In DepthCOVID-19

Side effect worry grows for AstraZeneca vaccine

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Science  02 Apr 2021:
Vol. 372, Issue 6537, pp. 14-15
DOI: 10.1126/science.372.6537.14

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

It's been one step forward, two back for AstraZeneca's COVID-19 vaccine. Even as the company rebutted criticism of its efficacy claims last week, a bigger problem loomed for the vaccine and the many millions depending on it. Evidence continues to accumulate that an unusual clotting disorder seen in dozens of European recipients is a real, albeit rare, side effect. A preprint has detailed a proposed mechanism, and multiple scientific groups have said the worry is legitimate and must be seriously weighed against the vaccine's COVID-19 protection.

This week, Canada and Germany joined Iceland, Sweden, Finland, and France in recommending against the vaccine's use in younger people, who seem to be at higher risk for the clotting problem and are less likely to develop severe COVID-19. The approach makes sense given that other vaccines are available, says Sandra Ciesek, a virologist at Goethe University Frankfurt. “We do not have just one vaccine. We have several.”

AstraZeneca's vaccine incorporates the spike gene from SARS-CoV-2 into another, nonpathogenic virus. Last month, many countries suspended its use following initial reports of the clotting issues in recipients, which have led to at least 15 deaths in Europe. Some researchers dismissed the cases as normal background levels of blood clots. And most countries resumed vaccinations after the European Medicines Agency (EMA) said the vaccine's benefits outweigh any risks, even though it couldn't rule out that the clotting symptoms were connected to the vaccine.

In parallel, the company's initial report of results from a key vaccine trial in the Americas drew unexpected criticism. In a press release, AstraZeneca claimed the trial had shown the vaccine had 79% efficacy in preventing symptomatic disease. But the independent board overseeing the trial protested that the data the company put out were “outdated” and potentially misleading. Two days later, AstraZeneca revised the efficacy down to 76%, leaving observers baffled by the dispute, but mostly reassured.

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Italy resumed administering AstraZeneca's vaccine, but some other countries now restrict its use by age.


The potential side effect, on the other hand, does not seem to be going away. An EMA expert group discussed it on 29 March, but the agency issued no immediate public update; EMA's risk assessment panel will evaluate the issue next week.

The highly unusual combination of symptoms—widespread blood clots and a low platelet count, sometimes associated with bleeding—has so far been reported from at least seven countries. Medical societies around the world have warned members to be on the lookout for the clotting disorder in vaccine recipients and report it. Estimates of the incidence range from one in 25,000 people given the AstraZeneca vaccine in Norway to at least one in 87,000 in Germany. “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.

So far, most of the clotting cases have been observed in women under age 65. That may be because many European countries used the shot only in younger, prioritized populations, such as health care workers and teachers, a majority of whom are women. They initially hesitated to give it to people older than 65 because the company's early clinical trial data included few in that group.

The United Kingdom remains a puzzle. Despite administering more than 11 million AstraZeneca doses, it has so far reported only a handful of suspicious clotting cases. But the U.K. did not limit the vaccine to younger groups, so the average age of recipients there may be older. AstraZeneca had not commented on the clotting cases as Science went to press, except to say the rare set of symptoms did not appear in the company's vaccine trials.

Researchers in Germany have proposed that some component of the vaccine triggers a rare immune reaction like one occasionally seen with the blood thinner heparin, in which antibodies trigger platelets to form dangerous clots throughout the body. This week the team posted case descriptions of what they call vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) on the preprint server Research Square. The team, led by Andreas Greinacher at the University of Greifswald, also recommends a way to test for the disorder and a treatment, which they say should help ease worries about the vaccine.

Even if VIPIT isn't the whole story, multiple other researchers told Science they are now convinced the vaccine somehow causes the rare set of symptoms. If true, that could be a serious blow to a vaccine that is central to 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.

Discussion of this possible side effect is likely to stoke short-term vaccine hesitancy, says Michael Bang Petersen, a political scientist at Aarhus University in Denmark. He stresses, however, that clear, transparent communication about possible risks is crucial for maintaining public trust in all COVID-19 vaccines. “It is very important that we do not lose the war because we are too eager to win the short-term battle,” he says.

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