BERLIN — For 18 hours a day, Andreas Greinacher and his team at Germany's Greifswald University Hospital have pored over blood samples from across Germany and Austria.
No link has been established with the vaccine, widely used in Europe and other countries, including Canada and India, and under review for possible approval in the United States.
But several teams of hematologists, including Greinacher’s, say that an overactive immune response appears to be triggering the rare clotting condition in some patients, leading to new treatment guidelines in Europe.
So scientists are scrambling to map patients’ genes and examine medical histories of those sickened for any clues about what might make one person more susceptible than another — and whether anything other than the vaccine might be at play.
“This is looking for the needle in the haystack,” Greinacher told reporters last week, explaining that any constellation of risk factors, not present in 99.9 percent of the population, could be to blame.
While the teams work, Europe is grappling with a rapidly unfolding third wave in the pandemic, driven by variants. AstraZeneca’s vaccine is seen as one of the key tools in leading the continent — and the world — to recovery.
The question of how to balance dueling concerns — rising cases and a rare but potentially serious side effect — has split regulators and experts.
Britain has moved forward with vaccinations for all age groups, continuing its backing of the homegrown vaccine, developed jointly by the Swedish-British pharmaceutical giant AstraZeneca and the University of Oxford.
France, Germany, Sweden and Canada are among those restricting its use in younger people, while Denmark and Norway have maintained a complete pause.
AstraZeneca has said that “patient safety remains the company’s highest priority” and points to the fact that no relationship has been found between the vaccine and blood clots by British or European regulators.
The company said it is analyzing its databases to better understand whether such incidents are occurring more than one would normally expect.
But in a statement to British media, Oxford researchers said that a small trial of the AstraZeneca vaccine among children would be paused until the outcome of a review by British regulators, despite the participants showing no health issues.
If a link to the vaccine is confirmed, it could hurt inoculation programs globally. AstraZeneca’s doses are cheap and easy to store, and there are plans to roll them out in more than 140 countries through a program designed to ensure equitable distribution.
Rare brain clot
The chief concerns center on cases of cerebral venous sinus thrombosis, or CVST, an unusual kind of vein clot that can cause bleeding on the brain.
Numbers are small, with Britain’s figures pointing to an incidence of about 1 in 500,000 shots. But higher rates in countries that began using AstraZeneca’s vaccine only among younger people have spurred debate as to whether the risks might be higher for certain age groups, or for women.
The European Medicines Agency, the European Union’s regulator, said it is investigating at least 44 cases of the rare brain clots and at least 14 deaths among about 9.2 million vaccinations in 30 European countries.
Overall, that’s about 4.6 cases, developing within a few weeks after vaccination, for every 1 million shots. That rate is higher than expected over a short time period, experts say. The brain clots normally affect around five people per 1 million over the course of a full year, according to Johns Hopkins.
The level for those receiving the Pfizer vaccine — which is more widely used in Europe than AstraZeneca’s — has been 0.2 per million following vaccination, and Moderna’s vaccine, which has seen limited distribution in Europe, is zero, the EMA said.
The overall European figures do not include Britain and do not count cases from other countries after March 22, with the EMA expected to give an update later this month. As of March 29, Germany’s regulator has reported 31 cases of the unusual blood clots in 2.7 million people vaccinated with the AstraZeneca vaccine, nine of whom have died.
Britain, meanwhile, recorded 30 cases of the brain clots and other clots among 18 million vaccinated patients up to March 21. Seven people have died, British officials said.
No cases of the rare clots had been reported among recipients of Pfizer vaccinations in the country, it said.
In Norway, regulators have said the AstraZeneca vaccine “likely” caused clots in six medical workers among 120,000 people vaccinated. Four have died.
The AstraZeneca vaccine is also the backbone of the inoculation drive in India, where it is being made locally under an agreement with the country’s largest vaccine manufacturer.
More than 70 million doses of the vaccine have been administered in India since January. So far, authorities have not publicly reported any instances of the rare blood clots of concern to European regulators.
Benefits versus risks
Groups such as the EMA and World Health Organization and the British regulator say the benefits of vaccines outweigh any possible risks — and even those risks are small — and urge people to get their shots as normal.
