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A rare clotting disorder may cloud the world's hopes for AstraZeneca's COVID-19 vaccine – Science Magazine

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A man receives a dose of AstraZeneca’s COVID-19 vaccine at a conference center in Rome on 24 March. Italy halted use of the vaccine on 15 March but resumed immunizations four days later.

Antonio Masiello/Getty Images

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

In the tumultuous rollout of AstraZeneca’s COVID-19 vaccine, all eyes were on the United States this week, where the company had a highly public communication breakdown over the vaccine’s efficacy with an expert panel overseeing a large study in the Americas. But on the other side of the Atlantic, the vaccine faces new concerns about safety as an explanation gains ground for the unusual strokes and clotting disorders recorded in at least 30 recipients.

Many European countries suspended use of AstraZeneca’s vaccine earlier this month following initial reports of the symptoms, which have led to at least 15 deaths. Most resumed vaccinations after the European Medicines Agency (EMA) recommended doing so on 18 March, saying the benefits of the vaccine outweigh any risks. EMA is continuing to investigate the matter and will convene a wideranging committee of experts on 29 March.

Now, a group of researchers led by German clotting specialist Andreas Greinacher of the University of Greifswald says the highly unusual combination of symptoms—widespread blood clots and a low platelet count, sometimes with bleeding—resembles a rare side effect of the blood thinner heparin, called heparin-induced thrombocytopenia (HIT).

The scientists, who first described their findings during a 19 March press conference, recommend a way to test for and treat the disorder and say this can help ease worries about the vaccine. “We know what to do: how to diagnose it, and how to treat it,” says Greinacher, who calls the syndrome vaccine-induced prothrombotic immune thrombocytopenia, or VIPIT. Greinacher says he has submitted a manuscript to the preprint server Research Square.

Even if Greinacher’s mechanism isn’t the whole story, multiple researchers told Science they were convinced that the vaccine was causing the rare set of symptoms. If that turns out to be true, it could have major consequences for the vaccine, which is one of the cornerstones of the World Health Organization’s push to immunize the world. AstraZeneca is working with partners around the globe to make and distribute billions of doses in low- and middle-income countries, which might have a harder time identifying and treating rare side effects.

Europe is relying heavily on the vaccine as well; the European Union bought 400 million doses. The company’s failure to deliver on time has delayed vaccine rollouts on the continent, but now, dented confidence is exacerbating the delays. And even if the risk is very low, it may make sense to use the vaccine only in those who also stand to gain the most from it: elderly people at high risk of dying from COVID-19. Several European countries have started to do this. The situation has scientists walking a tightrope: They want to make the medical profession aware of their concerns without sowing panic.

But Greinacher’s hypothesis is being taken seriously. Two German medical societies put out press releases lauding him for solving the issue. In the Netherlands, the Dutch Internal Medicine Society urged internists to be aware of the symptoms and the recommended course of action. The United Kingdom has officially reported only 5 cases—despite administering 11 million doses of the AstraZeneca vaccine—but the British Society of Haematology has urged its members to be aware of “an important and emerging area of haemostasis and thrombosis practice” and to report any possible cases. The Australian Technical Advisory Group on Immunisation has recommended against giving any COVID-19 vaccine to people with a history of HIT.

It is not yet clear how the vaccine could trigger VIPIT, and not everyone thinks the case is closed. “It’s intriguing, but I am not entirely convinced,” says Robert Brodsky, a hematologist at Johns Hopkins University. AstraZeneca, meanwhile, has not directly responded to the reports of the rare constellation of symptoms except to say that they did not appear in any of the company’s clinical trials.

“People are absolutely working like crazy behind the scenes to provide more clarity,” says Saskia Middeldorp, a vascular internist at Radboud University Medical Center in the Netherlands, who disagreed with the temporary halt of the vaccine because she says the benefits clearly outweigh the risks.

A ‘very striking’ disorder

The VIPIT story began on 27 February, when Sabine Eichinger, a hematologist at Medical University Vienna, was confronted with an unusual patient. A 49-year old nurse had sought help at a local hospital the day before, suffering from nausea and stomach discomfort, and was transferred to Eichinger’s hospital. She had a low platelet count and computed tomography scans found thromboses—blood clots—in the veins in her abdomen and later in arteries as well. “There was little we could do at this stage,” says Eichinger. The patient died the next day.

