As Canada backs away from the AstraZeneca vaccine in favour of other options, global health experts warn that the rest of the world does not have the same luxury in the battle against COVID-19.
The global vaccine distribution initiative known as COVAX said this week that it has now shipped 59 million doses of the vaccine to 122 participating countries worldwide. The lion’s share of those doses consist of the vaccine produced by AstraZeneca or its made-in-India counterpart, also known as Covishield.
“It’s a hugely important vaccine,” said Srinivas Murthy, an infections-disease specialist at the BC Children’s Hospital in Vancouver. “It’s the workhorse for global vaccination in terms of supply available to places that don’t have their own domestic capacity.”
The strategic importance of the vaccine, which does not require freezing to be shipped and stored, heightens the urgency for scientists who are trying to understand why, in very few cases, the vaccine causes blood clots – a condition dubbed vaccine-induced immune thrombotic thrombocytopenia, or VITT.
So rare is the syndrome that it has been difficult to pin down precisely how rare. As of Thursday, 18 cases had been confirmed in Canada with at least 10 more people undergoing testing. Because of a four- to 28-day lag time between vaccination and the appearance of symptoms, it is possible that more cases will emerge from the roughly two million doses of the AstraZeneca vaccine that have so far been administered across the country. Estimates from the Public Health Agency of Canada suggest the frequency could be around one in 55,000.
Most provinces, including Ontario, Alberta and British Columbia, have suspended use of AstraZeneca pending further reports.
The one-shot COVID-19 vaccine made by Johnson & Johnson has also been linked to VITT, but with an even lower frequency. This accounts for why the syndrome did not crop up during clinical trials of either vaccine, or in the initial rollout to older recipients, when it was disguised by the normal background rate of blood clots among older individuals. In a more conventional vaccination scenario, such as might occur with a seasonal flu shot, it’s highly unlikely VITT would have ever been noticed at all.
“Nobody would have spotted that there’s something going on here,” said Andreas Greinacher, a clinical researcher who specializes in transfusion medicine at the University of Greifswald in Germany. Only because so many people were vaccinated in a relatively short time did the telltale pattern of VITT make itself apparent, he added.
It was Dr. Greinacher who, in March, first made the connection between the blood clots associated with the AstraZeneca and similar condition triggered by the blood thinner heparin that he had studied for decades. In that version of the syndrome, heparin can link up with antibodies and a blood factor known as PL4 to activate platelets, which can then bunch up to form blood clots. His familiarity with the condition allowed Dr. Greinacher and colleagues to identify how to test when the same thing is happening in response to a vaccine.
The work quickly turned the tide on a brewing scientific debate about whether the vaccine was truly implicated in the blood clots. But that was just the beginning of the quest to pinpoint why VITT occurs and how it might be averted.
One question that experts have pondered in recent weeks is whether VITT is as rare as it seems or whether there are milder cases that have gone undiagnosed.
“Our radar is up,” said Mary Cushman, a clinician researcher at the University of Vermont who has been conducting studies on blood clots caused by COVID-19 itself. Dr. Cushman described one patient she encountered who complained of severe headaches and exhibited other telltale symptoms after receiving the Johnson & Johnson vaccine. Yet, in the end, the patient was found not to have VITT.
Dr. Greinacher said a study his group conducted of 250 individuals after vaccination did not reveal a large population of milder cases. Instead, VITT may be an all-or-nothing condition that is genuinely infrequent – possibly because it requires several coincident factors to be present at the same time.
This is mirrored by the heparin-induced version of the syndrome. Not everyone who receives heparin appears to be at risk of clots. Previous work by Dr. Greinacher shows that when it occurs it is found only in those who have had major surgery. The implication is that the immune system has to first be woken up by some kind of inflammation-generating event, like the surgery, before the antibodies that can lead to blood clots are formed.
In some cases, the inflammation may lead to clots even without the blood-thinner present, said Ted Warkentin, a professor at McMaster University in Hamilton, and a long-time collaborator with Dr. Greinacher.
Dr. Warkentin described one case he studied a decade ago in which a knee-replacement surgery triggered an effect very much like VITT, leading unexpectedly to a fatal blood clot about one week after the surgery. He said he is aware of at least 30 such cases across North America but that the incidence is rare enough that “most orthopedic surgeons won’t see one in their entire career.”
When it comes to the vaccine-related cases, Dr. Greinacher has hypothesized a different source of inflammation. In a recent paper that is still undergoing peer review, his team investigated samples of the AstraZeneca vaccine and found that a large number of the vaccine’s constituents, typically about 40 per cent, are made up of human proteins that are a byproduct of the vaccine production process.
He said that the proteins may poke the immune system into action and stimulate production of the wrong kind of antibodies. These then link up with the adenovirus particles that are the vaccine’s active ingredient, beginning the processes that leads to platelet activation and clotting. The growing complexes can draw in white blood cells called neutrophils, which dump DNA into the mix in an effort to gum up what they perceive to be a microbial invader.
Another possible additional factor identified by Dr. Greinacher’s team is the molecule EDTA, whose properties include the ability to loosen blood vessels, which might then allow vaccine components to enter more easily into the blood stream. The Johnson & Johnson product does not use EDTA, which might then offer a clue as to why the occurrences of VITT are different between the two vaccines.
In a statement to The Globe and Mail, AstraZeneca noted that no experimental evidence has been provided to support this picture.
“Based on clinical experience, evidence indicate that the proteins that remain in the AstraZeneca vaccine are at safe levels, which are similar to or lower than levels seen in other vaccines produced in a similar way,” the company wrote. The statement also noted that EDTA is used in a wide range of medicinal products.
Richard Aster, a noted hematologist at the Versiti Blood Center of Wisconsin in Milwaukee, said he is also unconvinced by Dr. Greinacher’s hypothesis, which he said does not fully explain why VITT occurs so infrequently.
“I suspect answering that question is going to require a careful dissection of the immune response in affected individuals – something that has not yet been attempted as far as I know and will not be easy,” Dr. Aster said.
Dr. Greinacher said that numerous other factors may determine whether VITT occurs, from the genetics of the patient receiving the vaccine to the location of the vaccine injection point in relation to surrounding blood vessels. He said his lab is continuing to conduct investigations and is in the process of obtaining samples of the Johnson & Johnson vaccine.
Russia’s Sputnik V COVID-19 vaccine and the vaccine produced by CanSino in China also use adenoviruses as an active ingredient. The makers of both have issued statements saying their vaccines do not cause blood clots.
In spite of Canada’s growing ambivalence, Dr. Murthy in Vancouver said he expects that the AstraZeneca vaccine will continue to be used globally given the current state of the pandemic.
What happens next will depend both on how quickly scientists can get to the bottom of VITT and on the performance of the next wave of COVID-19 vaccines that are still in clinical trials, including the vaccine developed by the Canadian biopharmaceutical company Medicago.
After that Dr. Murthy, said, “We’ll see what AstraZeneca’s place is in the long term.”
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