But scientific reviews continue. The EMA says it will update with the findings of its expert team as early as Wednesday.
As she announced that Germany would restrict the AstraZeneca vaccine’s use in those under 60 last week, German Chancellor Angela Merkel said the government “cannot ignore” the data.
While it may damage confidence in the vaccine, she argued it would be worse not to be transparent.
“But what will erode confidence more? To sweep such a thing under the rug, not to take it seriously?” she asked.
Efforts to determine whether some groups may be affected more than others are complicated by the small number of cases and differences in how the vaccine has been rolled out.
Unlike other European countries, Britain began AstraZeneca vaccinations among the elderly.
It reported five cases in its initial 11 million shots. Commenting on the updated British figures on Twitter on Saturday, statistician David Spiegelhalter said that if caused by the vaccine, the risk appears “low.”
But it is “important to know whether this risk is substantially higher in younger age groups, as has been found elsewhere.”
The EMA has said there is no scientific evidence to back any age-specific restrictions like those imposed by some European countries. But the agency said that looking at shots given to those under 60, risk levels appear to be more like 1 in 100,000.
Researchers are also trying to work out whether women might be more at risk. In Germany, 29 out of 31 patients with the brain clots have been women. But the European regulator says that may be because countries like Germany began by vaccinating communities like health-care workers, which include more women.
“If you look at who was being vaccinated in the European Union with the AstraZeneca vaccine back in January, February and early March, there is about a 2-to-1 ratio of women to men,” said Peter Arlett, the EMA’s head of pharmacovigilance and epidemiology.
That makes any potential vaccine risks hard to “disentangle,” he said.
Still, some doctors argue that because risks associated with the coronavirus diminish with younger age, so does the benefit of the AstraZeneca vaccine.
Risk factors for women?
In a letter to German health authorities this week urging a rapid change to vaccine regulations stopping the AstraZeneca inoculations, five German university hospital heads described the risk-to-benefit balance for women between 20 and 29 as “unacceptable.”
But delays to vaccination programs can also cost lives. Spiegelhalter pointed to comments from England’s chief medical officer, Patrick Vallance, saying that a month’s delay in vaccinating 500,000 people between 44 and 54 could to lead to around 85 hospitalizations and five deaths.
Still, the choice is not between AstraZeneca and nothing, Merkel reasoned, as she announced the German restrictions. Not all countries, however, have the luxury of picking between vaccines.
Elevating concerns is the fact that the clotting cases are generally more complex and severe than regular cases of cerebral thrombosis, said Edgar Schömig, the head of University Hospital Cologne and one of the signatories of the letter to German health officials.
The cases are most similar to a rare kind of CVST seen occasionally in adverse reactions to a particular blood-thinning drug, medical experts say.
In a bulletin to members last week, Andrew Goddard, president of the Royal College of Physicians in Britain, said there was “growing consensus” among experts over the similarities to the rare drug reaction.
“How the vaccine might induce such an effect is unclear,” he said, mentioning that “frenzied” research is ongoing.
Greinacher said screening tests can help differentiate whether blood clots are caused by an antibody response. Hematology societies in Germany and Britain are recommending the tests be used on those presenting symptoms — including headaches and blurred vision — more than four days after vaccination.
And advances are being made on treatment.
For those testing positive for the specific antibody response in emergency rooms, doctors in Europe have recommended injections of immunoglobulin, which is used to fight immune-system disorders and can slow the progression of the clotting.
“It is extremely important this syndrome is recognized, as there is appropriate and effective treatment,” said Adele Fielding, president of the British Society for Haematology, stressing that the causal link with the vaccine has not yet been established.
“It is important that we recognize the difference between alert and alarm,” she added.
Arnold Ganser, a hematologist at Hannover Medical School in Germany who has had three patients with the rare clotting following AstraZeneca vaccinations in his hospital since early March, said his second two patients were caught at an earlier stage and have been discharged. The first patient remains intubated.
Health authorities must be willing to adapt to new data, but in the meantime, the benefits of the vaccine are obvious, he said.
“Vaccination is the only way to get out of the pandemic,” he said. “Vaccination, vaccination.”
Luisa Beck in Berlin, Martin Selsoe Sorensen in Copenhagen and Joanna Slater in New Delhi contributed to this report.