The combination of low platelet count, or thrombocytopenia, and clots kept Eichinger thinking, however. “It’s very striking,” she says. Platelets, also known as thrombocytes, help to form blood clots, so low levels usually lead to bleeding, not clotting. “You would think that low platelets and thromboses are opposites really.” One condition where they occur together is called disseminated intravascular coagulation, when severe infection, injury, or cancer trigger clotting so widespread it uses up all the platelets, “but she had none of these things,” Eichinger says.

The unusual combination also appears in HIT, which can occur in patients given heparin as a drug. Heparin binds to a protein called platelet factor 4 (PF4), forming a complex. For reasons that aren’t understood, some people produce antibodies against the complex, setting off an out-of-control clotting reaction. Eichinger’s patient had not received heparin, but she had gotten a shot of the AstraZeneca vaccine 5 days before her symptoms began. “I thought maybe this is some kind of immune reaction,” Eichinger says.

She reached out to Greinacher, who had studied HIT for decades. “Then things started happening thick and fast,” she says, as multiple countries responded to reports of clotting by suspending use of the AstraZeneca vaccine.

Greinacher says he contacted other colleagues who had studied HIT in Canada and Germany and asked the Paul Ehrlich Institute (PEI), which oversees vaccine safety in Germany, if they had seen any cases. They had. PEI recommended that Germany pause use of the vaccine as well and asked Greinacher to help investigate. He soon received blood samples from eight additional patients. All had both low platelets and unusual clotting, he says. In four samples, the researchers also found evidence for antibodies against PF4, a hallmark of HIT. He and his colleagues are now checking whether other vaccine recipients and former COVID-19 patients have similar antibodies.

People are absolutely working like crazy behind the scenes to provide more clarity.

Saskia Middeldorp, Radboud University Medical Center

Brodsky says it isn’t clear whether VIPIT explains all of the cases. He agrees that the PF4 antibodies and the clotting seen in patients resemble HIT, but the link has not been proven, he says: “I’m convinced that these patients have platelet factor 4 antibodies, at least four of them. But I’m not convinced that those … antibodies are explaining the thrombocytopenia or the clotting.”

Treatable condition

Greinacher agrees on the need for more data. But he says it’s crucial to alert doctors to the potential complication. When recognized in time, HIT can be treated with immunoglobulins—nonspecific antibodies from blood donors—that help put the brakes on platelet activation. Non-heparin blood thinners can help dissolve the clots. VIPIT should be treated in a similar way, he says. In at least one case, Greinacher says, a doctor sought the group’s advice and the patient recovered. The German Society for the Study of Thrombosis and Hemostasis, of which Greinacher is a member, has issued a set of recommendations for diagnosing and treating VIPIT. Greinacher says he has also been in touch with safety representatives at AstraZeneca.

Nigel Key, a hematologist at the University of North Carolina at Chapel Hill, agrees on the need to alert doctors. “Maybe it is too much to expect at this point that there would be a very detailed molecular mechanism,” he says, but the advice to physicians who may encounter patients is crucial.

Brodsky and Key say the cases are striking enough that they probably represent a real side effect. “I think the vaccine is mostly safe. I think the benefits probably outweigh the risk for a general population,” Brodsky says. “But these cases raise concern that this vaccine is potentially life-threatening in a small subset of patients.”

Scientists are now scrambling to understand how big that subset is and who’s in it. So far, most cases have been observed in women under 65. But that could be because of the vaccinated population: Many countries initially used AstraZeneca only in people under 65 because early clinical trials included few older recipients. That meant the vaccine was used in priority groups such as health care workers and teachers, a majority of whom are women. In Norway, for example, 78% of the AstraZeneca doses went to women, says Sara Viksmoen Watle, chief physician at the Norway Institute of Public Health. The United Kingdom, however, used the vaccine first in older people, which may explain why fewer unusual clotting events have been spotted there.

