What the heck is going on with the AstraZeneca vaccine in Europe?

After more than a dozen European countries stopped distribution of the AstraZeneca/Oxford Covid-19 vaccine due to concerns about blood clots, the European Union’s top pharmaceutical regulator on Thursday concluded the vaccine was safe.

“The committee has come to a clear scientific conclusion: This is a safe and effective vaccine. Its benefits in protecting people from Covid-19 with the associated risks of deaths and hospitalizations outweigh the possible risks,” said Emer Cooke, executive director of the European Medicines Agency (EMA), during a press conference. “The committee also concluded that the vaccine is not associated with an increase in the overall risk of thromboembolic events or blood clots.”

The agency’s guidance echoed that of the World Health Organization, which said on Wednesday that “the benefits of the AstraZeneca [Covid-19] vaccine outweigh its risks” and recommended that vaccinations continue.

The two public health heavyweights were forced to weigh in after several reports surfaced in Europe of severe side effects such as bleeding and blood clots (also known as thrombosis) in patients earlier this month following injections of the Covid-19 vaccine developed by the pharmaceutical giant AstraZeneca and the University of Oxford. The cases emerged out of more than 17 million recipients of the vaccine between the United Kingdom and the EU to date.

The complications of concern so far are rare, with 37 reported cases.

Yet several national public health agencies, including those in Germany, Spain, and the Netherlands, decided to pause distribution pending further review of the clotting events and their potential link to the vaccine. Some countries limited their restrictions to specific batches of the vaccine. France and Italy said they would restart immunizations with the AstraZeneca/Oxford vaccine once the EMA completed its assessment.

Europe is not the only place that halted the vaccine. South Africa stopped distribution of the AstraZeneca/Oxford vaccine last month after health officials found that the inoculation offered little protection against the B.1.351 variant of the SARS-CoV-2 virus, the pathogen that causes Covid-19.

The United States, meanwhile, has not greenlit the two-dose AstraZeneca/Oxford vaccine for distribution at all, despite already acquiring millions of doses. An emergency use authorization for the vaccine in the US could come from the Food and Drug Administration in April after its review of a US-based phase 3 clinical trial.

But the broader question around the possible safety concerns with the AstraZeneca/Oxford vaccine is one that will likely emerge again: How much precaution is too much?

Faced with a disease that has now killed more than 2.6 million people around the world — caused by a virus that continues to spread and mutate — there is fierce urgency to distribute vaccines to prevent further carnage. Regulators in Europe and the United States have faced criticism for taking too long to approve Covid-19 vaccines. The recent halt in Europe and the FDA’s ongoing review of the AstraZeneca/Oxford vaccine have sharpened those complaints. Some have alleged that Europe’s pause has political motivations, with governments being afraid of continuing shots when their neighbors are holding back.

For health officials, it’s tricky to balance the need to investigate rare events that may or may not be caused by a vaccine with the need to protect the public from a raging pandemic. Shifting the balance too much in any direction would either leave people vulnerable to infection or undermine fragile public confidence in Covid-19 vaccines.

Here’s what scientists have learned so far about the purported clotting risks associated with the AstraZeneca/Oxford vaccine — and how health officials are balancing them against the Covid-19 crisis.

There is little evidence the AstraZeneca Covid-19 vaccine causes blood disorders, but it’s too soon to dismiss the possibility

AstraZeneca reported this week that based on the reports it received by March 8, there were just 15 cases of deep vein thrombosis and 22 cases of pulmonary embolism among the 17 million people who received its vaccine in the EU and the UK.

These are potentially life-threatening events where blood clots choke off blood vessels, which can cause severe pain and kill off downstream tissue. AstraZeneca also noted there was no increase in bleeding events in the more than 60,000 people participating in its clinical trials.

One problem with sorting out blood clots is that they’re quite common in the general population, so in some cases they may have occurred by chance after vaccination. According to the WHO, deep vein thrombosis is the third most common cardiovascular disease globally.

