinks the vaccine has an important role to play. “Last night I was talking to a GP and she was saying ‘I have seen so much Covid, so many young people dying’, so it’s important to see the other side of the argument,” she said.
“If the Indian variant comes sweeping by, the risk of someone under 40 dying increases,” she added.
There is still no definitive answer about the mechanism causing the strange side-effects, though scientist Andreas Greinacher has postulated that it is a “class reaction” against adenovirus vaccines, a group that also includes the J&J vaccine, which has triggered similar side-effects, though at an even lower rate.
In his latest paper, he put forward a theory that a mix of vaccine components causes the reaction, including stray proteins and an additive called EDTA.
“My recommendation [to vaccine producers] would be to try to get rid of the EDTA and try to remove other proteins in the vaccine,” he said last month.
Building on Greinacher’s theory, this week another group of German scientists claimed a breakthrough. Rolf Marschalek, professor in pharmacy at Goethe university in Frankfurt, said he had found that the clotting problem is linked to floating mutant proteins in an individual’s body fluids.
Yet even if Marschalek and his co-authors are right, it may be a challenge to adapt the vaccine to prevent such a rare occurrence. Bell said researchers at Oxford were examining whether the vaccine could be modified. But he added that it would be very difficult to prove that any adaptation had made a significant difference. Even if Oxford made a change that reduced the reaction by 50 per cent, it would take a trial of 5m-10m people to prove it.
Many feel it would be easier to try to identify who should be excluded from taking the vaccine. Pavord and her colleagues have arranged for blood samples from at least 34 people who suffered a severe or fatal reaction to be sent to a government lab where their 3bn-letter genome will be sequenced and cross-checked against others. If a meaningful genetic overlap is found, those deemed at risk could be asked to take a different vaccine.
Soriot said the “most important piece” is that people know the symptoms to look out for and described how Australia — where he is a naturalised citizen — has dealt with its cases. “The people are well informed, the doctors are well informed and people are diagnosed early. They are treated and they go home. Most people who get a clot actually go home,” he said.
Despite all AstraZeneca’s troubles, Soriot said the board had never once told him that taking on the vaccine had been a bad idea. He added that the company would “soon enough” have delivered 500m doses of its vaccine.
“Ninety per cent of vaccinations in India are with our vaccines. Ninety-eight per cent of the supply to Covax [the programme that provides doses to many poor countries] are our vaccines,” he added. “Would we have preferred to not have these ups and downs? Of course, but at the end of the day, you’ve got to stay focused on what it is you’re achieving.”
Additional reporting by Donato Paolo Mancini and Sarah Neville in London, Leila Abboud in Paris, Richard Milne in Oslo and Samir Daoudi in Tangiers
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