Data from Norway—whose extensive health registries make this type of research easier—suggests previous COVID-19 infection does not predispose vaccinees to a severe reaction, Watle says. Alerting clinicians will help ensure that fewer cases are missed for analysis, Key says. A global database of cases may be helpful too.

Many countries are, for now, accept the risk that the AstraZeneca may carry, but several have restricted its use to people who are at the highest risk of dying from COVID-19: those aged 55 or older in France, 65 or older in Sweden and Finland, and 70 or older in Iceland. That approach makes sense, says Sandra Ciesek, a virologist at Goethe University Frankfurt. “The argument I keep hearing is that the risk-benefit ratio is still positive. But we do not have just one vaccine, we have several. So restricting the AstraZeneca vaccine to older people makes sense to me, and it does not waste any doses.”

Denmark and Norway are waiting for more data. Norway, which has administered the AstraZeneca vaccine to 130,000 people under 65, has reported five patients who had low platelets, hemorrhage, and widespread thromboses, three of whom died. That’s about one case in 25,000 vaccinees, “a high number with a very critical outcome in previously healthy, young individuals,” says Watle. The country hopes to make a decision on the vaccine within 3 weeks. It can afford to hold off: COVID-19 cases are relatively low and AstraZeneca is delivering so few doses that the extended pause won’t make a big difference in the short-term.

Middeldorp says she expects more clarity after Monday’s meeting of EMA’s expert group, which includes clotting experts, neurologists, virologists, immunologists and epidemiologists. The agency says it will issue an update on the vaccine during the next meeting of its safety committee, being held from 6 to 9 April. Ideally that meeting will help clarify how frequently the condition occurs and whether the risk varies by age or sex, Middeldorp says. The world needs AstraZeneca’s vaccine, she says—but that means it is crucial to fully understand its benefits and its risks.

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CANADA STOCKS – TSX falls 0.14% to 19,201.28

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* The Toronto Stock Exchange’s TSX falls 0.14 percent to 19,201.28

* Leading the index were Stantec Inc <STN.TO​>, up 3.4%, Imperial Oil Ltd​, up 3.3%, and Corus Entertainment Inc​, higher by 2.9%.

* Lagging shares were Aphria Inc​​, down 14.2%, Village Farms International Inc​, down 9.9%, and Aurora Cannabis Inc​, lower by 9.4%.

* On the TSX 91 issues rose and 134 fell as a 0.7-to-1 ratio favored decliners. There were 24 new highs and no new lows, with total volume of 228.0 million shares.

* The most heavily traded shares by volume were Toronto-dominion Bank, Royal Bank Of Canada and Suncor Energy Inc.

* The TSX’s energy group fell 0.32 points, or 0.3%, while the financials sector climbed 2.46 points, or 0.7%.

* West Texas Intermediate crude futures rose 0.52%, or $0.31, to $59.63 a barrel. Brent crude  rose 0.4%, or $0.25, to $63.2 [O/R]

* The TSX is up 10.1% for the year.

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Air Canada signs C$5.9 billion government aid package, agrees to buy Airbus, Boeing jets

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By David Ljunggren and Allison Lampert

OTTAWA/MONTREAL (Reuters) -Air Canada, struggling with a collapse in traffic due to the COVID-19 pandemic, reached a deal on Monday on a long-awaited aid package with the federal government that would allow it to access up to C$5.9 billion ($4.69 billion) in funds.

The agreement – the largest individual coronavirus-related loan that Ottawa has arranged with a company – was announced after the airline industry criticized Prime Minister Justin Trudeau’s Liberal government for dawdling. The United States and France acted much more quickly to help major carriers.

Canada‘s largest carrier, which last year cut over half its workforce, or 20,000 jobs, and other airlines have been negotiating with the government for months on a coronavirus aid package.

In February, Air Canada reported a net loss for 2020 of C$4.65 billion, compared with a 2019 profit of C$1.48 billion.

As part of the deal, Air Canada agreed to ban share buybacks and dividends, cap annual compensation for senior executives at C$1 million a year and preserve jobs at the current level, which is 14,859.

It will also proceed with planned purchases of 33 Airbus SE 220 airliners and 40 Boeing Co 737 MAX airliners.