Deep vein thrombosis and pulmonary embolism are estimated to afflict between one and two adults per 1,000 each year in the US, per the CDC. That’s orders of magnitude higher than Europe’s 37 such events out of 17 million AstraZeneca/Oxford vaccine recipients.

However, that’s not the whole story, and the fact that these events are rare among vaccine recipients doesn’t mean they don’t deserve more study. “I think it’s wrong to blow this off,” said Robert Brodsky, director of the hematology division at Johns Hopkins University.

For one thing, not all blood clots are the same. Though blood clots are common in the general population, the clotting disorders that triggered the alarm about the AstraZeneca/Oxford vaccine are rare, especially in patients ages 20 to 50, which is where these events occurred.

The types of clots found included cerebral venous sinus thrombosis, where clots block blood from leaving the brain. Health officials also identified patients with disseminated intravascular coagulation, which spreads tiny clots and chokes off blood vessels in various parts of the body. Several of the patients also presented with thrombocytopenia, a condition where platelets in the blood that help it clot drop to unusually low levels, leading to bruising and bleeding. These patients also had schistocytes, which are broken and damaged red blood cells that ordinarily carry oxygen throughout the body. These complications arose between seven and 14 days after vaccination.

“These are not your typical blood clots. … These are one-in-a-million-type blood clots,” Brodsky said. “That’s cause for concern. That type of clotting is life-threatening.”

According to Sabine Straus, chair of the EMA’s Pharmacovigilance Risk Assessment Committee, there were seven cases of disseminated intravascular coagulation and 18 cases of cerebral venous sinus thrombosis suspected of links to the AstraZeneca/Oxford vaccine in the EU as of Thursday.

However, the mechanism that connects the AstraZeneca/Oxford vaccine to blood clots is not yet clear. “For the moment, it’s all speculation,” Strauss said during a press conference.

Courtesy of European Medicines Agency

But while the EMA did say vaccinations are safe on balance, officials acknowledged that a connection between the AstraZeneca/Oxford vaccine and blood clots could still emerge. “We still cannot rule out definitively a link between these cases and the vaccine,” Cooke said.

Brodsky noted one hypothesis is that the problem stems from the mechanism of the vaccine. The AstraZeneca/Oxford vaccine gives human cells the instructions for making the spike protein of the SARS-CoV-2 virus. In ordinary cases, this protein then coaches the immune system to fight off the virus if it ever arrives. But in rare cases, perhaps due to genetic factors, the spike protein may trigger an immune system response that interferes with the regulation of blood clots.

Understanding the mechanism could help health officials identify people at high risk of complications and direct them to use other vaccines. But since these blood-clotting events are so rare to begin with, it’s going to take some time to figure out just what those variables are.

Covid-19 carries its own dangerous blood-clotting risks, and they’re well established

If a vaccine that helps the body manufacture a fragment of the virus can trigger a blood-clotting disorder, it stands to reason that the whole infectious virus poses an even greater risk.

Scientists have found ample evidence that Covid-19 can have dangerous effects on the cardiovascular system, including the forming of blood clots. “The clotting system itself seems to be revved,” Donald Landry, chair of the department of medicine at Columbia University, told Vox last year. “It’s not just inflamed blood vessels; it’s a hypercoagulable state, so it would seem.”

In fact, researchers are beginning to attribute many of the strange symptoms of Covid-19, including some of the reported long-term outcomes, to blood clots and other cardiovascular effects.

So given the rampant spread of Covid-19, preventing the disease via inoculation with the AstraZeneca vaccine would be a far more effective step toward reducing the rate of blood clots and related cardiovascular disorders than cutting off access to the vaccine right now.

“Because the vaccine is effective in preventing Covid-19 disease, which in itself is a cause of blood clots, it likely reduces the risk of thrombotic events overall,” said Straus.

And it would still behoove people with blood-clotting disorders to get vaccinated for Covid-19, even with the AstraZeneca vaccine.

“Actually, the people who are susceptible to [blood-clotting disorders from] the vaccine may be even more susceptible to the virus,” Brodsky said. “I’m still recommending patients with [blood disorders] get vaccinated. I’m just telling them and their doctors ‘be careful.’”

