Thomas Thiele, Linda Schönborn and Andreas Greinacher of the University of Greifswald in Germany were among the first to recognize and study vaccine-induced immune thrombocytopenia and thrombosis (VITT) in 2021. All three were co-authors on the new study linking the syndrome to a mutation in the genetic sequence of a single antibody.Jan Wesche/Greifswald University Medicine |
In March, 2021, as health officials around the world raced to immunize their populations against COVID-19, two vaccines that were part of the effort became associated with rare but dangerous blood clots.
In the weeks that followed, experts in Canada and elsewhere debated and then began advising against the use of COVID-19 vaccines produced by AstraZeneca and Johnson & Johnson, particularly if other options were available.
Now an international team of researchers, including those who first helped to verify the syndrome, say they have identified a genetic trigger that made some individuals susceptible to blood clots after vaccination.
The discovery, published Wednesday in the New England Journal of Medicine, caps a five-year odyssey to get to the bottom of one of the most puzzling chapters of the COVID-19 pandemic.
If the picture the new research paints is correct, it suggests how the genetic trigger associated with the blood clots can be disarmed in future vaccines that rely on the same biological method of delivery. And it may offer clues to other rare conditions associated with the immune system that have defied explanation.
“I think we found a brand new mechanism of disease,” said Ted Warkentin, an emeritus professor of hematology at McMaster University in Hamilton, Ont., and a co-author on the study. “It could be a roadmap for other rare immune disorders.”
Ted Warkentin, hematologist and professor emeritus at McMaster University, was involved early on in the quest to understand the cause of vaccine related blood clots.Nick Iwanyshyn/The Globe and Mail
Dr. Warkentin’s involvement in the quest to understand the blood clots began within weeks of the problem surfacing, first among some early recipients of the AstraZeneca vaccine in Europe and then in other parts of the world including Canada. Cases also appeared in the United States in connection with the Johnson & Johnson vaccine, though the incidence of blood clots was lower.
The effect was not seen in other COVID-19 vaccines, including the mRNA vaccines made by Pfizer and Moderna. This strongly suggested the problem had something to do with the fact that both the AstraZeneca and the Johnson & Johnson vaccines were delivered inside modified adenoviruses. These are viruses that can cause colds in their natural form. But here they acted as carriers of genetic information that helped train the body to fight off COVID-19.
Working with colleagues at McMaster University and with a team led by Andreas Greinacher, a long-time collaborator at the University of Greifswald in Germany, Dr. Warkentin helped to show that the vaccine-related blood clots resembled another rare condition in which blood clots can be triggered by heparin, a medication that is normally used as a blood thinner.
Although the two conditions are not identical, they are both distinguished by the presence of antibodies that bind to a blood protein called platelet factor 4 (PF4).
This immediately raised a red flag. Antibodies are created by the immune system to stick to viruses and other pathogens in order to render them harmless. But in this case, they were clinging to a normal component of blood, which then triggered the clotting.
The researchers dubbed the newly discovered condition vaccine-induced immune thrombocytopenia and thrombosis, or VITT. Its occurrence was rare and it varied by population. In Canada, federal figures show that about 2.3 million people received at least one dose of the AstraZeneca vaccine leading to 56 cases of VITT reported by July, 2021, including six deaths. This translates to an incidence rate of approximately one in 41,000.
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In Germany, Dr. Greinacher said the discovery helped to save the COVID-19 vaccination campaign during a moment of public doubt by clarifying the underlying cause of VITT and providing a way to test for the condition as well as treatment options if it arose.
Eventually, the adenovirus-based vaccines were discontinued but scientists were left with the puzzle of what triggered the production of antibodies that led to blood clots.
An intriguing clue was uncovered in 2022 when a team based at Flinders University in Adelaide, Australia, used a technique they had developed to study lupus and other autoimmune diseases to deduce the structure of the VITT antibodies. To their surprise, the antibodies all seemed to be near-identical copies, even when sourced from different patients with VITT.
“Normally these antibodies have many different species, so it’s very hard to sort them out,” said Tom Gordon who leads the Australian team. In a career spanning decades, it was first time he had come across such uniformity.
In 2023, Dr. Warkentin’s lab reported on two cases where the same condition arose through a natural adenovirus infection without the involvement of a vaccine. And last year, more sleuthing revealed another surprise: People can sometimes develop a VITT-like reaction spontaneously, without any apparent external cause.
Tom Gordon, professor of immunology, and Jing Jing Wang senior research fellow at Flinders University in Adelaide, Australia, deduced the genetic sequence of antibodies that produced vaccine-related blood clots.David Summerhayes/Flinders University
The latest study, which builds on the previous work of the Australian, German and Canadian teams ties it all together.
In the study, the researchers did a deep dive into the structure of the antibody that causes VITT and deduced the genetic sequence that allows it to be created. They found it bears a strong resemblance to another antibody that many individuals can produce in response to one particular protein found inside an adenovirus known as pIIV.
The researchers then realized that a single mutation in the sequence would produce the VITT antibody instead of the antibody that reacts to the adenovirus protein. If an individual is unlucky enough to have the mutation arise in an immune cell while it is producing antibodies against pIIV, the result can be amplified with many copies and eventually lead to blood clots.
“The more we examined the data, the more it made sense,” said Jing Jing Wang, a senior research fellow with the Australian team who pioneered the technique that was used in the study.
“It truly felt like an ‘aha’ moment,” she said.
The team also showed that reversing the effect of the mutation in VITT antibodies removed their clotting potential, which they confirmed with tests on mice that were genetically tailored to mimic the human immune system.
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“These findings will have important implications for identifying at-risk individuals and for vaccine modifications,” said Sue Pavord, a consulting hematologist with Oxford University Hospitals who led an effort to characterize VITT when it first appeared in Britain, but who was not involved in the new study.
Although the harmful mutation may not be detectable ahead of time – because it arises in immune cells while they are at work – the study raises the possibility that an adenovirus vaccine can be designed that does not trigger the effect.
The results remain relevant even though mRNA vaccines took over as the mainstay of the COVID-19 response in Canada and many other countries. In general, adenovirus vaccines remain an important tool, particularly in the developing world, because they are more durable and do not require storage in ultracold freezers before they are administered.
“Nobody knows when the next pandemic will hit us and at the moment the only vaccination platform I know which will enable to vaccinate a large part of the human population at affordable costs is the adenovirus platform,” Dr. Greinacher said.
Julie Bettinger, a vaccine safety scientist at the BC Children’s Hospital in Vancouver, said that studies of VITT, including the latest work, are crucial for helping to allay public uncertainty around vaccines.
She added that while a harmful effect of a vaccine is never desirable, the VITT episode illustrates that when there is a such a risk, it can be investigated swiftly and managed.
“This is exactly the reason that we have vaccine safety surveillance systems in place,” she said. “This is exactly what they’re supposed to do.”
Dr. Warkentin added that the same approach that was used to untangle the VITT mystery could help explain other rare diseases where a mutated antibody may play a key role. He said one example worth investigating is post-transfusion purpura, a rare and sometimes fatal reaction that can occur several days after a blood transfusion.