Chris Murray, managing director, equity research at ATB Capital Markets, said the deal took into account the “specific needs of Air Canada in the short and medium term without being overly onerous.”

He added: “It gives them some flexibility in drawing down additional liquidity as needed.”

Transport Minister Omar Alghabra said the government was still in negotiations with other airlines about possible aid.

Canada, the world’s second-largest nation by area, depends heavily on civil aviation to keep remote communities connected.

Opposition politicians fretted that further delays in announcing aid could result in permanent damage to the country.

Air Canada said it would resume services on nearly all of the routes it had suspended because of COVID-19.

‘SIGNIFICANT LAYER OF INSURANCE’

The deal removes a potential political challenge for the Liberals, who insiders say are set to trigger an election later this year.

The government has agreed to buy C$500 million worth of shares in the airline, at C$23.1793 each, or a 14.2% discount to Monday’s close, a roughly 6% stake.

“Maintaining a competitive airline sector and good jobs is crucially important,” Finance Minister Chrystia Freeland told reporters, adding the equity stake would allow taxpayers to benefit when the airline’s fortunes recovered.

The Canadian government previously approved similar loans for four other companies worth up to C$1.billion, including up to C$375 million to low-cost airline Sunwing Vacations Inc. The government has paid out C$73.47 billion under its wage subsidy program and C$46.11 billion in loans to hard-hit small businesses.

Michael Rousseau, Air Canada‘s president and chief executive officer, said the liquidity “provides a significant layer of insurance for Air Canada.”

Jerry Dias, head of the Unifor private-sector union, described the announcement as “a good deal for everybody.”

Unifor represents more than 16,000 members working in the air transportation sector.

But the Canadian Union of Public Employees, which represents roughly 10,000 Air Canada flight attendants, said the package protected the jobs of current workers rather than the 7,500 members of its union who had been let go by the carrier.

($1=1.2567 Canadian dollars)

(Reporting by David Ljunggren in Ottawa and Allison Lampert in Montreal; Additional reporting by Julie Gordon in Ottawa and Munsif Vengattil in Bengaluru; Editing by Dan Grebler and Peter Cooney)

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U.K. advises limiting AstraZeneca in under-30s amid clot worry

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LONDON —
British authorities recommended Wednesday that the AstraZeneca COVID-19 vaccine not be given to adults under 30 where possible because of strengthening evidence that the shot may be linked to rare blood clots.

The recommendation came as regulators both in the United Kingdom and the European Union emphasized that the benefits of receiving the vaccine continue to outweigh the risks for most people — even though the European Medicines Agency said it had found a “possible link” between the shot and the rare clots. British authorities recommended that people under 30 be offered alternatives to AstraZeneca. But the EMA advised no such age restrictions, leaving it up to its member-countries to decide whether to limit its use.

Several countries have already imposed limits on who can receive the vaccine, and any restrictions are closely watched since the vaccine, which is cheaper and easier to store than many others, is critical to global immunization campaigns and is a pillar of the UN-backed program known as COVAX that aims to get vaccines to some of the world’s poorest countries.

“This is a course correction, there’s no question about that,” Jonathan Van-Tam, England’s deputy chief medical officer, said during a press briefing. “But it is, in a sense, in medicine quite normal for physicians to alter their preferences for how patients are treated over time.”

Van-Tam said the effect on Britain’s vaccination timetable — one of the speediest in the world — should be “zero or negligible,” assuming the National Health Service receives expected deliveries of other vaccines, including those produced by Pfizer and Moderna.

EU and U.K. regulators held simultaneous press conferences Wednesday afternoon to announce the results of investigations into reports of blood clots that sparked concern about the rollout of the AstraZeneca vaccine.

The EU agency described the clots as “very rare” side effects. Dr Sabine Straus, chair of EMA’s Safety Committee, said the best data is coming from Germany where there is one report of the rare clots for every 100,000 doses given, although she noted far fewer reports in the U.K. Still, that’s less than the clot risk that healthy women face from birth control pills, noted another expert, Dr. Peter Arlett.