The AstraZeneca/Oxford vaccine does have some drawbacks — and some unanswered questions

According to the BBC, the AstraZeneca/Oxford Covid-19 vaccine has already played a big role in the global fight against the virus: It has been used in 65 countries, second only to the Pfizer/BioNTech vaccine, which has been administered in 70.

It stands out from some of the other Covid-19 vaccines for its low cost: $3 to $4 per dose, compared with $15 to $25 per dose for those developed by Moderna and Pfizer/BioNTech. The AstraZeneca/Oxford vaccine also needs only refrigerator storage, while both Moderna and Pfizer/BioNTech vaccines require freezers, adding to the cost and complexity of distribution. That’s why many middle- and lower-income countries have been placing their bets on the AstraZeneca/Oxford vaccine. This vaccine also uses an adenovirus vector as its platform, while Moderna and Pfizer/BioNTech use mRNA. All of these vaccines don’t use the virus itself but instead deliver the code for making a fragment of it to human cells.

But vaccine experts had some concerns with how the AstraZeneca/Oxford vaccine was initially tested. Earlier clinical trials showed the vaccine had up to 90 percent efficacy at preventing symptomatic Covid-19 cases, but that result came from an arm of the trial where experimenters made a mistake in dosing the vaccine.

In another arm, the efficacy dropped to 62 percent. These trial arms also didn’t use a consistent placebo control, making it harder to make direct comparisons.

Oli Scarff/AFP via Getty Images

During the UK trial of the vaccine, two volunteers reported neurological problems. Investigations later found no link between the vaccine and these symptoms, and regulators allowed the trial to resume.

As Hilda Bastian, an expert in analyzing clinical trial data, told Vox’s Julia Belluz in a recent interview:

[They went] about their clinical trial program in such a problematic way. [They] overlapped the early phases of their trials too much. They didn’t do early phase tests in older people as a result, leaving us struggling now with the results in a way we don’t have to with other EuroAmerican vaccines.

The publicly available details about the trial kept changing while it was in progress — and didn’t even say clearly what the dose was, for example.

For some countries, these results were good enough to commence distribution, but for others, notably the US, they were not. The FDA is now reviewing the results of a larger, US-based clinical trial of the AstraZeneca/Oxford vaccine that only recently produced an adequate number of events.

Meanwhile, a recent study found that the AstraZeneca/Oxford vaccine offers little protection against disease caused by the B.1.351 variant. This variant was first detected in South Africa and became the dominant strain there, and has since spread to several other countries, including the US. Other vaccines, including ones from Moderna, Pfizer/BioNTech, and Johnson & Johnson do seem to offer protection against B.1.351, but to a lesser degree than others.

So there are some real concerns about how useful this vaccine is during this stage of the pandemic, depending on which variants are in circulation.

As for the purported side effects, it’s important to keep the context in mind. When a vaccine is distributed to millions and potentially billions of people, there are bound to be unrelated events that get grouped as consequences of the vaccine. In the UK, a listing of self-reported adverse events following inoculation with the AstraZeneca/Oxford Covid-19 vaccine included “crying,” “sunburn,” and “road traffic accident.” But more serious side effects, even rare ones, deserve scrutiny so health officials can take steps to mitigate them.

“When you vaccinate millions of people, it’s inevitable that you have rare or serious incidences of illnesses that occur after vaccination,” said Cooke.

It may become clear that the pause of the AstraZeneca/Oxford vaccine in Europe is an overreaction, but similar risk-reward questions will likely continue to emerge as the pandemic continues. Should booster doses of vaccines receive speedy approval? Will lockdowns be necessary to contain the new variants?

For the time being, the AstraZeneca/Oxford vaccine is still an important tool for containing the pandemic. And even with its unknowns, the known harms from Covid-19 are far, far greater — and will continue to grow unless the virus is contained. “If it was me, I would want to be vaccinated tomorrow,” Cooke said.

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