The agency said most of the cases reported have occurred in women under 60 within two weeks of vaccination — but based on the currently available evidence, it was not able to identify specific risk factors. Experts reviewed several dozen cases that came mainly from Europe and the U.K., where around 25 million people have received the AstraZeneca vaccine.

“The reported cases of unusual blood clotting following vaccination with the AstraZeneca vaccine should be listed as possible side effects of the vaccine,” said Emer Cooke, the agency’s executive director. “The risk of mortality from COVID is much greater than the risk of mortality from these side effects.”

Arlett said there is no information suggesting an increased risk from the other major COVID-19 vaccines.

The EMA’s investigation focused on unusual types of blood clots that are occurring along with low blood platelets. One rare clot type appears in multiple blood vessels and the other in veins that drain blood from the brain.

While the benefits of the vaccine still outweigh the risks, that assessment is “more finely balanced” among younger people who are less likely to become seriously ill with COVID-19, the U.K’s Van-Tam said.

“We are not advising a stop to any vaccination for any individual in any age group,” said Wei Shen Lim, who chairs Britain’s Joint Committee on Vaccination and Immunization. “We are advising a preference for one vaccine over another vaccine for a particular age group, really out of the utmost caution rather than because we have any serious safety concerns.”

In March, more than a dozen countries, mostly in Europe, suspended their use of AstraZeneca over the blood clot issue. Most restarted — some with age restrictions — after the EMA said countries should continue using the potentially life-saving vaccine.

Britain, which relies heavily on AstraZeneca, however, continued to use it.

The suspensions were seen as particularly damaging for AstraZeneca because they came after repeated missteps in how the company reported data on the vaccine’s effectiveness and concerns over how well its shot worked in older people. That has led to frequently changing advice in some countries on who can take the vaccine, raising worries that AstraZeneca’s credibility could be permanently damaged, spurring more vaccine hesitancy and prolonging the pandemic.

Dr. Peter English, who formerly chaired the British Medical Association’s Public Health Medicine Committee, said the back-and-forth over the AstraZeneca vaccine globally could have serious consequences.

“We can’t afford not to use this vaccine if we are going to end the pandemic,” he said.

In some countries, authorities have already noted hesitance toward the AstraZeneca shot.

“People come and they are reluctant to take the AstraZeneca vaccine, they ask us if we also use anything else,” said Florentina Nastase, a doctor and co-ordinator at a vaccination centre in Bucharest, Romania. “There were cases in which people (scheduled for the AstraZeneca) didn’t show up, there were cases when people came to the centre and saw that we use only AstraZeneca and refused (to be inoculated).”

Meanwhile, the governor of Italy’s northern Veneto region had said earlier Wednesday that any decision to change the guidance on AstraZeneca would cause major disruptions to immunizations — at a time when Europe is already struggling to ramp them up — and could create more confusion about the shot.

“If they do like Germany, and allow Astra Zeneca only to people over 65, that would be absurd. Before it was only for people under 55. Put yourself in the place of citizens, it is hard to understand anything,” Luca Zaia told reporters.

The latest suspension of AstraZeneca came in Spain’s Castilla y Leon region, where health chief Veronica Casado said Wednesday that “the principle of prudence” drove her to put a temporary hold on the vaccine that she still backed as being both effective and necessary.

French health authorities had said they, too, were awaiting EMA’s conclusions, as were some officials in Asia.

On Wednesday, South Korea said it would temporarily suspend the use of AstraZeneca’s vaccine in people 60 and younger. In that age group, the country is only currently vaccinating health workers and people in long-term care settings.

The Korea Disease Control and Prevention Agency said it would also pause a vaccine rollout to school nurses and teachers that was to begin on Thursday, while awaiting the outcome of the EMA’s review.

But some experts urged perspective. Prof Anthony Harnden, the deputy chair of Britain’s vaccination committee, said that the program has saved at least 6,000 lives in the first three months and will help pave the way back to normal life.

“What is clear it that for the vast majority of people the benefits of the Oxford AZ vaccine far outweigh any extremely small risk,” he said. “And the Oxford AZ vaccine will continue to save many from suffering the devastating effects that can result from a COVID infection.”

Source: – CTV News

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